(1) Background: Some evidence suggests that cannabidiol (CBD) has potential to help alleviate HIV symptoms due to its antioxidant and anti-inflammatory properties. Here we examined acute CBD effects on various behaviors and the endocannabinoid system in HIV Tat transgenic mice. (2) Methods: Tat transgenic mice (female/male) were injected with CBD (3,10,30 mg/kg) and assessed for antinociception, activity, coordination, anxiety, and recognition memory. Brains were taken to quantify endocannabinoids and related lipids. Additionally, CBD and metabolite 7-hydroxy-CBD were quantified in the plasma and cortex. (3) Results: Tat decreased striatal-related nociception and locomotion, with some sex-dependent effects on coordination. CBD had no effect on nociception and coordination, but increased locomotor activity. For anxiety, differential CBD effects were noted for sex, with decreasing anxiety-like behavior in males only. In the striatum and spinal cord, male sex was associated with lower 2-arachidonoylglycerol and with elevated concentrations of its proinflammatory metabolite arachidonic acid. CBD metabolism was altered by sex and Tat. (4) Conclusion: Findings indicate that acute CBD effects are not altered by HIV Tat, and CBD has minimal effects on behavior and the endocannabinoid system. Interestingly, sex-dependent alterations were noted for endocannabinoids and related lipids, which may be of relevance in view of potential CBD-based treatment options for people living with HIV.

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 enters the host by infecting nasal ciliated cells. Then, the virus can spread towards the oropharyngeal cavity and the pulmonary tissues. The antiviral adaptive immunity is promptly induced in response to virus detection, with virus-specific T lymphocytes appearing before antiviral antibodies. Both breadth and potency of the antiviral CD8+ T cell immunity have a key role in containing viral spread and disease severity. Current anti-SARS-CoV-2 vaccines do not impede the virus replication in the upper respiratory tract, and there is consensus on the fact that the best potency of the antiviral immune response in both blood and upper respiratory tract can be reached upon infection in vaccinees (i.e., breakthrough infection). However, whether the antiviral CD8+ T cells developing in response to the breakthrough infection in the upper respiratory tract diffuse to the lungs also is still largely unknown. To fill the gap, we checked the CD8+ T cell immunity elicited after infection of K18-hACE2 transgenic mice both 3 weeks and 3 months after anti-Spike vaccination. The virus-specific CD8+ T cell immunity was monitored in both blood and the lungs before and after infection. By investigating the de novo generation of CD8+ T cells specific for SARS-CoV-2 viral proteins, we found that both membrane (M) and/or nucleocapsid (N)-specific CD8+ T cells were induced at comparable levels in blood of both unvaccinated and vaccinated mice. Conversely, N-specific CD8+ T cells were readily found in the lungs of control mice, but were either rare or absent in those of vaccinated mice. These results support the idea that the hybrid cell immunity developing after asymptomatic/mild breakthrough infection strengthens the antiviral cell immunity at lungs only marginally, implying that the direct exposition of the viral antigens is required for the induction of an efficient antiviral cell immunity in the lungs.

Large animal experiments are important for preclinical studies of regenerative stem cell transplantation therapy. Therefore, we investigated the differentiation capacity of pig skeletal muscle-derived stem cells (Sk-MSCs) as an intermediate model between mice and humans for nerve muscle regenerative therapy. Enzymatically extracted cells were obtained from green-fluorescence transgenic micro-mini pigs (GFP-Tg MMP) and sorted as CD34+/45- (Sk-34) and CD34-/45-/29+ (Sk-DN) fractions. The ability to differentiate into skeletal muscle, peripheral nerve, and vascular cell lineages was examined by in vitro cell culture and in vivo cell transplantation into the damaged tibialis anterior muscle and sciatic nerves of nude mice and rats. Protein and mRNA levels were analyzed using RT-PCR, immunohistochemistry, and immunoelectron microscopy. The myogenic potential, which was tested by Pax7 and MyoD expression and the formation of muscle fibers, was higher in Sk-DN cells than in Sk-34 cells but remained weak in the latter. In contrast, the capacity to differentiate into peripheral nerve and vascular cell lineages was totally stronger in Sk-34 cells. In particular, Sk-DN cells did not engraft to the damaged nerve, whereas Sk-34 cells showed active engraftment and differentiation into perineurial/endoneurial cells, endothelial cells, and vascular smooth muscle cells, similar to the human case, as previously reported. Therefore, we concluded that Sk-34 and Sk-DN cells in pigs were closer to those in humans than to those in mice.

This study documents the conditions associated to white spruce and balsam fir regeneration after partial cutting. Measurements were collected 9 to 30 years after partial cutting in 12 natural fir stands and 5 white spruce plantations. We estimated seed input, measured light reaching the undergrowth, recorded seedlings (<150 cm) and their age on 6 different seedling establishment substrates: mineral soil, moss, rotten wood, litterfall, herbaceous and dead wood. Partial cutting generally favours the establishment and growth of seedlings. The number of fir and spruce seedlings is always greater in natural stands than in plantations, a trend likely associated with the reduced abundance of preferential establishment substrate in the latter. White spruce significantly prefers rotten wood while fir settles on all types of substrates that cover at least 10% of the forest floor. There is a strong relationship between light intensity and the median height of spruce seedlings, but this relationship is non-significant for fir. Seedlings of both species can survive at incident light intensities as low as 3%, but an intensity of 15% or more seems to offer the best growth conditions. The conditions for successful forest regeneration proposed in this study should be applied when the goal is to establish a new stand prior to clear cutting or to convert stand structure.

The peroxiredoxin (PRDX) family, a new family of proteins with a pivotal antioxidative function, is ubiquitously synthesized and abundantly identified in various organisms. In contrast to the intracellular localization of other family members (PRDX1/2/3/5/6), PRDX4 is the only known secretory form and protects against oxidative damage by scavenging reactive oxygen species in both the intracellular (especially the endoplasmic reticulum) compartments and the extracellular space. Recently, we generated unique human PRDX4 (hPRDX4) transgenic (Tg) mice on a C57BL/6J background and investigated the critical and diverse protective roles of PRDX4 against diabetes mellitus, atherosclerosis, insulin resistance, and nonalcoholic fatty liver disease (NAFLD) as well as evaluated its role in the intestinal function in various animal models. Our published data have shown that PRDX4 helps prevent the progression of metabolic syndrome by reducing local and systemic oxidative stress and synergistically suppressing steatosis, inflammatory reactions, and/or apoptotic activity. These observations suggest that Tg mice may be a useful animal model for studying the relevance of oxidative stress on inflammation and the dysregulation of lipid/bile acid/glucose metabolism upon the progression of human metabolic syndrome, and that specific accelerators of PRDX4 may be useful as therapeutic agents for ameliorating various chronic inflammatory diseases.

Mucosal vaccination appears to be suitable to protect against SARS-CoV-2 infection. In this study, we tested an intranasal mucosal vaccine candidate to COVID-19 constituted of a cationic liposome containing a trimeric SARS-CoV-2 spike protein and CpG-ODNs, a Toll-like receptor 9 agonist, as adjuvant. In vitro and in vivo experiments indicated the absence of toxicity following the intranasal administration of this vaccine formulation. First, we found that subcutaneous or intranasal vaccination protected hACE-2 transgenic mice from infection with the wild-type (Wuhan) SARS-CoV-2 strain, as shown by weight lost and mortality indicators. However, when compared to the subcutaneous administration, the intranasal route was more effective in the pulmonary clearance of the virus and induced higher neutralizing antibodies and anti-S IgA titers. In addition, the intranasal vaccination afforded protection against gamma, delta and omicron virus variants of concern. Furthermore, the intranasal vaccine formulation was superior to intramuscular vaccination with a recombinant, replication-deficient chimpanzee adenovirus vector encoding the SARS-CoV-2 spike glycoprotein (Oxford/AstraZeneca) in terms of virus lung clearance and production of neutralizing antibodies in serum and bronchial alveolar lavage (BAL). Finally, the intranasal liposomal formulation boosted heterologous immunity induced by previous intramuscular vaccination with the Oxford/AstraZeneca vaccine that was more robust than homologous immunity.

Plants significantly shape root-associated microbiota, making rhizosphere microbes useful environmental indicator organisms for safety assessment. Here, we report the pyrosequencing of the bacterial 16S ribosomal RNA in rhizosphere soil samples collected from transgenic cry1Ab/cry1Ac Bt rice Huahui No. 1 (GM crop) and its parental counterpart, Minghui63. We identified a total of 2,579 quantifiable bacterial operational taxonomic units (OTUs). Many treatment-enriched microbial OTUs were identified, including 14 NonGM-enriched OTUs and 10 GM-enriched OTUs. The rhizosphere microbiota communities were influenced more strongly by growth in the field than by rice varieties. Furthermore, Huahui No. 1 transgenic Bt rice had a greater impact on the rhizosphere bacterial communities than Minghui63. Early developmental stages of the transgenic Bt rice had a significant impact on many Bacillaceae communities. While soil chemical properties were not significantly altered by the presence of transgenic Bt rice, we found peak expression level of Bt proteins during the seedling stage, which may be an intriguing factor for bacterial diversity variations. Based on these findings, we conclude that transgenic Bt rice has a significant impact on root-associated bacteria. This information may be leveraged in future environmental safety assessments of transgenic Bt rice varieties.

The normal growth and development of skeletal muscle is essential for the health of the body. The regulation of skeletal muscle by intestinal microorganisms and their metabolites has been continuously revealed. Acetate is the predominant short-chain fatty acid synthesized by gut microbiota through the fermentation of dietary fiber, however, the underlying molecular mechanisms governing the interaction between acetate and skeletal muscle during rapid growth stage remain to be further elucidated; Here, specific pathogen-free (SPF) mice, germ-free (GF) mice, and germ-free mice supplemented with sodium acetate (GS) were used to evaluate the effects of acetate on skeletal muscle growth and development of young mice with gut microbiota deficiency; We found the concentration of serum acetate, body mass gain, succinate dehydrogenase activity and expression of myogenesis maker gene of skeletal muscle in the GS group was higher than GF group following sodium acetate supplement. Furthermore, the transcriptome analysis revealed that acetate activated biological processes regulating skeletal muscle growth and development in GF group that are inhibited due to gut microbiota deficiency. In vitro experiment, we proved that acetate up-regulated Gm16062 to promote skeletal muscle cell differentiation; Overall, our findings proved that acetate promote skeletal muscle growth and development in young mice via increase Gm16062 expression.

The wealth of data obtained during the past 20 years using Laser-Induced Breakdown Spectroscopy (LIBS) indicates that the technique is very promising to detect small chemical contents of alloying elements. The potential of LIBS was looked more seriously during the past two decades or so as more data were obtained on Aluminum and steel to study the phenomena in the condition of local thermodynamic equilibrium and time-delay between a Q-switch laser and an intensified CCD camera. Since the past decade, some data on compounds were also shown to be useful in determining small concentrations of harmful elements. This manuscript is intended to show that the technique of LIBS performance is very promising in fields such as micro-machining, in alloying element analysis, surface cleaning and environmental applications even with lightweight spectrometers having a relatively low resolution, which can potentially be air-borne.

Understanding the effect of staking sequences and identifying the damage occurring within a structure using a structural health monitoring system are the keys to an efficient design of composite-based parts. In this research, a combination of digital image correlation (DIC) and acoustic emission (AE) is used to locate and classify the type of damage depending on the stacking sequence of the laminate during flexural loading. A comparison of the strain field results for unidirectional, cross-ply, and quasi-isotropic laminates was made in a first attempt to discuss their global behavior and to correlate the different damage patterns with the possible failure mechanisms. The damage was then addressed using a comprehensive interpretation of the acoustic emission signatures using the K-means classification of the acoustic events. The development of each damage mechanism was correlated to the applied load and expressed as a function of the loading rate to highlight the effect of the stacking sequence. Finally, the results of DIC and AE were combined to improve the reliability of the damage investigation without limiting the failure mechanism to matrix cracking, interfacial failure, and fiber breakage, as expected by the unsupervised event clustering.

Small interfering RNA (siRNA) holds significant therapeutic potential by silencing target genes through RNA interference. Current clinical applications of siRNA have been primarily limited to liver diseases, while achievements in delivery methods are expanding its applications to various organs, including the lungs. Cholesterol-conjugated siRNA emerges as a promising delivery approach due to its low toxicity and high efficiency. This study focuses on developing a cholesterol-conjugated anti-Il6 siRNA and the evaluation of its potency for the potential treatment of inflammatory diseases using the example of acute lung injury (ALI). The biological activities of different Il6-targeted siRNAs containing chemical modifications were evaluated in J774 cells in vitro. The lead cholesterol-conjugated anti-Il6 siRNA after intranasal instillation demonstrated dose-dependent therapeutic effects in a mouse model of ALI induced by lipopolysaccharide (LPS). The treatment significantly reduced Il6 mRNA levels, inflammatory cell infiltration, and the severity of lung inflammation. IL6 silencing by cholesterol-conjugated siRNA proves to be a promising strategy for treating inflammatory diseases, with potential applications beyond the lungs.

Perception of flavor is a dynamic process during which the concentration of aroma molecules at the olfactory epithelium varies with time as they are released progressively from the food in the mouth during consumption. The release kinetics depends on the food matrix itself, but also on food oral processing, such as mastication behavior and food bolus formation with saliva, for which huge inter-individual variations exist due to physiological differences. Sensory methods, such as time-intensity (TI), or the more recent methods temporal dominance of sensations (TDS) and temporal check-all-that-apply (TCATA), are used to account for the dynamic and time-related aspects of flavor perception. Direct injection mass spectrometry (DIMS) techniques that measure in real-time aroma compounds directly in the nose (nosespace), aimed at obtaining data that reflect the pattern of aroma release in real-time during food consumption, supposed to be representative of perception, have been developed since 25 years. Examples obtained with MS operated in chemical ionization mode at atmospheric or sub-atmospheric pressure (atmospheric pressure chemical ionization APCI or proton transfer reaction PTR) will be given, with emphases on studies conducted with simultaneous dynamic sensory evaluation. Inter-individual variations in terms of aroma release and their relevance for understanding flavor perception will be discussed, as well as evidenced cross-modal interactions.

Dipeptidyl peptidase 9 (DPP9) is a multifunctional intracellular protease with roles in tumour growth, inflammation and mitochondrial function. We developed a hepatocyte-specific DPP9 knockout mouse (DPP9-KO) to explore DPP9 in a mouse model of hepatocellular carcinoma (HCC). DPP9-KO mice were generated by crossing Albumin-Cre mice (Wt/Wt Cre+/+) with DPP9 floxed mice (Fl/Fl Cre-/-). Mice were treated with Diethylnitrosamine and Thioacetamide then an atherogenic High Fat Diet until 28 weeks of age. DPP9-KO mice had reduced liver and subcuta-neous adipose tissue mass and lower fasting plasma glucose, fewer small macroscopic liver nod-ules compared to DPP9-WT mice. However, there were no differences in the total number of mac-roscopic liver nodules, tumour burden, inflammation score and steatosis score. Consistent with the known ability of DPP9 to suppress NLRP1 activation, activated caspase-1 protein was ele-vated in DPP9-KO mouse liver. Additionally, Nfkbib, Cxcl10 and Ccl5 mRNA and protein levels of autophagy marker beclin1 and tumour suppressor p53 were increased. In conclusion, DPP9 de-pletion in hepatocytes may reduce liver cancer initiation, via mechanisms that may include in-creased autophagy and innate tumour suppression in this experimental model. Finally, the data supports DPP9 having a role in glucose regulation by the liver.

Flavonoids are major secondary metabolites in plants, which play important roles in maintaining the cellular redox balance in cells. Chalcone synthase (CHS) is the key enzyme in the flavonoids biosynthesis pathway, and has been proved to monitor the changes to drought stress tolerance. In this work, we overexpressed a CHS gene in tobacco (Nicotiana tabacum). The transgenic tobacco plants were more tolerant than the control plants to drought stress. The transcription levels of the key genes involved in the flavonoids pathway and the contents of seven flavonoids were also significantly raised in the transgenic tobacco plants. In addition, overexpression of the CHS gene lead to a lower concentration of the oxidative stress product malondialdehyde. Overall, the NtCHS gene studied in this work was considered as a candidate gene for genetic engineering to enhance drought tolerance of plants and improve response to oxidative stress.

Objective: Lower extremity ischemia-reperfusion injury (IRI) may occur with trauma-related vascular injury and various vascular diseases, during the use of a tourniquet, temporary clamping of the aorta in aortic surgery, and acute or bilateral acute femoral artery occlusion. Mitochondrial dysfunction and increased basal oxidative stress in diabetes may cause an increase in the effects of increased reactive oxygen species (ROS) and mitochondrial dysfunction due to IRI. It is of great importance to examine therapeutic approaches that can minimize the effects of IRI, especially for patient groups under chronic oxidative stress. Cerium oxide (CeO2) nanoparticles mimic the antioxidant enzymes and act as a catalyst that scavenges ROS. In this study, it was aimed to investigate whether CeO2 has protective effects on skeletal muscles in lower extremity IRI in mice with streptozocin-induced diabetes. Methods: A total of 38 Swiss albino mice were divided into six groups as follows: control group (group C, n=6), diabetes group (group D, n=8), diabetes-CeO2 (group DCO, n=8), diabetes-ischemia/reperfusion (group DIR, n=8), and diabetes-ischemia/reperfusion-CeO2 (group DIRCO, n=8). DCO and DIRCO groups were given doses of CeO2 0.5mg/kg intraperitoneally 30 minutes before the IR procedure. A 120-minute ischemia-120-minute reperfusion period with 100% O2 was performed. At the end of the reperfusion period, muscle tissues were removed for histopathological and biochemical examinations. Results: Total antioxidant status (TAS) levels were found to be significantly lower in group DIR compared with group D (p=0.047 and p=0.022, respectively). In group DIRCO and total oxidant status (TOS) levels were found to be significantly higher than in group DIR (p

In areas where conventional fundus cameras are logistically unaffordable, the smartphone-based approach is considered as a promising future of glaucoma screening due to their affordability and ease-of-use. Optic disc localization is a critical stage during glaucoma screenings. For fundus images captured with standard fundus cameras, the majority of the models available out there can locate the optic disc with satisfactory performance. However, for images that are captured with smartphone-based fundus cameras, the inherent noise and lower quality of the fundus image makes it difficult for models to detect the optic disc region. In this study, we have proposed to utilize YOLOv8n for optic disc localization due to the model’s cutting-edge performance in diverse tasks and its lightweight nature. We have used a public dataset which has 2000 low quality fundus images that are captured using a smartphone-based fundoscopy device. From these, 60% of the data was used for fine-tuning the model, and 25% for testing. By using a confidence of 50% set as threshold, the model was able to detect the optic disc successfully on over 97% of test images with intersection over union of above 0.85. These results highlight the potential of the lightweight YOLOv8n model for deployment on resource-constrained environments, offering a promising performance on accurately localizing the OD and enhancing the feasibility of affordable glaucoma screening on smartphones.

According to previous studies the median raphe region (MRR) is known to contribute significantly to social behavior. Beside serotonin, there are reports of a small population of dopaminergic neu-rons in this region. Dopamine is linked to reward and locomotion, but very little has been known about its role in the MRR. To address that, we first confirmed the presence of dopaminergic cells in the MRR of mice (immunohistochemistry, RT-PCR) and humans (RT-PCR). Next, we used chemogenetic technology in mice containing Cre enzyme under the promoter of the dopamine transporter (DAT). With the help of an adeno-associated virus, artificial receptors were expressed in the dopaminergic cells of the MRR (DAT-MRR). Four weeks later, extensive behavioral charac-terization started 30 minutes after the injection of the artificial ligand (Clozapine-N-Oxide). Stimu-lation of DAT-MRR decreased social interest without influencing aggression and with an increase in social discrimination. Additionally, inhibition of the same cells increased the friendly social be-havior during social interaction test. No behavioral changes were detected in anxiety, memory and locomotion. All in all, dopaminergic cells were present both in the mice and human MRR, and manipulation of dopaminergic neurons of the MRR elicited a specific social response.

Much research has been conducted to determine how hair regeneration is regulated, as this could provide therapeutic, cosmetic, and even psychological interventions for hair loss. The current study focused on the hair growth effect and effective utilization of fatty oil obtained from Bryde's whales through high-throughput DNA microarray approach in conjunction with immunohistochemical observations. The research also examined the mechanisms and factors involved in hair growth. In an experiment using female C57BL/6J mice, the vehicle control group (VC: propylene glycol: ethanol: water), the positive control group (MXD: 3% minoxidil), and the experimental group (WO: 20% Whale Oil) were topically applied to the back of the mouse. The results showed that 3% MXD and 20% WO were more effective than VC in promoting hair growth, especially 20% WO. Furthermore, in hematoxylin and eosin-stained skin tissue, an increase in the number of hair follicles and subcutaneous tissue thickness was observed with 20% WO. Whole-genome transcriptomic analysis also showed that 20% WO may have lower stress- and inflammation-related responses than 3% MXD. Therefore, whale oil can be expected to be used as a safe hair growth agent.

Matrix metalloproteinases have been implicated in muscular dystrophy progression and recent studies described the role of MMP-10 in skeletal muscle pathology of young dystrophic mice. Nevertheless, its implication in dystrophin deficient hearts is still missing. Here, we aimed at investigating MMP-10 implication in severe muscular dystrophic progression and characterize MMP-10 loss in skeletal and cardiac muscles of aged dystrophic mice. We examined the histopathological effect of MMP-10 ablation in aged mdx mice, both in the hind limb muscles and heart tissues. We have found that MMP-10 loss compromises survival rates of aged mdx mice, with skeletal and cardiac muscles developing a chronic inflammatory response. Our findings indicate that MMP-10 is implicated in severe muscular dystrophy progression, identifying a new area of investigation that could lead to future therapies for dystrophic muscles.

The amount and spatial distribution of foliage in a tree canopy have fundamental functions in ecosystems as they affect energy and mass fluxes through photosynthesis and transpiration. They are usually described by the Leaf Area Index (LAI) and the Leaf Area Density (LAD), which can be measured through a variety of methods, including voxel-based methods applied to LiDAR point clouds. A theoretical study recently compared the numerical errors arising from different voxel-based estimation methods for Plant Area Density (PAD) based on Beer’s law-based, contact frequency and Maximum-Likelihood Estimation, showing that the bias-corrected Maximum Likelihood Estimator was theoretically the most efficient. However, this earlier study i) ignored wood volumes; ii) neglected vegetation clumping inside the voxel; iii) ignored instrument characteristics in terms of effective footprint, iv) was limited to a single viewpoint. In practice, retrieving LAD from PAD is not straightforward, vegetation is not randomly distributed in volumes of interest, beams are divergent and forestry plots are usually sampled from more than one viewpoint, to mitigate the effect of occlusion. In the present short communication, we extend the previous efficient formulation to actual field conditions to i) account for the presence of both wood volumes and wood hits, ii) rigorously include correction terms for vegetation and instrument characteristics, iii) integrate multiview data. A numerical comparison with other methods commonly used to combine information from different viewpoints led to error reduction, especially in poorly-explored volumes, which are frequent in actual canopies. Beyond its concision, completeness and efficiency, this new formulation -which can be applied to multiview TLS, but also UAV LiDAR scanning - can help reducing errors in LAD estimation.

Modern research into carcinogenesis has undergone three phases. Surgeons and pathologists started the first phase and established autopsy and biopsy as routine pathology services, in turn establishing morphological traits for tumors and establishing immortality and autonomy as indispensable criteria for neoplasms. A century ago medical doctors and biologists initiated “experimental cancer research” as the second phase, in which they, with help from chemists, established many chemical-induced animal models of carcinogenesis. In this phase, the two-hit theory and stepwise carcinogenesis of “initiation-promotion” or “initiation-promotion-progression” were established, with an illustrious finding that outgrowths induced in animals depend on the inducers, and thus are not authentically neoplastic, until late stages. For the last 40 years, molecular biologists have gradually dominated the carcinogenesis research fraternity and have established numerous genetically-modified animal models of carcinogenesis. However, evidence has not been provided for immortality and autonomy of the lesions from most of these models. Probably, many peers had already collected the lesions from animals for analyses of “cancer” mechanisms before the lesions became autonomous. We herein review monumental work of many predecessors to reinforce that evidence for immortality and autonomy is essential for confirming a neoplastic nature. We extrapolate that immortality and autonomy are established early during sporadic human carcinogenesis, unlike the late establishment in all animal models. It is imperative to resume many forerunners’ work by determining the genetic bases for initiation, promotion and progression, the genetic bases for immortality and autonomy, and which animal models are, in fact, good for identifying such genetic bases.

A hallmark of Alzheimer’s disease (AD) are the proteinaceous aggregates formed by the amyloid-beta peptide (Aβ) that is deposited inside the brain as amyloid plaques. The accumulation of aggregated Aβ may initiate or enhance pathologic processes in AD. According to the amyloid hypothesis any agent that has the capability to inhibit Aβ aggregation and/or destroy amyloid plaques represents a potential disease modifying drug. In 2023, a humanized IgG1 monoclonal antibody (lecanemab) against the Aβ soluble protofibrils was approved by US FDA for AD therapy thus providing compelling support to the amyloid hypothesis. To acquire a deeper insight on the in vivo Aβ aggregation, various animal models, including aged herbivores and carnivores, non-human primates, transgenic rodents, fish and worms are widely exploited. This review is based on the recent data obtained using transgenic animal AD models and presents experimental verification of the critical role in Aβ aggregation seeding of the interactions between zinc ions, Aβ with the isomerized Asp7 (isoD7- Aβ) and the α4β2 nicotinic acetylcholine receptor.

Fifteen transgenic shoot clones (TS A-TS O) regenerated from Hypericum perforatum hairy roots were evaluated for growth characteristics, phenylpropanoid, and naphthodianthrone production, as well as non-enzymatic and enzymatic antioxidant status. Transgenic shoots displayed higher biomass production and non-altered phenotype compared to control shoots. Phenylpropanoid production in TS was not related to phenylalanine ammonia lyase activity indicating that alternative enzymes could be involved in the regulation of phenylpropanoid/flavonoid biosynthesis. The positive correlation between phenylpropanoids (phenolic acids, flavonoids, flavan-3-ols, tannins) and non-enzymatic antioxidant assays suggested that these compounds are the main contributors to the redox state and radical scavenging properties of TS clones. More importantly, enhanced naphthodianthrone production (hypericin, pseudohypericin and protopseudohypericin) in TS was associated with the number of leaf dark glands. Concerning the enzymatic antioxidant status of TS, guaiacol peroxidase was shown as the main enzyme that turn down H2O2 levels, while the up-regulation of superoxide dismutase coincided with decreased O2•− production. The efficiency of antioxidant enzymes for O2•− and H2O2 neutralization declined the MDA level and consequently delayed lipid peroxidation in TS clones. Altogether, H. perforatum transgenic shoots could be proposed as a prospective biotechnological system for scale-up production of naphthodianthrones and phenylpropanoids with antioxidant properties.

This paper focuses on quantifying the economic and financial viability of NB-IoT and LoRaWAN technologies, two low-power wide-area network (LPWAN) technologies with unique characteristics that make them suitable for IoT applications. The purpose of the study is to propose an artefact for performing life cycle cost analysis and demonstrate its application to these technologies. The methodology uses pragmatic computational tools to facilitate the analysis and considers all relevant economic and financial factors, such as operating costs, equipment costs, and revenue potential. The main finding of the study is that NB-IoT and LoRaWAN technologies have different cost structures and revenue potentials, which may affect their economic and financial viability for different IoT applications. Ultimately, the study concludes that a comprehensive life cycle cost analysis is critical to making informed decisions about technology adoption, and that the proposed methodology can be applied to other IoT technologies to gain insight into their economic and financial viability.

In the 21st century, the effects of HIV-associated neurocognitive disorders (HAND) have been significantly reduced in individuals due to the development of antiretroviral therapies (ARTs). However, the growing epidemic of polysubstance use (PSU) has led to concern for the effects of PSU on HIV-seropositive individuals. To effectively treat individuals affected by HAND, it is critical to understand the biological mechanisms affected by PSU including identification of novel markers. To fill this important knowledge gap, we used an in vivo HIV-Transgenic (HIV-Tg) animal model, to investigate the effects of the combined use of chronic methamphetamine (METH) and oxycodone (oxy). RNA-Seq analysis on the striatum - a brain region that is primarily targeted by both HIV and drugs of abuse - identified key differentially expressed markers post-METH and oxy exposure. Furthermore, ClueGO analysis and Ingenuity Pathway Analysis (IPA) revealed crucial molecular and biological functions associated with ATP-activated adenosine receptor, neuropeptide hormone activity, and the oxytocin signaling pathway to be altered between the different treatment groups. The current study further reveals the harmful effects of chronic PSU and HIV infection that can subsequently impact neurological outcomes in polysubstance users with HAND.

Profiling technologies, such as proteomics, allow the simultaneous measurement and comparison of thousands of plant components without prior knowledge of their identity. The combination of these non-targeted methods facilitates a more comprehensive approach than targeted methods and thus provides additional opportunities to identify genotypic changes resulting from genetic modification, including new allergens or toxins. The purpose of this study was to investigate unintended changes in GM Bt maize grown in South Africa. In the present study, we used bi-dimensional gel electrophoresis based on fluorescence staining, coupled with mass spectrometry in order to compare the proteome of the field-grown transgenic hybrid (MON810) and its near-isogenic counterpart. Proteomic data showed that energy metabolism and redox homeostasis were unequally modulated in GM Bt and non-GM maize variety samples. In addition, a potential allergenic protein – pathogenesis related protein -1 has been identified in our sample set. These finding highlight the suitability of unbiased profiling approaches to complement current GMO risk assessment practices worldwide.

Combinatoric measures of entropy capture the complexity of a graph, but rely upon the calculation of its independent sets, or collections of non-adjacent vertices. This decomposition of the vertex set is a known NP-Complete problem and for most real world graphs is an inaccessible calculation. Recent work by Dehmer et al. and Tee et al. identified a number of alternative vertex level measures of entropy that do not suffer from this pathological computational complexity. It can be demonstrated that they are still effective at quantifying graph complexity. It is intriguing to consider whether there is a fundamental link between local and global entropy measures. In this paper, we investigate the existence of correlation between vertex level and global measures of entropy, for a narrow subset of random graphs. We use the greedy algorithm approximation for calculating the chromatic information and therefore Körner entropy. We are able to demonstrate close correlation for this subset of graphs and outline how this may arise theoretically.

Proteinuria is known to be associated with all-cause and cardiovascular mortality, and nephrotic syndrome is defined by the level of proteinuria and hypoalbuminemia. With advances in medicine, new causative genes for genetic kidney diseases are being discovered increasingly frequently. We reviewed articles on proteinuria/nephrotic syndrome, focal segmental glomerulosclerosis, membranous nephropathy, diabetic kidney disease/nephropathy, hypertension/nephrosclerosis, Alport syndrome, and rare diseases, which have been studied in mouse models. Significant progress has been made in understanding the genetics and pathophysiology of kidney diseases thanks to advances in science, but research in this area is ongoing. In the future, genetic analyses of patients with proteinuric kidney disease/nephrotic syndrome may ultimately lead to personalized treatment options.

This paper deals with the viscoelastic behavior during crystallization and melting of semicrystalline polymers with the aim of later modeling the residual stresses after processing in case where crystallization occurs in quasi static conditions (in additive manufacturing for example). Despite of an abundant literature on polymer crystallization, the current state of scientific knowledge does not yet allow ab initio modeling. Therefore, an alternative and pragmatic way has been explored to propose a first approximation of the impact of crystallization and melting on the storage and the loss moduli during crystallization-melting-crystallization cycle. An experimental approach, combining DSC, optical microscopy and oscillatory shear rheology was used to define macroscopic parameters related to the microstructure. These parameters have been integrated into a phenomenological model. Isothermal measurements were used to describe the general framework, and crystallization at a constant cooling rate was used to evaluate the feasibility of a general approach. It can be concluded that relying solely on the crystalline fraction is inadequate to model the rheology. Instead accounting for the microstructure at the spherulitic level could be more useful. Additionally, the results obtained from the experiments help to enhance our understanding of the correlations between crystallization kinetics and its mechanical effects.

We introduce linear probing hashing schemes that construct a hash table of size $n$, with constant load factor $\alpha$, on which the worst-case unsuccessful search time is asymptotically almost surely $O(\log \log n)$. The schemes employ two linear probe sequences to find empty cells for the keys. Matching lower bounds on the maximum cluster size produced by any algorithm that uses two linear probe sequences are obtained as well.

RNAi is considered a major antiviral defense mechanism in insects but its relative importance compared to other antiviral pathways has not been evaluated comprehensively. Here, it is attempted to give an overview of the antiviral defense mechanisms in Drosophila that involve both RNAi and non-RNAi to acquire a sense of their relative importance. While RNAi is considered important in most viral infections, many other pathways can exist that confer antiviral resistance. It is noted that very few direct recognition mechanisms of virus infections have been identified in Drosophila and that the activation of immune pathways may be accomplished indirectly through cell damage incurred by viral replication. In several cases, protection against viral infection can be obtained in RNAi mutants by non-RNAi mechanisms, confirming the variability of the RNAi defense mechanism according to the type of infection and the physiological status of the host. This analysis invites to investigate more systematically the relative contribution of RNAi in the antiviral response and more specifically to ask whether RNAi efficiency is affected when other defense mechanisms predominate. While Drosophila can function as a useful model, this issue may be more critical for economically important insects that are either controlled (agricultural pests and vectors of diseases) or protected from parasite infection (beneficial insects as bees) by RNAi products.

The key enzyme, 1-hydroxy-2-methyl-2-(E)-butenyl-4-pyrophosphate reductase HDR, responsible for the final step in the MEP pathway, was successfully cloned from the petals of Narcissus tazetta var. chinensis, herein referred to as NtHDR (accession number OQ739816). NtHDR exhibits a full-length coding sequence spanning 1380 base pairs, encoding a total of 460 amino acids. Through phylogenetic tree analysis, it has been determined that NtHDR shared the closest evolutionary relationship with monocotyledons, specifically Asparagus officinalis and Zingiber officinale. Utilizing quantitative real-time PCR analysis, it was observed that NtHDR exhibited significant expression in both petals and corona, with expression levels varying throughout the flowering process of Narcissus. Specifically, in petals, NtHDR expression demonstrated a pattern of initial increase followed by subsequent decrease, while in corona, it consistently increased. Subsequent subcellular localization experiments indicated that NtHDR was localized within the chloroplasts. To investigate the functional impact of NtHDR, stable transformation was performed, where NtHDR was introduced into Nicotiana benthamiana. The resulting transgenic N. benthamiana flowers were analyzed using solid-phase microextraction coupled with gas chromatography–mass spectrometry (SPME-GC-MS) to characterize their volatile components. The analysis revealed the presence of the monoterpene compound linalool, as well as the phenylpropanoids benzyl alcohol and phenylethanol, within the floral fragrance components of the transgenic N.benthamiana plants. However, these compounds were absent in the floral fragrance components of wild-type tobacco plants, thus highlighting the impact of NtHDR transformation on the floral scent profile.

We summarize structural instabilities exhibited by the one dimensional (1D) (arene)2X family of organic conductors in relation with their electronic and magnetic properties. With a charge transfer of one electron to each anion X these salts exhibit a quarter-filled (hole) conduction band located on the donor stacks. Compounds built with donors such as fluorenthene and perylene derivatives and anions X such PF6 or AsF6 exhibit a high temperature (TP~170K) conventional Peierls transition which is announced by a sizeable regime of 1D 2kF charge density wave fluctuations (kF is the Fermi wave vector of the 1D electron gas located on Per stacks). Surprisingly, and probably because of the presence of a multi-sheet warped Fermi surface, the Peierls transition is considerably reduced in the perylene series α-(Per)2[M(mnt)2] where X is the dithiolate molecule with M=Au, Cu, Co and Fe. A special attention is devoted in this paper to physical properties of α-(Per)2[M(mnt)2] salts which with M=Pt, Pd and Ni incorporate segregated S=1/2 1D antiferromagnetic (AF) dithiolate stacks with 1D metallic Per stacks. We analyse conjointly the structural and magnetic properties of these salts in relation with the 1D spin-Peierls (SP) instability located on the dithiolate stacks. We show that the SP instability of the Pd and Ni derivatives occurs in the classical (adiabatic limit) while the SP instability of the Pt derivative occurs in the quantum (anti-adiabatic limit). Furthermore we show that in the Pd and Ni derivatives frustrated 1st neighbour direct and 2nd neighbour indirect (through a fine tuning with the mediated 2kF RKKY coupling interaction on Per stacks) AF interactions add their contribution to the SP instability to open a singlet-triplet gap. Our analysis of the data show unambiguously that magnetic α-(Per)2[M(mnt)2] salts are a typical realization of the physics predicted for two chain 1D Kondo lattices.

Mass insect rearing can have a range of applications, for example in biological control of insects. Since the performance of released biological control agents determines efficacy, the competitive fitness of insects post release is a key variable. Here, we tested whether inoculation with a gut symbiont, Enterobacter cloacae, and gnotobiotic rearing of larvae could improve insect growth and male competitive fitness of a transgenic diamondback moth, which has shown variation in fitness when reared in different insectaries. All larvae were readily infected with the focal symbiont. Under gnotobiotic rearing pupal weights were reduced and there was a marginal reduction in larval survival. However, gnotobiotic rearing substantially improved the fitness of transgenic males. In addition, in gnotobiotic conditions, inoculation with the gut symbiont increased pupal weights and male fitness, increasing the proportion of transgenic progeny from 20 to 30% relative to symbiont-free insects. Gnotobiotic conditions may improve the fitness of transgenic males by excluding microbial contaminants, while symbiont inoculation could further improve fitness by providing additional protection against infections, or by normalizing insect physiology. The simple innovation of incorporating antibiotic into diet, and inoculating insects with symbiotic bacteria that are resistant to that antibiotic, could provide a readily transferable tool for other insect rearing systems.

Terrestrial LiDAR becomes more and more popular to estimate leaf and plant area density. Voxel-based approaches account for this vegetation heterogeneity and significant work has been done in this recent research field, but no general theoretical analysis is available. Although estimators have been proposed and several causes of biases have been identified, their consistency and efficiency have not been evaluated. Also, confidence intervals are almost never provided. In the present paper, we solve the transmittance equation and use the Maximum Likelihood Estimation (MLE), to derive unbiased estimators and confidence intervals for the attenuation coefficient, which is proportional to leaf area density. The new estimators and confidence intervals are defined at voxel scale, and account for the number of beams crossing the voxel, the inequality of path lengths in voxel, the size of vegetation elements, as well as for the variability of element positions between vegetation samples. They are completed by numerous numerical simulations for the evaluation of estimator consistency and efficiency, as well as the assessment of the coverage probabilities of confidence intervals. • Although commonly used when the beam number is low, the usual estimators are strongly biased and the 95% confidence intervals can be ≈±100% of the estimate. • Our unbiased estimators are consistent in a wider range of validity than the usual ones, especially for the unbiased MLE, which is consistent when the beam number is as low as 5. The unbiased MLE is efficient, meaning it reaches the lowest residual errors that can be expected (for an unbiased estimator). Also the unbiased MLE does not require any bias correction when path lengths are unequal. • When elements are small (or voxel is large), 103 beams entering the voxel leads to some confidence intervals ≈±10%, but when elements are larger (or voxel smaller), it can remain wider than ±50%, even for a large beam number. This is explained by the variability of element positions between vegetation samples. Such a result shows that a significant part of residual error can be explained by random effects. • Confidence intervals are much smaller (±5 to 10%) when LAD estimates are averaged over several small voxels, typically within a horizontal layer or in the crown of individual plants. In this context, our unbiased estimators show a reduction of 50% of the radius of confidence intervals, in comparison to usual estimators. Our study provides some new ready-to-use estimators and confidence intervals for attenuation coefficients, which are consistent and efficient within a fairly large range of parameter values. The consistency is achieved for a low beam number, which is promising for application to airborne LiDAR data. They entail to raise the level of understanding and confidence on LAD estimation. Among other applications, their usage should help determine the most suitable voxel size, for given vegetation types and scanning density, whereas existing guidelines are highly variable among studies, probably because of differences in vegetation, scanning design and estimators.

Since alternative methods (AAs), such as in vitro cultures, organs in silico, or mathematical methods, are not fully able to reproduce the complexity of the human organism, particularly neu-ral processes, and brain structures, animal experimentation remains the only way in which re-search can obtain the necessary knowledge to suggest drug therapies or targeted therapeutic in-terventions. Particularly in neuroscience, transgenic animals allow us to model neurological dis-eases, study the relationship between the brain and behavior, and decipher the function of genes involved in pathological conditions. However, it should never be forgotten that animals are "sen-tient beings" capable of feeling pleasure and pain (Art. 13 of the 2007 Lisbon Treaty). For this rea-son, it is crucial to prioritize the welfare of animals involved in testing by considering their phys-ical, psychological, adaptive, and relational well-being. This is where the concept of a Culture of Care comes in, where the responsibility of care extends beyond the veterinary aspects to include everything that can safeguard the welfare of animals before, during, and after experimentation. This chapter explains the advantages of using the animal model while practicing the culture of care in neuroscience, as both animals and research outcomes benefit from this approach.

Rojolele is an Indonesian traditional rice variety from Klaten (Central Java) that classified as tropical japonica and low land rice which become a premium rice variety and have higher price in the market due to a delicious taste and a fragrance aroma. The agronomic characteristics of Rojolele are having high plant stature with sturdy stems and upright plant shape, thick and rough leaves, strong and deeper root systems, long panicle length, and long duration of life. Rojolele rice cultivation is facing important challenges from drought, diseases, long duration, and lodging. Thus, breeding Rojolele cultivars with resistance to drought, diseases, lodging, and short duration is the major focus for Rojolele rice improvement. Indonesian farmer have learned to successfully cultivate Rojolele by applying practical skills, leading to increase the rice productivity. Molecular breeding program, including quantitative trait loci (QTL), genome-wide association study (GWAS), genomic selection, and genome editing can be applied to improve Rojolele characteristics. In this review, important agronomic and quality traits, intensification system for irrigation and pest control, mutation breeding, transgenic lines, and also future perspectives for Rojolele research were presented. Rojolele is useful for rice breeding program in order to guarantee the food security to overcome increasing population and climate change.

To control the COVID-19 pandemic, many countries implemented vaccination and imposed societal restrictions both at the national level and for international travel. As a check of the corona status, a COVID pass has been issued. A COVID pass could be obtained when fully vaccinated against COVID-19, having recovered from a documented COVID-19 episode, or a recent (24-48 hours) negative SARS-CoV-2 antigen test. A global analysis of SARS-CoV-2 immune status (determined by past infection and/or vaccination), vaccination rates, as well as societal restrictions in controlling the COVID-19 pandemic is presented.

Soil bacteria drive key ecosystem functions, including nutrient mobilization, soil aggregation and crop bioprotection against pathogens. Bacterial diversity is thus considered a key component of soil health. Conventional agriculture reduces bacterial diversity in many ways. Compost tea has been suggested as a bioinoculant that may restore bacterial community diversity and promote crop performance under conventional agriculture. Here, we conducted a field experiment to test this hypothesis in a soybean-maize rotation. Compost tea application had no influence on bacterial diversity or community structure. Plant growth and yield were also unresponsive to compost tea application. Combined, our results suggest that our compost tea bacteria did not thrive in the soil, and that the positive impacts of compost tea applications reported elsewhere may be caused by different microbial groups (e.g., fungi, protists, nematodes) or by abiotic effects on soil (e.g., contribution of nutrients and dissolved organic matter). Further investigations are needed to elucidate the mechanisms through which compost tea influences crop performance.

(1) Background: TNF inhibitors (TNFi) have revolutionized the treatment of rheumatoid arthritis (RA). However, 30-40 % of RA patients do not respond adequately to those biologics. In addition to neutralizing soluble TNF, TNFi have the ability to bind the transmembrane form of TNF, tmTNF. Importantly, tmTNF can act itself as a receptor that induces a “Reverse Signaling” (RS) in cells. We previously showed that certolizumab, a Fab’ TNFi, activates RS in human primary monocytes, at least in part through the transcription factor NRF2 that is known to regulate the expression of genes involved in anti-inflammatory response and oxidative stress. (2) Methods: Here, we have developed an assay for the prediction of clinical response of RA patients to TNF inhibitors. This assay is based on mRNA quantitation of CD36 activation and of 6 genes induced by NRF2 following tmTNF RS in fresh monocytes. (3) Results: We could predict the response to anti-TNF monoclonal antibodies (mAbs) with 93.3 % accuracy. However, our method was not suitable for the prediction of the response to TNF soluble receptor etanercept. (4) Conclusions: We have developed a rather simple, short-term, test that can be standardized. Predicting the response to TNF mAbs will help physicians offer the best available treatment and provide patients with personalized medicine.

Gram-negative bacterial infections pose a significant threat to public health. Toll-like receptor 4 (TLR4) recognizes bacterial lipopolysaccharide (LPS) and induces innate immune responses, autophagy and cell death, which have major impacts on the body physiological homeostasis. However, the role of TLR4 in bacterial LPS-induced autophagy and apoptosis in large mammals remains unknown, which are closer to humans than rodents in many physiological characteristics. So far, few reports focus on the relationship between TLR, autophagy and apoptosis in large mammal levels. We urgently need more tools to further explore their crosstalk. Here, we generated a TLR4-enriched mammal model (sheep) and found that a high-dose LPS treatment blocked autophagic degradation and caused strong innate immune responses and severe apoptosis in PBMCs of transgenic offspring. Excessive accumulation of autophagosomes/autolysosomes might contribute to LPS-induced apoptosis in PBMCs of transgenic animals. Further study demonstrated that inhibiting TLR4 downstream NF-κB or p38 MAPK signaling pathways reversed the LPS-induced autophagy activity and apoptosis. These results indicate that the elevated TLR4 aggravates LPS-induced PBMCs apoptosis by leading to lysosomal dysfunction and impaired autophagic flux, which is associated with TLR4 downstream NF-κB and MAPK signaling pathways. This study provides a novel TLR4-enriched mammal model to study its potential effects on autophagy activity, inflammation, oxidative stress and cell death. These findings also enriched the biological functions of TLR4 and provided powerful evidence for bacterial infection.

Endoplasmic reticulum (ER) is an important organelle responsible as protein synthesis regulator in plant. High salinity can also lead to the activation of ER stress, caused by the accumulation of misfolded protein. This could lead to a stress response mechanism, unfolded protein response (UPR). Failure of UPR to reverse the effect of protein misfolding will activate Programmed Cell Death (PCD). Metacaspase genes regulate programmed cell death (PCD) in plants. The present study was focused on comprehensive gene analyses of the expression patterns of type II rice metacaspase (OsMC) genes in response to the endoplasmic reticulum (ER) and salinity stress in rice leaf and OsMC4 in callus. A strong evidence of unfolded protein response (UPR) during tolerance to both ER and salinity stress was found in the present study. Overexpression of OsMC4 in rice callus as a fusion protein with TagRFP and controlled by the CaMV35 promoter caused major changes in the expression of the stress ER-marker genes, protein disulfide isomerase (PDI) and Binding immunoglobulin Protein (BiP), and OsMC4 in overexpressing calli. These expression analyses of the OsMC family provide valuable information for further functional studies on the biological roles of OsMCs in PCD related to ER and salinity stress responses.

This study compared the relative effect of two trace mineral supplementation strategies recom-mended in France for newborn beef calves. 600 calves were supplemented with 20 mg oral sele-nium (OTM group) at birth (D0) or by injection (ITM group) of a multi-mineral solution (60 mg of Zn, 10 mg of Mn, 15 mg of Cu, 5 mg of Se) on D0, D30 and D60. Mortality and the incidence rate of diseases, including diarrhea, omphalitis, pneumonia, as well as medicinal treatments, were recorded from D0 to D210. The incidence rate of omphalitis was significantly lower in the ITM group than in the OTM group (respectively 11% vs. 17%, P = 0.036). The cumulative inci-dence rate of all health troubles was lower in the ITM group than in the OTM group (P=0.007). Except for pneumonia, incidence of diarrhea (24% vs. 22%), use of oral (7% vs. 6%) or IV rehydra-tion therapy (4% vs. 2%) or use of antibiotics (43.3% vs. 38.0%) and mortality (3% vs 2%) were numerically higher in OTM group than in ITM group (n.s.). In this study, ITM supplementation is as efficient as oral supplementation regarding calves' health status. It reduces the risk of ompha-litis at the calf level effectively.

Congenital Disorders of Glycosylation (CDG) are a heterogenous group of primarily autosomal recessive mendelian diseases caused by disruptions in the synthesis of lipid linked oligosaccha-rides and their transfer to proteins. CDGs affect multiple organ systems and vary in presentation, even within families. Here we describe a chemically induced mouse mutant, tvrm76, with early onset photoreceptor degeneration. The recessive mutation was mapped to Chromosome 9 and as-sociated with a missense mutation in the Dpagt1 gene encoding UDP-N-acetyl-D-glucosamine:dolichyl-phosphate N-acetyl-D-glucosaminephosphotransferase (EC 2.7.8.15). The mutation is predicted to cause a substitution of aspartic acid with glycine at residue 166 of DPAGT1. Increased expression of Ddit3, and elevated levels of HSPA5 (BiP) sug-gest the presence of early-onset endoplasmic reticulum (ER) stress. These changes were associated with induction of photoreceptor apoptosis in tvrm76 retinas. Mutations in human DPAGT1 cause Myasthenic Syndrome 13 and severe forms of Congenital Disorder of Glycosylation Type Ij. In contrast, Dpagt1tvrm76 homozygous mice present with congenital photoreceptor degeneration without overt muscle or muscular junction involvement. Our results suggest the possibility of DPAGT1 mutations in human patients that present primarily with retinitis pigmentosa with little or no muscle disease. Variants in DPAGT1 should be considered when evaluating cases of non-syndromic retinal degeneration.

The climate change is likely to modify the freezing-thawing cycles in soils and surface waters of permafrost-affected and subarctic regions. Yet, the change of solution chemical composition during ice formation and evolution of remaining fluids remain very poorly known. Towards better understanding of dissolved (&lt; 0.45 µm) organic carbon, major and trace elements behavior in permafrost peatland environments, here we performed laboratory freezing of peat leachates, from complete freezing to complete thawing in order to quantify the partitioning of solutes between the aqueous solution and the remaining ice. We hypothesized the existence of two main groups of solutes, behaving conservatively or non-conservatively during freezing depending on their incorporation into the ice or ability to coagulate in the form of insoluble minerals or amorphous materials in the fluid phase. An unexpected result of this work was that, despite sizable degree of element concentration in the remaining fluid and possible coagulation of organic, organo-mineral and inorganic compounds, the freezing and subsequent thawing produced the final concentrations of most solutes which were not drastically different from initial concentrations in starting leachates, prior freezing. This demonstrates high stability of dissolved (&lt; 0.45 µm) OC, Fe, Al and some trace metals to repetitive freezing and thawing of surface waters in permafrost peatlands.

Myocilin is an enigmatic glaucoma-associated glycoprotein whose biological role remains incompletely understood. To gain novel insight into its normal function, we used transposon-mediated transgenesis to generate the first zebrafish line stably overexpressing myocilin [Tg(actb1:myoc-2A-mCherry)]. qPCR showed an approximately four-fold increased myocilin expression in transgenic zebrafish embryos (144 hpf). Adult (13 months old) transgenic animals displayed variable and age-dependent ocular anterior segment alterations. Almost 60% of two-years old male, but not female, transgenic zebrafish developed enlarged eyes with severe asymmetrical and variable abnormalities in the anterior segment, characterized by corneal limbus hypertrophy, and thickening of the cornea, iris, annular ligament and lens capsule. The most severe phenotype presented small or absent ocular anterior chamber and pupils, due to iris overgrowth along with dysplastic retinal growth and optic nerve hypertrophy. Immunohistochemistry revealed increased presence of myocilin in most altered ocular tissues of adult transgenic animals, as well as signs of retinal gliosis, and expanded ganglion cells and nerve fibers. The preliminary results indicate that these cells contributed to retinal dysplasia. Visual impairment was demonstrated in all old male transgenic zebrafish. Transcriptomic analysis of the abnormal transgenic eyes identified disrupted expression of genes involved in lens, muscular and extracellular matrix activities, among other processes. In summary, the developed transgenic zebrafish provides a new tool to investigate this puzzling protein and provides evidence for the role of zebrafish myocilin in ocular anterior segment and retinal biology, through the influence of extracellular matrix organization and cellular proliferation.

Phosphorus deficiency highly interferes with plant growth and development. Plants respond to the persistent P deficiency by coordinating the expression of genes involved in the alleviation of the stress. Promoters of phosphate transporter genes are of great choice for the development of genetically modified plants with enhanced phosphate uptake abilities, which improve crop yields in phosphate-deficient soils. In our previous study, the sugarcane phosphate transporter PHT1;2 gene, showed a significantly high expression under salinity stress. In this study, the Erianthus arundinaceus EaPHT1;2 gene was isolated and characterized using various in-silico tools. The deduced 542 amino acid residues have 10 transmembrane domains, with a molecular weight and isoelectric point of 58.9 kDa and 9.80, respectively. They displayed 71–96% similarity with Arabidopsis thaliana, Zea mays, and Saccharum hybrid. To elucidate the function of the 5’ regulatory region, the 1.1kb promoter was isolated and validated in tobacco transgenics under Pi stress. The EaPHT1;2 promoter activity was detected using the β-glucuronidase (GUS) assay. While the EaPHT1;2 promoter showed 3 to 4.2-fold higher expression than the most widely used CaMV35S promoter. The 5’ deletion analysis with and without 5’UTR regions, revealed that a small size 374 bp fragment with the highest promoter activity among 5′ truncated fragments, which was 2.7 and 4.2 times higher than the well-used CaMV35S promoter under normal and Pi-deprivation conditions, respectively. The strong and short promoter of EaPHT1;2 with 374 bp showed significant expression in low Pi-stress conditions and it could be a valuable source for the development of stress-tolerant transgenic crops

Mutations in the LMNA gene (encoding lamin A/C proteins) cause several human cardiac diseases, including dilated cardiomyopathies (LMNA-DCM). The main clinical risks in LMNA-DCM patients are sudden cardiac death and progressive left ventricular ejection fraction deterioration, and therefore most human and animal studies have sought to define the mechanisms through which LMNA mutations provoke cardiac alterations, with particular focus on cardiomyocytes. To investigate if LMNA mutations also cause vascular alterations that might contribute to the etiopathogenesis of LMNA-DCM, we generated and characterized Lmnaflox/floxSM22αCre mice, which constitutively lack lamin A/C in vascular smooth muscle cells (VSMCs), cardiac fibroblasts, and cardiomyocytes. Like mice with whole body or cardiomyocyte-specific lamin A/C ablation, Lmnaflox/floxSM22αCre mice recapitulated the main hallmarks of human LMNA-DCM, including ventricular systolic dysfunction, cardiac conduction defects, cardiac fibrosis, and premature death. These alterations were associated with hyperactivation of Smad3 and elevated expression of the proapoptotic protein caspase 3 in the heart. Lmnaflox/floxSM22αCre mice also exhibited perivascular fibrosis in the coronary arteries, and a switch of aortic VSMCs from the ‘contractile’ to the ‘synthetic’ phenotype. Ex vivo wire myography in isolated aortic rings revealed impaired maximum contraction capacity and an altered response to vasoconstrictor and vasodilator agents in Lmnaflox/floxSM22αCre mice. To our knowledge, our results provide the first evidence of phenotypic alterations in VSMCs that might contribute significantly to the pathophysiology of some forms of LMNA-DCM. Future work addressing the mechanisms underlying vascular defects in LMNA-DCM may open new therapeutic avenues for these diseases.

Trauma to the spinal cord causes extensive neuronal death contributing to the loss of sensory-motor and autonomic functions below the injury level. Apoptosis affects neurons after spinal cord injury (SCI) and is associated with increased caspase activity. Cleavage of X-linked inhibitor of apoptosis protein (XIAP) after SCI may contribute to this rise of caspase activity. Accordingly, we have shown that the elevation of XIAP resulted in increased neuronal survival after SCI and improved functional recovery. Therefore, we hypothesize that neuronal overexpression of XIAP can be neuroprotective after SCI with improved functional recovery. In line with this, studies of a transgenic mouse with overexpression of XIAP in neurons revealed that higher levels of XIAP after spinal cord trauma favours neuronal survival, tissue preservation, and motor recovery after the spinal cord trauma. Using the human SH-SY5Y cells overexpressing XIAP we show further that XIAP reduced caspase activity and apoptotic cell death after pro-apoptotic stimuli. In conclusion, this study shows that the levels of XIAP expression are an important factor for the outcome after spinal cord trauma and identifies XIAP as an important therapeutic target for alleviating the deleterious effects of SCI.

(1) Background: Angiotensin II, a major culprit in cardiovascular disease, activates mediators that are also involved in pathological cardiac remodelling. We aimed at investigating the effects of two of them: aldosterone (Ald) and transforming growth factor-beta-1 (TGF-β1 ), on cardiac remodelling in an in vivo model. (2) Methods: Six-week-old male wild-type (WT) and TGF-β1 -overexpressing transgenic (TGF-β1 -TG) mice were infused with subhypertensive doses of Ald for 2 weeks, and/or treated orally with eplerenone from postnatal day 21. Heart’s ventricles were examined: by morphometry, immunoblotting to assess intracellular signalling pathways, RT qPCR to determine hypertrophy and fibrosis marker genes. (3) Results: TGF-β1 -TG mice spontaneously developed cardiac hypertrophy and interstitial fibrosis, exhibited higher baseline phosphorylation of p44/42 and p38 kinases, fibronectin and ANP mRNA expression. Ald induced a comparable increase in ventricular heart weight-to-body-weight ratio and cardiomyocyte diameter in both strains, but less pronounced increase in interstitial fibrosis in transgenic compared to WT mice (23.6% vs 80.9%, p&lt;0.005). Ald increased phosphorylation of p44/42 and p38 in WT but not TGF-β1 -TG mice. While eplerenone-enriched chow partially prevented Ald-induced cardiac hypertrophy in both genotypes and interstitial fibrosis in WT controls, it completely protected from additional fibrosis in transgenic mice. (4) Conclusions: Ald appears to induce cardiac hypertrophy independently of TGF-β1 , while in case of fibrosis downstream signalling pathways of these two factors probably converge

Furfuryl alcohol (FA) is a biobased monomer derived from lignocellulosic biomass. The present work describes its polymerization in presence of protic polar solvents, i.e. water or isopropyl alcohol (IPA), using maleic anhydride (MA) as acidic initiator. The polymerization was followed from the liquid to the rubbery state by combining DSC and DMA data. In the liquid state, IPA disrupts the expected reactions during all the FA polymerization due to a stabilization of the furfuryl carbenium center. This causes the initiation of the polymerization at higher temperature, which is also reflected by higher activation energy. In water system, the MA opening allows to start the reaction at lower temperature. A higher pre-exponential factor value is obtained in that case. The DMA study of final branching reaction occurring in the rubbery state has highlighted continuous increase of elastic modulus until 290 °C. This increasing tendency of modulus was exploited to obtain activation energy dependences (Eα) of FA polymerization in the rubbery state.

Redox balance is increasingly identified as a major player in cellular signaling. A fundamentally simple reaction of oxidation and reduction of cysteine residues in cellular proteins is the central concept in this complex mode of protein function regulation. Oxidation of key cysteine residues occurs at the physiological levels of reactive oxygen species (ROS) but are reduced by a supply of thiol antioxidant molecules including glutathione, glutaredoxin and thioredoxin. While these molecules show complex compensatory roles in experimental conditions, transgenic animal models provide a comprehensive picture to pinpoint the role of each antioxidant. In this review we have specifically focused on the available literature on Thioredoxin-1 system transgenic models that includes Thioredoxin and Thioredoxin reductase proteins. As identification of Thioredoxin protein targets is technically challenging the true contribution of this system in maintaining cellular balance remains unidentified, including the role of this system in the brain.

Genetic engineering technology offers opportunities to improve many important agronomic traits in crops, including insect-resistance. However, genetically modified (GM) exogenous proteins in edible tissues of transgenic crops has become an issue of intense public concern. To advance the application of GM techniques in maize, a Cre/loxP-based strategy was developed for manipulating the transgenes in green tissues while locking it in non-green tissues. In the strategy, the site-specific excision can be used to switch on or off the expression of transgenes at specific tissues. In this work, two basic transgenic maize named KEY carrying the Cre gene and LOCK containing the Vip3A gene with a blocked element, were obtained based on their separate fusion gene cassettes. The expression level and concentration of Vip3A were observed with high specific accumulation in green tissues (leaf and stem), and only a small amount in root and kernel tissues in the KEY × LOCK hybrids. The insect-resistance of transgenic maize against two common lepidopteran pests, Ostrinia furnacalis and Spodoptera frugiperda, was assessed in the laboratory and field. The results indicated that the hybrids possessed high resistance levels against the two pests, with mortality rates above 73.6% and damage scales below 2.4 compared with the control group. Our results suggested that the Cre/loxP-mediated genetic engineering approach has a competitive advantage in GM maize. Overall, findings from this study are significant for providing a feasible strategy for transgenes avoiding expression in edible parts and exploring novel techniques toward the biosafety of GM plants.

Cempo Ireng (Oryza sativa L. var. Cempo Ireng) is one of the black rice variety in Indonesia that consumed as functional food, not as a staple food because of the black rice contains anthocyanin pigment which has beneficial to human health. High concentration of anthocyanin reaching 393.93 ppm cause black color in the pericarp layer of Cempo Ireng which make this variety as an antioxidant source, low glycemic index, and free of gluten, leading to have higher price in the rice market. However, most of the farmers are not cultivate Cempo Ireng due to the longer vegetative phase up to 150 days compared to the white rice varieties which only takes 90 days, the taller phenotype of Cempo Ireng cause problems in cultivation, and also the purple color of Cempo Ireng attract birds and earhead bug (Leptocorisa oratorius) to feed on black rice caryopsis that cause severe yield loss. Transgenic methods, mutation technique, intensification systems, and physical treatment have been applied in Cempo Ireng to overcome those lack characteristics. In the future, Cempo Ireng also has a big potential to become a parent in cross breeding program because of the positive characters. The aim of this review is to describe the potential of Cempo Ireng in rice breeding program for improving food sustainability.

The biotic and abiotic stresses are the main causes of the loss of agricultural crops productivity, their normal growth and development in the environment. It has been calculated that two-thirds of the major crops are frequently lost due to adverse environmental conditions. The productivity of crops under unfavorable environmental stresses is apparently the main challenge to the breeders and farmers where polyamines (PAs) play diverse roles in environmental stimuli. PAs (putrescine, spermidine, and spermine) are low molecular weight positively charge compounds have the active potential power to negative charge molecules (DNA, RNA, and proteins) is widely distributed in all living organisms. Evidence showed that PAs contribute a lot of different physiological and biological functions, such as cell growth and development, controlling the cell cycle, involve in gene expression, cell signaling, replication, transcription, translation, and membrane stabilization. Naturally occurring polyamines activity acuminated to their involvement with different biotic and abiotic stresses and contribute to the survival of the plant in the environment. Here, we have described the potential mechanisms, synthesis, and various roles of PAs during stresses tolerant and disease resistance.

In a recent article, Smoom et al. identified an important amino acid variation in the helicase RTEL1 of the Algerian mouse (Mus spretus). Since the latter has telomeres five times shorter than the laboratory mouse (belonging to the Mus musculus species), they introduced this variation in laboratory mice, in order to obtain an engineered strain with human-length telomeres. Succeeding in doing this, they established the “Telomouse” strain. Here I demonstrate that, in reality, Mus spretus does not show this variation: the key amino acid is conserved in all rodent species, which all have human-length telomeres (including wild Mus musculus species). This finding in no way compromises the value of the research of Smoom et al. and the utility of the Telomouse strain. Rather, it raises the question of how the telomere length of Mus musculus (as a species) should be considered and the important consequences it has on studies on inter-species comparison.

The pervasive presence of atmospheric pollution, particularly polycyclic aromatic hydrocarbons such as 7,12-dimethylbenz(a)anthracene, instigates aberrant cellular and tissue conditions, precipitating oxidative damage and inflammatory cascades conducive to the onset of cancer, notably mammary cancer. Given the hepatic metabolism of 7,12-dimethylbenz(a)anthracene, the imperative of employing natural antioxidants becomes apparent. In this study, we delve into the antioxidant and hepato-protective properties of Pistacia lentiscus against 7,12-dimethylbenz(a)anthracene-induced toxicity, alongside exploring its potential anticancer attributes. Our investigations unveil Pistacia lentiscus's anti-proliferative efficacy against human breast cancer cell lines. Notably, 7,12-dimethylbenz(a)anthracene-intoxication escalates body weight, disrupts lipid profiles, and incites serum oxidative damage. Concurrently, hepatic and renal oxidative stress ensue, accompanied by heightened antioxidant enzyme activity in the 7,12-dimethylbenz(a)anthracene-exposed-group compared to controls (p&lt;0.05). Nonetheless, Pistacia lentiscus co-administration rectifies biochemical imbalances, significantly attenuates oxidative stress aberrations, and augments antioxidant enzyme responses (p&lt;0.05). Importantly, histological analysis evinces Pistacia lentiscus's shielding effect against 7,12-dimethylbenz(a)anthracene induced hepatocyte injury and steatosis. Our findings underscore Pistacia lentiscus's robust anti-proliferative, antioxidant, and hepato-protective capacities, mitigating metabolic disturbances, oxidative stress propagation in liver and kidney functions, and potential histological alterations, thereby impeding 7,12-dimethylbenz(a)anthracene-induced mammary cancer initiation. We posit that Pistacia lentiscus may serve as a prophylactic agent against breast cancer instigated by this carcinogen.

Live fuel moisture content (LFMC) influences fire activity at landscape scale and fire behavior in laboratory experiments. However, field evidences linking LFMC to fire behavior are very limited despite numerous field experiments. In the present study, we reanalyze a shrubland fire dataset with a special focus on LFMC to explain this counterintuitive outcome. We found that this controversy might result from three reasons. First, the range of experimental LFMC data was too moist to reveal significant effect with the widespread exponential or power functions. Indeed, LFMC exhibited a strong effect below 100%, but marginal above this threshold, contrary to these functions. Second, we found that the LFMC significance was unlikely when the size of the dataset was smaller than 40. Finally, a complementary analysis suggested that 10 to 15% of random measurement error in variables could lead to an underestimation by 30 % of the LFMC effect. The effect of LFMC in field experiments is thus stronger than previously reported in the range prevailing during the actual French fire season and in accordance with observations at different scales. This highlights the need to improve our understanding of the relationship between LFMC and fire behavior to refine fire danger predictions.

Turbulent flows over and within forest canopies have recently been modeled with success using Large Eddy Simulations (LES). Validation exercises against experimental data suggest that models can be applied with a high degree of confidence for many applications, mechanical and physiological plant/atmosphere interaction analysis, seed or pollen dispersal, wildfire spread and firebrand transport, or investigation of causes of eddy-covariance technique bias. Long distances required for shear-induced turbulence to equilibrate, result in the widespread use of cyclic boundary conditions in LES atmospheric boundary layer studies. Vegetation drag dissipates air momentum in the atmosphere, but equilibrium is often achieved through compensatory momentum source, supplied by macro-scale pressure gradient forcing. Unfortunately, both classical Ekman balance or simple spatially-constant pressure gradient techniques for implementing this forcing have major drawbacks in the context of cyclic boundary conditions for the applications listed above. Among them, it is difficult to specify aspects of the mean velocity profile such as a specific desired wind velocity and direction at a reference height. In the present paper, we propose a new technique for capturing the effects of a large-scale pressure gradient force (LSPGF) that can be used at stand scale and enables simulation of realistic and specifiable wind fields. Several variants of this LSPGF are developed and analyzed here and validated against experimental data. Although this LSPGF technique is developed in the context of HIGRAD/FIRETEC wildfire simulations, LSPGF can be used for any LES wind modeling application aimed at generating detailed stand-scale wind fields with resolved turbulence and shear profiles consistent with vegetation structure in the boundary layer.

We have previously reported that 60% sucrose diet-fed ChREBP knockout mice (KO) showed body weight loss resulting in lethality. We aimed to elucidate whether sucrose and fructose metabolism are impaired in KO. Wild type mice (WT) and KO were fed a diet containing 30% sucrose with/without 0.08% miglitol, an α-glucosidase inhibitor, and these effects on phenotypes were tested. Furthermore, we compared metabolic changes of oral and peritoneal fructose injection. Thirty percent sucrose diet feeding did not affect phenotypes in KO. However, miglitol induced lethality in 30% sucrose-fed KO. Thirty percent sucrose plus miglitol diet-fed KO showed increased cecal contents, increased fecal lactate contents, increased growth of lactobacillales and Bifidobacterium and decreased growth of clostridium cluster XIVa. ChREBP gene deletion suppressed the mRNA levels of sucrose and fructose related genes. Next, oral fructose injection did not affect plasma glucose levels and liver fructose contents; however, intestinal sucrose and fructose related mRNA levels were increased only in WT. In contrast, peritoneal fructose injection increased plasma glucose levels in both mice; however, the hepatic fructose content in KO was much higher owing to decreased hepatic Khk mRNA expression. Taken together, KO showed sucrose intolerance and fructose malabsorption owing to decreased gene expression.

An improved method for Fluctuation Enhanced Sensing (FES) is introduced. We enhanced the old binary fingerprinting method, where the fingerprint bit values were ± 1, by introducing ternary fingerprints utilizing a reference odor. In the ternary method, the fingerprint bit values are -1, 0, and +1 where the 0 value stands for the situation where the slope of the spectrum is identical to that of the reference odor. The application of the reference odor spectrum makes the fingerprint relative to the reference. This feature increases the information entropy of the fingerprints. The method is briefly illustrated by sensing bacterial odor in cow manure isolates.

Significant amounts of anthropogenic radionuclides were introduced in ocean waters following nuclear atmospheric tests and development of the nuclear industry. Dispersion of artificial dissolved radionuclides has been extensively measured for decades over the European continental shelf. The radionuclide measurement and release fluxes databases provided here represent an exceptional opportunity to validate dispersion hydrodynamic models. MARS hydrodynamic model have been applied at different scales to reproduce in realistic conditions the measured dispersion. Specific methods have been developed to obtain qualitative and quantitative results and perform model/measurement comparisons. Model validation concerns short to large scales with dedicated surveys following the dispersion: it was performed within two and three dimensions framework and from minutes and hours following a release up to several years. Results are presented concerning the dispersion of radionuclides in marine systems deduced from standalone measurements, or according to model comparisons. It allows characterising dispersion over the continental shelf, pathways, transit times, budgets and source terms. This review exhibits the main features retained from the point of view of radiotracers, hydrodynamic models and model/measurement methods with perspectives of applications in other areas or oceanographic domains.

High-resolution forecasting of vegetation type shifts may prove essential for anticipating and mitigating the impacts of future climate change on bird populations. Here, we used the US Forest Service Ecological Response Unit (ERU) classification to develop and assess vegetation-based breeding habitat profiles for eight owl species occurring in foothills and mountains of the southwestern US. Shifts in mapped habitat were forecast using an ecosystem vulnerability model based on the pre-1990 climate envelopes of ERUs and the A1B moderate IPCC emission scenario of future climate. For five of the eight owl species, regional breeding habitat extent was projected to decline by at least 60% by 2090. Three species, the boreal owl (Aegolius funereus; at the trailing edge of its distribution), flammulated owl (Psiloscops flammeolus), and northern pygmy-owl (Glaucidium gnoma) were projected to experience the steepest habitat-loss rates, or 85%, 85%, and 76%, respectively. Projected vegetation shifts overlaid with well-documented flammulated owl breeding populations showed complete or near complete loss of habitat by 2090 in areas of montane forest currently supporting dense aggregations of owl territories. Generalist or lower-elevation owl species were predicted to be less impacted, while for the whiskered screech-owl (Megascops trichopsis), the contraction of current habitat was nearly offset by a projected northward expansion. In general, the results of this study suggest high exposure to climate change impacts for upper-elevation forest owls of semi-arid southwestern North America. Long distance migration and low natal philopatry may prove important to some montane owl populations for adapting to regional loss of habitat.

Important policy developments in dementia and palliative care in nursing homes between 2010 and 2015 in Flanders, Belgium might have influenced which people die in nursing homes and how they die. We aimed to examine differences between 2010 and 2015 in the prevalence and characteristics of residents with dementia in nursing homes in Flanders, and their palliative care service use and comfort in the last week of life. We used two retrospective epidemiological studies, including 198 residents in 2010 and 183 in 2015, who died with dementia in representative samples of nursing homes in Flanders. We found a 23%-point increase in dementia prevalence (P-value<0.001), with a total of 11%-point decrease in severe to very severe cognitive impairment (P=0.04). Controlling for this difference in resident characteristics, in the last week of life, there were increases in the use of pain assessment (+20%-point; P<0.001) and assistance with eating and drinking (+10%-point; P=0.02) but no change in total comfort. The higher prevalence of dementia in nursing homes with no improvement in residents’ total comfort while dying emphasize an urgent need to better support nursing homes in improving their capacities to provide timely and high-quality palliative care services to more residents dying with dementia.

Huntington’s disease (HD) is a late-onset; progressive, dominantly inherited neurological disorder marked by an abnormal expansion of polyglutamine (poly Q) repeats in Huntingtin (HTT) protein. The pathological effects of mutant Huntingtin (mHTT) are not restricted to the nervous system but systemic abnormalities including immune dysregulation have been evidenced in clinical and experimental settings of HD. Indeed, mutant huntingtin (mHTT) is ubiquitously expressed and could induce cellular toxicity by directly acting on immune cells. However, it is still unclear if selective expression ofmHTT exon1 in neurons could induce immune responses and hemocyte function. In the present study, we intended to monitor perturbations in the hemocytes population and their physiological functions in Drosophila, caused by pan-neuronal expression of mHTT protein. We found that pan-neuronal expression of mHtt significantly alters crystal cells and plasmatocyte count in larvae and adults with disease progression. Interestingly, plasmatocytes isolated from diseased conditions exhibit a gradual decline in phagocytic activity ex vivo at progressive stages of the disease as compared to age-matched control groups. We also observed an increased production of reactive oxygen species (ROS) in plasmatocytes at advanced stages of the disease. In addition, diseased flies displayed elevated reactive oxygen species (ROS) in circulating plasmatocytes at the larval stage and in sessile plasmatocytes of hematopoietic pockets at of disease. All the parameters were monitored progressively, targeting the circulation at larvae stage and hematopoietic pockets in adults at different disease stages, and many alterations were documented in the early stage itself. These findings strongly implicate that neuronal expression of mHtt alone is sufficient to induce non-cell-autonomous immune dysregulation in vivo. Based on these findings, we propose that further insight into the mechanisms through which neuronal expression of mHtt might be inflicting the innate immune responses would facilitate therapeutic inventions aimed at amelioration of HD pathology and improving the quality of life of the patients.

This study investigates whether a chronotherapeutic treatment of hepatocellular carcinoma (HCC) may improve treatment efficacy and mitigate side effects on healthy liver (HL). HCC was induced in Per2::luc mice which were irradiated at four time points of the day. Proliferation and DNA-double strand breaks were investigated in irradiated and non-irradiated organotypic slice culture (OSC) and ex vivo samples by detection of Ki67 and γ-H2AX. OSC proved useful to determine dose-dependent effects on proliferation and DNA damage but appeared unsuited to test the chronotherapeutic approach. Irradiation of ex vivo samples was most effective at the proliferation peaks in HCC at ZT02 (early inactivity phase) and ZT20 (late activity phase). Irradiation effects on HL were minimal at ZT20. Ex vivo samples revealed disruption in daily variation and down-regulation of all investigated clock genes except Per1 in non-irradiated HCC as compared with HL. Irradiation affected rhythmic clock gene expression in HL and HCC at all ZTs except at ZT20. Irradiation at ZT20 had no effect on total leukocyte numbers. Our results indicate ZT20 as the optimal time point for irradiation of HCC in mice. Translational studies are now needed to evaluate whether the late activity phase is the optimal time point for irradiation of HCC in man.

Yerba maté, an herbal tea derived from Ilex paraguariensis, has previously been reported to be protective against obesity-related and other cardiometabolic disorders. Using high-resolution respirometry and reverse-phase high-performance liquid chromatography, the effects of four weeks of yerba maté consumption on mitochondrial efficiency and cellular redox status in skeletal muscle, adipose, and liver, tissues highly relevant to whole body metabolism, were explored in healthy adult mice. Yerba maté treatment increased mitochondrial oxygen consumption in adipose, but not in other tissues examined. Yerba maté increased ATP concentration in skeletal muscle and decreased ATP concentration in adipose. Combined with observed changes in oxygen consumption, these data yielded a significantly higher ATP:O2, a measure of mitochondrial efficiency, in muscle and a significantly lower ATP:O2 in adipose, which were consistent with yerba maté-induced weight loss. Yerba maté treatment also altered the hepatic glutathione (GSH)/glutathione disulfide (GSSG) redox potential to a more reduced redox state, suggesting potential protective effects against oxidative stress and preservation of cellular function. Together, these data indicate beneficial, tissue-specific effects of yerba maté supplementation on mitochondrial bioenergetics and redox states in healthy mice that are protective against obesity.

Background and Objective: In an experiment designed to explore the mechanisms of fludrocortisone-induced high blood pressure, we serendipitously observed aortic aneurysms in mice infused with fludrocortisone. The purpose of this study was to investigate whether fludrocortisone induces aortic pathologies in both normocholesterolemic and hypercholesterolemic mice. Methods and Results: Male adult C57BL/6J mice were infused with either vehicle (85% polyethylene glycol 400 (PEG-400) and 15% dimethyl sulfoxide (DMSO); N=5) or fludrocortisone (12 mg/kg/day dissolved in 85% PEG-400 and 15% DMSO; N=15) for 28 days. Fludrocortisone-infused mice had higher systolic blood pressure, compared to mice infused with vehicle. Fludrocortisone induced aortic pathologies in 4 of 15 mice with 3 having pathologies in the ascending and aortic arch regions and 1 having pathology in both the ascending and descending thoracic aorta. No pathologies were noted in abdominal aortas. Subsequently, we infused either vehicle (N=5/group) or fludrocortisone (N=15/group) into male ApoE -/- mice fed a normal laboratory diet or LDL receptor -/- mice fed either normal or Western diet. Fludrocortisone increased systolic blood pressure, irrespective of mouse strain or diet. In ApoE -/- mice infused with fludrocortisone, 2 of 15 mice had ascending aortic pathologies, but no mice had abdominal aortic pathologies. In LDL receptor -/- mice fed normal diet, 5 had ascending/arch pathologies, 1 had pathologies in the ascending, arch, and suprarenal aortic regions. In LDL receptor -/- mice fed Western diet, 2 died of aortic rupture in either the descending thoracic or abdominal region, and 2 of the 13 survived mice had ascending/arch aortic pathologies. Aortic pathologies included hemorrhage, wall thickening or thinning, or dilation. Given the low incidence, only ascending aortic diameter in LDLR -/- mice fed Western diet reached statistical significance, compared to their vehicle. Conclusion: Fludrocortisone induces aortic pathologies independent of hypercholesterolemia. The findings in mouse studies have the potential to provide caution to people who are taking or have taken fludrocortisone that could have an increased risk of aortic pathologies.

This study aimed to characterize the long non-coding RNA (lncRNA) expression in the bovine mammary gland and to infer their functions in dietary response to 5% linseed oil (LSO) or 5% safflower oil (SFO). Twelve cows (six per treatment) in mid lactation were fed a control diet for 28 days followed by a treatment period (control diet supplemented with 5% LSO or 5% SFO) of 28 days. Mammary gland biopsies were collected from each animal on day-14 (D-14, control period), D+7 (early treatment period) and D+28 (late treatment period) and were subjected to RNA-Sequencing and subsequent bioinformatics analyses. Functional enrichment of lncRNA was performed via potential cis regulated target genes located within 50 Kb flanking regions of lncRNAs and having expression correlation of >0.7 with mRNAs. A total of 4955 lncRNAs (325 known and 4630 novel) were identified which potentially cis targeted 59 and 494 genes in LSO and SFO treatments, respectively. Enrichments of cis target genes of lncRNAs indicated potential roles of lncRNAs in immune function, nucleic acid metabolism and cell membrane organization processes as well as involvement in Notch, cAMP and TGF-β signaling pathways. Thirty-two and 21 lncRNAs were differentially expressed (DE) in LSO and SFO treatments, respectively. Six genes (KCNF1, STARD13, BCL6, NXPE2, HHIPL2 and MMD) were identified as potential cis target genes of six DE lncRNAs. In conclusion, this study indicated potential roles for lncRNAs in mammary gland immune functions and development and provided potential candidate genes and pathways via which lncRNAs can function in diet responses.

DEXTER (Detection of EXplosives and firearms to counter TERrorism) is a project funded by NATO’s Science for Peace and Security (SPS) program with the goal of developing an integrated system capable of remotely and accurately detecting explosives and firearms in public places without impeding the flow of pedestrians. The active microwave component of the DEXTER project is referred to as MIC (Microwave Imaging Curtain), supported by the French SGDSN (General Secretariat of Defense and National Security), and utilizes a radar system capable of generating 3D images in real time to address non-checkpoint detection of explosives and fire-arms. The project, led by the ONERA (France), is based on a radar imaging system developed by the Fraunhofer FHR institute, using a MIMO architecture with an Ultra Wide-Band waveform. Although high-resolution 3D microwave imaging is already being used in expensive body scanners to detect firearms concealed under clothing, MIC's innovative approach lies in utilizing a high-resolution 3D imaging device that can detect larger dangerous objects carried by moving individuals at a longer range, in addition to providing discrete detection in pedestrian flow. Automatic detection and classification of these dangerous objects is carried out on 3D radar im-ages using a deep-learning network. This paper will outline the project's objectives and constraints, as well as the design, architecture, and performance of the final system. Additionally, it will present real-time imaging results ob-tained during a live demonstration in a relevant environment.

In soil erosion estimation models, the variable with the greatest impact is rainfall erosivity (RE), which is the measurement of precipitation energy and its potential capacity to cause erosion, and erosivity density (ED), which relates RE to precipitation. The RE requires high temporal resolution records for its estimation. However, due to the limited observed information and the increasing availability of rainfall estimates based on remote sensing, recent research has shown the usefulness of using observed-corrected satellite data for RE estimation. This study evaluates the performance of a new gridded dataset of RE and ED in Peru (PISCO_reed) by merging data from the IMERG v06 product, through a new calibration approach with hourly records of automatic weather stations, during the period of 2000-2020. By using this method, a correlation of 0.7 was found between the PISCO\_reed and RE obtained by the observed data. An average annual RE for Peru of 4831 MJ·mm·ha-1·h-1 was estimated with a general increase towards the lowland Amazon regions and high values are found on the north-coast Pacific area of Peru. The spatial identification of the most risk areas of erosion, was carried out through a relationship between the ED and rainfall. Both erosivity data sets will allow us to expand our fundamental understanding and quantify soil erosion with greater precision.

: The interaction of the Activating Transcription Factor 6 (ATF6), a key effector of the unfolded protein response (UPR) in the endoplasmic reticulum, with the neuronal calcium sensor Downstream Regulatory Element Antagonist Modulator (DREAM) is a potential therapeutic target in neurodegeneration. Modulation of the interaction ATF6-DREAM with repaglinide (RP) induced neuroprotection in a model of Huntington´s disease. Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder with no cure, characterized by the progressive loss of motoneurons resulting in muscle denervation, atrophy, paralysis and death. The aim of this work was to investigate the potential therapeutic significance of DREAM as a target for intervention in ALS. We found that the expression of the DREAM protein was reduced in the spinal cord of SOD1G93A mice compared to wild type littermates. RP treatment improved motor strength and reduced the expression of the ALS progression marker collagen type XIX1 (Col191 mRNA) in the quadriceps muscle in SOD1G93A mice. Moreover, treated SOD1G93A mice showed reduced motoneuron loss and glial activation and increased ATF6 processing in the spinal cord. These results indicate that the modulation of the DREAM-ATF6 interaction ameliorates ALS symptoms in SOD1G93A mice.

Excess consumption of a high-fat diet has been identified as one of the contributing factors for obesity. Women are at higher risk for adult obesity than men, predisposing them to a different set of detrimental disease conditions. Furthermore, aging studies show that physiological decline also has a serious impact on changes in the endocrine properties of white adipose tissue. Howev-er, there is still relatively little known about the factors associated with obesity and aging and their compounding impact on women’s health. To investigate adipocytokine secretion profile changes, female C3H/HeJ mice were induced to obesity through long-term consumption of a high-fat diet. Weight gain measurements and Echo MRI analysis of fat composition showed in-creases were a due solely to the high fat content in the diet. Adipocytokine secretions were ana-lyzed in media conditioned from harvested visceral fat tissue that was organ cultured ex-vivo. Adipocytokine analysis across diets and age showed significant increases in Adiponectin and Leptin secretion in high-fat diets, accelerated increases in Resistin secretion with high-fat diets. Aging induced increased secretion of Lipcalin-2, Pentraxin-3 and Serpin E1, MCP-1 and ICAM-1, regardless of diet. Furthermore, comparisons of organoid cultured protein secretions and flash-frozen tissue samples differed greatly, suggesting the WAT organoid cultures may yield information more reflective of in situ conditions. Taken together, our results show that diet and aging significantly impact secretions from adipose tissue, that may contribute to women’s health issues.

SRC homology 3 (SH3) domains are critical interaction modules that orchestrate the assembly of protein complexes involved in diverse biological processes. They facilitate transient protein-protein interactions by selectively interacting with proline-rich motifs (PRMs). A database search revealed 298 SH3 domains in 221 human proteins. Multiple sequence alignment of human SH3 domains is useful for phylogenetic analysis and determination of their selectivity towards PRM-containing peptides (PRPs). However, a more precise functional classification of SH3 domains is achieved by constructing a phylogenetic tree only from PRM-binding residues and using existing SH3-PRP structures and biochemical data to determine the specificity within each of the 10 families for particular PRPs. In addition, the C-terminal proline-rich domain of the RAS activator SOS1 covers 13 of the 14 recognized proline-rich consensus sequence motifs, encompassing differential PRP pattern selectivity among all SH3 families. To evaluate binding capabilities and affinities, we conducted fluorescence dot blot and polarization experiments using 25 representative SH3 domains and various PRPs derived from SOS1. Our analysis has identified 45 interacting pairs with binding affinities ranging from 0.2 to 125 micromolar out of 300 tested and potential new interactors of SOS1. Furthermore, it establishes a framework to bridge the gap between SH3 and PRP interactions and provides predictive insights into potential interactions of SH3 domains with PRMs based on sequence specifications. This novel framework has the potential to enhance the understanding of protein networks mediated by SH3-PRM interactions and be utilized as a general approach for other domain-peptide interactions.

Iron (Fe) is a trace element that plays essential roles in various biological processes such as DNA synthesis and repair, as well as cellular energy production, or oxygen transport, and it is currently widely recognized that iron homeostasis is dysregulated in many cancers. Indeed, several iron homeostasis proteins may be responsible for malignant tumor initiation, proliferation, and for metastatic spread of tumors. A large number of studies demonstrated the potential clinical value of turning these deregulated proteins as prognostic and/or predictive biomarkers of malignancy and /or response to anticancer treatments. Additionally, the iron addiction of cancer cells and the importance of iron in ferroptosis cell death signaling pathways prompted the development of therapeutic strategies against advanced stage or resistant cancers. In this review, we selected relevant and promising studies in the field of iron metabolism in cancer research and clinical oncology. Besides, we discuss some co-existing discrepant findings. We will also present and discuss the latest lines of research related to targeting iron, or its regulatory pathways, as potential promising anti-cancer strategies for human therapy. Iron chelators, such as deferoxamine or iron-oxide based nanoparticles, which are already tested in clinical trials, alone or in combination with chemotherapy will also be reported.

A form of dementia distinct from healthy cognitive aging, Alzheimer's disease (AD) is a complex multi-stage disease that currently afflicts over 50 million people worldwide. Unfortunately, previous therapeutic strategies developed from murine models emulating different aspects of AD pathogenesis have failed. Consequently, researchers are now developing models that express several aspects of pathogenesis that better reflect the clinical situation in humans. As such, this review seeks to provide insight regarding current applications of mammalian models in AD research by addressing recent developments and characterizations of prominent transgenic models and their contributions to pathogenesis as well as discuss the advantages, limitations, and application of emerging models (hAβ-KI) that better capture genetic heterogeneity and mixed pathologies observed in the clinical situation.

Contrary to popular belief, we have known for many years that the endometrium is not a sterile environment and is considered to be a low-biomass milieu compared to the vagina. Numerous trials and studies have attempted to establish a valid sampling method and assess its physiological composition, but no consensus has been reached. Many factors such as ethnicity, age and inflammation, can influence the microbiome. Moreover, it possesses a higher alpha-diversity and therefore contains more diverse bacteria than the vagina. For instance, Lactobacillus has been shown to be a predominant genus in the vaginal microbiome of healthy women. Consequently, even if a majority of scientists postulate that a predominance of Lactobacillus inside the uterus improves reproductive outcomes, vaginal contamination by these bacteria during sampling cannot be ruled out. Certain pathologies, such as chronic endometritis, have been identified as inflammation perpetrators that hinder the embryo implantation process. This pro-inflammatory climate created by dysbiosis of the endometrial microbiota could induce secondary inflammatory mediators via Toll-like receptors, creating an environment conducive to the development of endometriosis and even promoting carcinogenesis. However, studies to this day have focused on small populations. In addition, there is no clearly defined healthy uterine composition yet. At most, only a few taxa have been identified as pathogenic. As sampling and analysis methods become increasingly precise, we can expect the endometrial microbiota to be incorporated into future diagnostic tools and treatments for women’s health.

In regions with limited precipitation information like Peru, many studies rely on precipitation data derived from satellite products (SPPs) and reanalysis products. These products provide near-real-time information and offer global spatial coverage, making them attractive for various applications. However, it is essential to consider their uncertainties when conducting hydrological simulations, especially in a key region like the Pacific drainage (Pd), where 56% of Peruvian population resides (including the capital Lima). This study evaluates the performance of three precipitation products: Reanalysis, ERA5-Land (top down approach), and two SPPs: GPM+SM2RAIN and SM2RAIN-ASCAT (bottom-up approaches). Hydrological modeling was conducted on 30 basins distributed across the Pd, which were grouped into five regions (I-V, ordered from south to north). The results showed that SM2RAIN-ASCAT performed well in regions I-III-IV, ERA5-Land in region II, and GPM+SM2RAIN in region V. The hydrological model GR4J was tested, and better efficiency criteria were obtained with SM2RAIN-ASCAT and GPM+SM2RAIN when comparing simulated versus observed streamflows. The hydrological modeling with SM2RAIN-ASCAT and GPM+SM2RAIN demonstrated satisfactory efficiency metrics (KGE > 0.75; NSE > 0.65). Additionally, ten hydrological signatures were quantified to assess the variability of simulated streamflows in each basin, with metrics such as Mean Flow (Q mean), 5th Quantile Flow (Q5), and 95th Quantile Flow (Q95) showing overall better performance. Finally, the results of this study demonstrate the reliability of using bottom-up satellite products in Pd basins.

Cysteine-glutathione mixed disulfide (CySSG), a prodrug of glutathione (GSH) --the “Master Antioxidant”, was found to be orally bioavailable in mice, and protected against a toxic dose of acetaminophen. If oral bioavailability can also be demonstrated in humans, this suggests a wide range of applicability for CySSG.

Rats, including those of the Sprague Dawley strain, may kill mice. Because of this muridical behavior, it is standard practice in many research animal housing facilities to separate mice from rats (i.e., the predators) to minimize stress for the mice. We therefore tested the effect of cohousing on the stress levels of mice from either the C57BL/6J (BL6) or the CD1 strain and Sprague Dawley (SD rat) by determining their fecal corticosterone or cortisol metabolites (FCM) concentration and investigated how cohousing impacts a behavioral assay, i.e., conditioned place preference for intragenus (i.e., mouse-mouse or rat-rat) dyadic social interaction (DSI CPP) that had been shown be sensitive to social factors, especially to handling by humans. We found that the two delivery batches of BL6 mice or SD rats, respectively, had different stress levels at delivery that were statistically significant for the BL6 mice. Even so, the BL6 mice cohoused with rats had significantly increased FCM concentrations, indicative of higher stress levels, as compared to (1) BL6 mice housed alone or (2) BL6 mice at delivery. In contrast to their elevated stress levels, the attractiveness for contextual cues associated with mouse-mouse social interaction (DSI CPP) even increased in rat-cohoused BL6 mice, albeit nonsignificantly. Thus, cohousing BL6 mice and rats did not impair a behavioral assay in BL6 mice that had proved to be sensitive to handling stress by humans in our laboratory. SD rats cohoused with BL6- or CD1 mice and CD1 mice cohoused with SD rats showed DSI CPP that was not different from our previously published data on SD rats and BL6 mice of the Jackson- or NIH substrain obtained in the absence of cohousing. Our findings suggest that the effect of cohousing rats and mice under the conditions described above on their stress levels as opposed to their behavior might be less clearcut than generally assumed and might be overriden by conditions that cannot be controlled, i.e., different deliveries. Our findings can help to use research animal housing resources, which usually are limited, more efficiently.

MicroRNAs (miRNAs) are small endogenous RNAs that regulate gene expression post-transcriptionally by targeting either the 3′ untranslated or coding regions of genes. They have been reported to play key roles in a wide range of biological processes. The recent remarkable developments of transcriptomics technologies, especially next-generation sequencing technologies and advanced bioinformatics tools, allow more in-depth exploration of messenger RNAs (mRNAs) and non-coding RNAs (ncRNAs) including miRNAs. These technologies have offered great opportunities for a deeper exploration of miRNA involvement in farm animal diseases, as well as livestock productivity and welfare. In this review, we provide an overview of the current knowledge of miRNA roles in farm animal diseases with a particular focus on diseases of economic importance. In addition, we discuss the steps and future perspectives of using miRNAs as biomarkers and molecular therapy for livestock disease management as well as the challenges and opportunities for understanding the regulatory mechanisms of miRNAs related to disease pathogenesis.

Pituitary adenylate cyclase-activating polypeptide receptor 1 (PAC1-R) has a higher affinity for pituitary adenylate cyclase- activating polypeptide (PACAP) than for vasoactive intestinal peptide (VIP). PACAP exerts its neuroprotective effects through PAC1-R. PAC1-R has become a target for drug development, and we targeted PAC1-R to screen small positive allosteric modulator 1 (SPAM1). SPAM1 has a neuroprotective effects, and in the D-galactose (D-gal) mouse model, SPAM1 improved the structure of the hippocampal dentate gyrus and restored the number of neurons. Compared with D-gal model mice, SPAM1 treatment upregulated the expression of Sirtuin 6 (SIRT6) and Lamin B1, and downregulated the expression of YinYang 1 (YY1) and p16. Consistent with this, the same results were obtained in senescent RGC-5 cells. Meanwhile, SPAM1 was also found to up-regulate SIRT6 and down-regulate YY1 expression in normal RGC-5 cells. Then, we further explored the mechanism of SPAM1 neuroprotection by whole transcriptome sequencing and proteomic analysis, and found that SPAM is involved in the longevity regulating pathway, and confirmed the up-regulation of neurofilament light polypeptide and neurofilament medium polypeptide by western blot, thus laying a pharmacological foundation for SPAM1 as a therapeutic agent for neurodegenerative diseases. polypeptide and neurofilament medium polypeptide. Thus, it lays a pharmacological foundation for SPAM1 as a therapeutic drug for neurodegenerative diseases.

Increased sugar intake is implicated in Type-2 diabetes and fatty liver disease. Mechanisms by which glucose and fructose components promote these conditions are unclear. We hypothesize that alterations in intestinal metabolite and microbiota profiles specific to each monosaccharide are involved. Two groups of six adult C57BL/6 mice were fed for 10-weeks with a diet where either glucose or fructose was the sole carbohydrate component (G and F, respectively). A third group was fed with normal chow (N). Fecal metabolites were profiled every 2-weeks by ¹H NMR and microbial composition was analysed by real-time PCR (qPCR). Glucose tolerance was also periodically assessed. N, G and F mice had similar weight gains and glucose tolerance. Multivariate analysis of NMR profiles indicated that F mice were separated from both N and G, with decreased butyrate and glutamate and increased fructose, succinate, taurine, tyrosine and xylose. Compared to N and G, F mice showed a shift in microbe populations from gram-positive Lactobacillus spp. to gram-negative Enterobacteria species. Substitution of normal chow carbohydrate mixture by either pure glucose or fructose for 10 weeks did not alter adiposity or glucose tolerance. However, F G and N mice generated distinctive fecal metabolite signatures with incomplete fructose absorption as a dominant feature of F mice.

Global agriculture has been forced to increase food production to feed the growing human population, while confronting various environmental obstacles such as global warming, resistance to pathogens, and constraints on arable land caused by soil salinity, drought, rising sea level, saltwater intrusion, and urbanization. Regarding abiotic stresses, salinity is a worldwide problem for agricultural production. Many efforts, therefore, have been made to cope with the environmental challenges, however, the progress of salinization, which is mainly caused and accelerated by anthropogenic activities, is likely faster than our progress in finding ways to deal with this problem. In addition, drought represents a global threat to the production of major crops. In addition, pests and pathogens cause significant crop losses and diminish global food security. Among the various strategies that have been investigated and applied in plant science, antimicrobial peptides derived from plants have caught widespread attention from scientists since these peptides exhibit beneficial biological activities. In agricultural science, there have been reports on the roles of antimicrobial peptides with active properties against biotic and abiotic stresses. Non-specific plant lipid transfer proteins, thionins, systemins, defensins, cyclotides, and heveins-like antimicrobial peptides are common antimicrobial peptides that have been found to be involved in the defense system against fungi and insect pests. Based on their potential ability to protect crops from pests, bacteria, and pathogenic fungi, the use of antimicrobial peptide genes in creating transgenic plants has been largely conducted during the last decades, and these studies have obtained positive results against the growth of fungi and bacteria. This review will focus on the latest progress in studies of antimicrobial peptides related to biotic and abiotic stress tolerance in plants. We will also update the current progress in the development of antimicrobial peptide-based transgenic crops.

The term neuroinflammation defines the reactions of astrocytes and microglia to alterations in homeostasis in the diseased central nervous system (CNS), the exacerbation of which contributes to the neurodegenerative effects of Alzheimer's disease (AD). Local environmental conditions, such as the presence of proinflammatory molecules, mechanical properties of the extracellular matrix (ECM) and local cell-cell interactions, are determinants of glial cell phenotypes. In AD, the load of the cytotoxic/proinflammatory amyloid β peptide (Aβ) is a microenvironmental component increasingly growing in the CNS, imposing time-evolving challenges on resident cells. This study aimed at investigating the temporal and spatial variations of the effects produced by this process on astrocytes and microglia, either directly or by interfering in their interactions. Ex vivo confocal analyses of hippocampal sections from the mouse model TgCRND8 at different ages have shown that overproduction of Aβ peptide induced early and time persistent disassembly of functional astroglia syncytium and promoted a senile phenotype of reactive microglia, hindering Aβ clearance. In the late stages of disease, these patterns were altered in the presence of Aβ-plaques, surrounded by typically reactive astrocytes and microglia. Morphofunctional characterization of peri-plaque gliosis revealed a direct contribution of astrocytes in plaque buildup that might result in shielding Aβ-peptide cytotoxicity and, as a side effect, in exacerbating neuroinflammation.

Norepinephrine plays an important role in modulating memory consolidation and evocation through its beta-adrenergic receptors (Adrβ: β1, β2 and β3), which are expressed in the hippocampus (HC) and amygdala (AMY). Here we hypothesized that multisensory stimulation would reverse the memory impairment caused by the inactivation of the Adrβ3 with consequent inhibition of sustained glial-mediated inflammation and glutamatergic depuration. To test this, 21- and 86-day-old Adrβ3KO mice and respective controls underwent to (i) gustative and olfactive stimuli of positive and negative valence associated with (ii) intellectual challenges to reach the food in addition to (iii) objects in hidden places (iv) foraging for 8 weeks followed by (v) analysis of GFAP, Iba-1 and EAAT2 protein expression in the HC and AMY. While this protocol restored the memory impairment when applied to Adrβ3KO animals immediately after weaning, it had no effect when applied to adult animals. In fact, we observed that aging worsens the memory of Adrβ3KO mice. Although no significant expression of GFAP and Iba1 were observed in HC of young and old mice, Adrβ3KO increased EAAT2 expression HC of old mice, while MS didn’t change EAAT2 in young mice but enhanced it expression in older. Relative to AMY of old mice Adrβ3KO increased GFAP expression compared whit WT mice and MS sustained the GFAP expression and increased the EAAT2 expression compared with WT group. These results suggest that a richer and more diverse environment helps to correct memory impairment when applied right after weaning Adrβ3KO animals, also show that the changes in GFAP, Iba1 and EAAT2 expression levels in young and old mice indicate a functional significance in the process of learning and memory and that the control of neuroinflammation in limbic areas mediates this response. They also reinforce the idea that disruption of noradrenergic signaling could be involved in the cognitive impairment observed later in life.

The search for more efficacy and fewer toxic effects in cancer treatments is the main objective of research into new therapies. Vincristine (VCR) is a chemotherapeutic used in different types of tumors. Epigallocatechin gallate (EGCG) is a green tea metabolite that has shown an antineoplastic effect in different investigations, so the objective of this work was to evaluate the antitumor effect of the EGCG/VCR combination on tumor volume and survival. To achieve this objective, the solid model of lymphoma L5178Y was used in BALB/c mice with different doses of VCR, EGCG and their combination; Tumor grow and survival time were recorded. Once the tumors were obtained, they were measured and immunohistochemistry was performed for p53, Bcl2 and CD1. The results showed that the EGCG/vincristine combination had a greater antitumor effect that vincristine and EGCG. This can be partly attributed to the fact that the greatest Bcl2 inhibition was present in the combination of EGCG with vincristine. Therefore, it can be concluded that the combination of EGCG with vincristine has a better antineoplastic effect by inhibiting tumor development and increasing survival than both substances independently.

The mouse visual system recently became the most popular model to study the cellular and circuit mechanisms of sensory processing. However, the importance of eye movements in mice only started to be appreciated recently. Eye movements provide a basis for active sensing and deliver insights into various brain functions and dysfunctions. A plethora of knowledge on the central control of eye movements and their role in perception and behaviour arose from work on primates. However, an overview of the known eye movement types in mice and a comparison to primates is missing.Here, we review the eye movement types described to date in mice and compare them to those observed in primates. We discuss the central neuronal mechanisms for their generation and control. Furthermore, we review the mounting literature on eye movements in mice during head-fixed and freely moving behaviours. Finally, we highlight gaps in our understanding and suggest future directions for research.

Background Epidemiological studies have associated plasma galectin-4 (Gal-4) levels with prevalent and incident diabetes, and with increased risk of coronary artery disease, but data regarding possible associations with stroke are lacking. Methods We tested Gal-4 association with prevalent stroke in a population-based cohort, and whether Gal-4 increases after ischemic stroke in mice fed a high-fat diet (HFD). Results Gal-4 was higher in subjects with compared to without prevalent ischemic stroke, and was associated with prevalent ischemic stroke (odds ratio 1.52; 95% confidence interval 1.01-2.30; p=0.048) adjusted for age, sex and covariates of cardiometabolic health. Plasma Gal-4 increased after stroke in both controls and HFD-fed mice, but HFD exposure was devoid of impact in Gal-4 levels. Conclusions This study demonstrates higher plasma Gal-4 levels in both a stroke mouse model and individuals with prevalent stroke.

B lymphocyte development has two DNA recombination processes: V(D)J recombination of the immunoglobulin (Igh) gene variable region and class switching of the Igh constant regions from IgM to IgG, IgA, or IgE. V(D)J recombination is required for successful maturation of B cells from pro-B to pre-B to immature-B and then to mature B cells in the bone marrow. CSR occurs outside of the bone marrow when mature B cells migrate to peripheral lymphoid organs, such as spleen and lymph nodes. Both V(D)J recombination and CSR depend on an “open chromatin” state that makes DNA accessible to specific enzymes, recombination activating gene (RAG), and activation-induced cytidine deaminase (AID). Acetyltransferases GCN5 and PCAF possess redundant functions acetylating histone H3 lysine 9 (H3K9). Here, we generated a mouse model that lacks both GCN5 and PCAF in B cells. We found that double-deficient mice possess low levels of mature B cells in the bone marrow and peripheral organs, an accumulation of pro-B cells in bone marrow, and reduced CSR levels. We conclude that both GCN5 and PCAF are required for B cell development in vivo.

An increasingly frail population in nursing homes accentuates the need for high quality care at the end of life and better access to palliative care in this context. Implementation of palliative care and its outcomes can be monitored by using quality indicators. Therefore, we developed a quality indicator set for palliative care in nursing homes and a tailored measurement procedure using a mixed-methods design. We developed the instrument in three phases: 1) literature search, 2) interviews with experts and 3) indicator and measurement selection by expert consensus (RAND/UCLA). Second, we pilot tested and evaluated the instrument in nine nursing homes in Flanders, Belgium. After identifying 26 indicators in the literature and expert interviews, 19 of them were selected through expert consensus. Setting-specific themes were advance care planning, autonomy and communication with family. The quantitative and qualitative analyses showed the indicators were measurable, had good preliminary face validity and discriminative power and were considered useful in terms of quality monitoring according to the caregivers. The quality indicators can be used in a large implementation study and process evaluation in order to achieve continuous monitoring of the access to palliative care for all residents in nursing homes.

The evolution of knowledge in biological and medical areas which made possible scientific and technological advances are attributed to anatomical studies, physiology and immunology in animals, contributing to the discovery of prophylactic measures and treatments of diseases that affect humans and animals. Currently, substitution is suggested by alternative methods that do not use laboratory animals, however in vitro methods may never be able to provide similar results to in vivo methods. Mice and rats are the most used animals in experimental researches, the anatomical, histological and genetic differences between species should be carefully evaluated, to better apply the study model and avoid unnecessary waste avoid. This study, aimed at an anatomical comparative and histological relationship between a rat´s and a mouse´s organs, is of great importance in experimental studies. For such, 30 Mus musculus (Swiss) mice and 15 Rattus norvegicus (Wistar) male and heterogenic rats, were used. All animals were kept free of pathogenic microorganisms, with the absence of surgical interventions that could cause anatomical and physiological changes. It was possible to observe significant anatomical and histological differences between spleens, brains, hearts, stomachs and intestines, livers, eyes, lungs and kidneys among species, which will serve as a basis to assist in choosing the most satisfactory research model. Few studies relate specific characteristics among laboratory animals, being restricted to a few veterinary and zoology books. The greater the organic, physiological and anatomical similarities are with the human being, the greater is the applicability of the animals in studies. However, it is not possible to lay down general rules to validate the extrapolation from one species to another.

Osteoporosis is an abnormal bone remodeling condition characterized by decreased bone density, which leads to high risks of broken bones. Previous studies have demonstrated that Lycii Radicis Cortex (LRC) extract inhibits bone loss in ovariectomized (OVX) mice by enhancing the osteoblast differentiation. A bioactive compound, Kukoamine B (KB), was identified from a fractionation of LRC extract as a candidate component responsible for an anti-osteoporotic effect. This study investigated the anti-osteoporotic effects of KB using in vitro and in vivo osteoporosis models. KB treatment significantly increased the osteoblastic differentiation and mineralized nodule formation of osteoblastic MC3T3-E1 cells, while it significantly decreased the osteoclast differentiation of primary-cultured monocytes derived from mouse bone marrow. The effects of KB on osteoblastic and osteoclastic differentiations under more physiological conditions were also examined. In the co-culture of MC3T3-E1 cells and monocytes, KB promoted osteoblast differentiation but did not affect osteoclast differentiation. For the in vivo experiments, KB significantly inhibited OVX-induced bone mineral density loss and restored the impaired bone structural properties in osteoporosis model mice. These results suggest that KB may be a potential therapeutic candidate for the treatment of osteoporosis.

Brassica yellows virus (BrYV) is a tentative species of the genus Polerovirus, which occurs widely and mostly damage Brassicaceae plants in East Asia. Since BrYV could not be transmitted mechanically, an insect transmission method is required for further virus research. Here, a reliable and unrestricted method was described, in which non-viruliferous aphids (Myzus persicae) acquired BrYV from transgenic Arabidopsis thaliana plants with virus full length genome germinated from seeds and frozen infected leaves were used to transmit the virus to healthy plants, and there was no significant difference in acquisition rate though transmission rate from frozen infected leaves was somehow lower compared to fresh infected leaves. This novel simple method could be applied to preservation of virus inocula, evaluation of variety resistance to BrYV, biological research on interaction among BrYV, aphid and host, which also provide a new idea on establishing a basic method using virus genomic transgenic plants or frozen infected leaves for other poleroviruses research.

In this work antiparasitic peptidomimetics inhibitors (PEP) of falcipain-3 (FP3) of Plasmodium falciparum (Pf) have been proposed using structure-based and computer-aided molecular design. Beginning with the crystal structure of PfFP3-K11017 complex (PDB ID: 3BWK), three-dimensional (3D) models of FP3-PEPx complexes with known activities (IC50exp) were prepared by in situ modification, based on molecular mechanics and implicit solvation to compute Gibbs free energies (GFE) of inhibitor-FP3 complex formation. This resulted in a quantitative structure-activity relationships (QSAR) model based on a linear correlation between computed GFE (ΔΔGcomp) and the experimentally measured IC50exp: (pIC50exp=-(IC50exp/109) =-0.4517×∆∆Gcomp+4.0865 ; R2 = 0.89). Apart from the structure-based relationship, a ligand-based quantitative pharmacophore model (PH4) of novel PEP analogs where substitutions were directed by comparative analysis of the active site interactions was derived using the proposed bound conformations of the PEPx. This provided structural information useful for the design of virtual combinatorial libraries (VL), which was virtually screened based on the 3D-QSAR PH4. The end results were predictory inhibitory activities falling within the low nanomolar concentration range.

Previous evidence links the formation of extranuclear inclusions of transcription factors, such as ERK, Jun, TDP-43, and REST with oxidative, endoplasmic-reticulum, proteasomal, and osmotic stress. To further characterize its extranuclear location, we performed a high-content screening based on confocal microscopy and automatized image analyses of an epithelial cell culture treated with hydrogen peroxide, thapsigargin, epoxomicin, or sorbitol at different concentrations and times to recreate the stresses mentioned above. We also performed subcellular fractionation of the brain from transgenic mice overexpressing the Q331K mutated TARDBP, and we analyzed REST-regulated mRNAs. The results show that these nuclear proteins exhibit a mitochondrial location, together with significant nuclear/extranuclear ratio changes, in a protein and stress-specific manner. The presence of these proteins in enriched mitochondrial fractions in vivo confirmed the results of image analyses. TDP-43 aggregation was associated with alteration in mRNA levels of REST target genes involved in calcium homeostasis, apoptosis, and metabolism. In conclusion, cell stress increased mitochondrial translocation of nuclear proteins, increasing the chance of proteostasis alterations. Further, TDP-43 aggregation impacts REST target genes, disclosing an exciting interaction between these two transcription factors in neurodegenerative processes.

Industrial radiography is a pivotal non-destructive testing (NDT) method that ensures quality and safety in a wide range of industrial sectors. Conventional human-based approaches, however, are prone to challenges in defect detection accuracy and efficiency, primarily due to the high inspection demand from manufacturing industries with high production throughput. To solve this challenge, numerous computer-based alternatives have been developed, including Auto-mated Defect Recognition (ADR) using deep learning algorithms. At the core of training, these algorithms demand large volumes of data that should be representative of real-world cases. However, the availability of digital X-ray radiography data for open research is limited by non-disclosure contractual terms in the industry. This study presents a pipeline that is capable of modeling synthetic images based on statistical information acquired from X-ray intensity distribution from real digital X-ray radiography images. Through meticulous analysis of the intensity distribution in digital X-ray images, the unique statistical patterns associated with the exposure conditions used during image acquisition, type of component, thickness variations, beam divergence, anode heel effect, etc., are extracted. The realized synthetic images were utilized to train deep learning models, yielding an impressive model performance with mean intersection over union (IoU) of 0.93, and mean dice coefficient of 0.96, on real unseen digital X-ray radiography images. This methodology is scalable and adaptable, making it suitable for diverse industrial applications.

The watershed hydrologic conditions in the Madre de Dios (MDD) basin in the Peruvian Amazon have been irreversibly impacted by deforestation and changes in land use cover. These changes have also had detrimental effects on the geomorphology, water quality, and aquatic habitat within the basin. However, there is a scarcity of hydrological modeling studies in this area primarily due to the limited availability of hydrometeorological data. The primary objective of this study was to examine how deforestation impacts the hydrological conditions in the MDD basin. By implementing the Soil and Water Assessment Tool (SWAT) model, this study determined that replacing 12% of the evergreen broadleaf forest area with bare land resulted in an significant increase in surface runoff by 38% monthly, a reduction of evapotranspiration by 1% annually, and an average monthly streamflow increase of 12%. Changes in spatial patterns reveal that the primary impacted watershed is the Inambari River subbasin, a significant tributary of the Madre de Dios River. This area experiences an annual average surge of 187% in surface runoff generation while witnessing an annual average reduction of 8% in evapotranspiration.These findings have important implications, as they can contribute to instances of flooding and extreme inundation events, which have already occurred in the MDD region.

Hydrogen sulfide (H2S) is an environmental toxicant of health concern. The brain is a major target in acute H2S poisoning. This study was to test the hypothesis that acute and subchronic ambient H2S exposures alter the brain metabolome. Male 7-8 week-old C57BL/6J mice were exposed by whole-body inhalation to 1000 ppm H2S for 45 min and euthanized at 5 min or 72 h for acute exposure. For subchronic study, mice were exposed to 5 ppm H2S 2 h/day, 5 days/week for 5 weeks. The brainstem was removed for metabolomic analysis. Enrichment analysis showed the metabolomic profiles in acute and subchronic H2S exposures matched with those of cerebral spinal fluid from patients with seizures or Alzheimer’s disease. Acute H2S exposure decreased excitatory neurotransmitters, aspartate and glutamate, while the inhibitory neurotransmitter, serotonin, was increased, which may explain H2S-induced loss of consciousness. Branched-chain amino acids and glucose were increased by acute H2S exposure. Subchronic H2S exposure within OSHA guideline surprisingly decreased serotonin altering central nervous system. In subchronic H2S exposure, glucose was decreased while polyunsaturated fatty acids, inosine, and hypoxanthine were increased. Collectively, these results provide important mechanistic clues of acute and subchronic ambient H2S poisonings and show that H2S alters brainstem metabolome.

The retinal pigment epithelium (RPE) is an important monolayer of cells present in the outer retina forming a major part of the blood-retina-barrier (BRB). It performs many essential tasks for the maintenance of retinal integrity and function. With increasing knowledge of the retina, it is getting clearer that both common retinal disorders, like age related macular degeneration, and rare genetic disorders originate in the RPE. This calls for a better understanding of the functions of various proteins within the RPE. In this regard, mice enabling an RPE-specific gene deletion are a powerful tool to study the role of a particular protein within the RPE cells in their native environment, simultaneously negating any potential influences of systemic changes. Moreover, since the RPE cells interact closely with the adjacent photoreceptors, these mice also provide an excellent avenue to study the importance of a particular gene function within the RPE to the retina as a whole. In this review, we outline and compare the features of various Cre mice created for this purpose, allowing researchers a well-informed decision on the choice of Cre mouse to use in relation to their research needs.