Zika virus (ZIKV) is an emerging human mosquito-transmitted pathogen of global concern, known to cause severe complications such as congenital defects and neurological disorders in adults. ZIKV infection is associated with cell death. However, previous studies suggest that the virally-induced apoptosis occurs at a slower rate compared to the course of viral production. In this present study, we investigated the capacity of ZIKV to delay host cell apoptosis. We provide evidence that ZIKV has the ability to control programmed cell death whether it is intrinsically or extrinsically induced. In cells expressing viral replicon-type constructions, we show that this control is achieved through replication. Finally, our work highlights an important role for anti-apoptotic Bcl-2 family protein in the ability of ZIKV to control apoptotic pathways, avoiding premature cell death and thereby promoting virus replication in the host-cell.

Aortic rupture is known as one of the potential causes of sudden cardiac death in athletes. Nevertheless, adaptation strategies for aortic root dilation in athletes vary. The purpose of this study was to investigate aortic root adaptation to physical workload and to determine if aortic root’s and left ventricle sizes are contingent upon the physical workload. Echocardiography was applied to 151 subjects to measure the aortic root at aortic valve annulus (AA) and at sinus of Valsalva (VS). 122 were athletes (41 females and 81 males) and 29 were non-athletes (14 females and 15 males). Of the 41 female athletes, 32 were endurance athletes, and 9 strength athletes. From 81 male athletes, 56 were endurance athletes, and 25 were strength athletes. AA and VS mean values for the body surface area were presented as rAA and rVS. Left ventricle (LV) meaures incuded LV end-diastolic diameter (LVEDD), interventricular septum thickness in diastole (IVSTd), LV posterior wall thickness in diastole (LVPWTd), LV mass (LVM), LV mass index, LV end-diastolic diameter index (LVEDDI). Results indicated that VS was higher in female athletes (28.9±2.36mm) than in non-athletes (27.19±2.87mm, p=0.03). On the other hand, rAA was higher in strength athletes (12.19±1.48mm/m2) than in endurance athletes (11.12±0.99mm/m2, p=0.04). Additionally, rVS and rAA were higher in female strength athletes (17.19±1.78mm/m2, 12.19±1.48mm/m2) than female basketball players (15.49±1.08mm/m2, p=0.03, 10.75±1.06 mm/m2, p=0.02). Statistically significant positive moderate correlations were found between VS and LVEDD, LVM, IVSTd, LVPWTd, rVS and LVEDDI parameters in all athletes. The diameter of Valsalva sinus was greater in female athletes compared to non-athletes. The rAA mean value for body surface area was greater in female athletes practising strength sports as compared to their counterparts who were practising endurance sports. The diameter of the aortic root at sinuses positively correlated with the LV size in all athletes. Trial was registered at ClinicalTrials.gov Identifier: NCT03656861, September 3, 2018 (retrospectively registered).

The human immunodeficiency virus 1 (HIV-1) viral protease (PR) is one of the most studied viral enzymes, and approval of drugs targeting its catalytic activity opened the door to the develop-ment of highly active antiretroviral therapy (HAART). Despite the fact that its crucial role in viri-on maturation is well characterized, an increasing body of research is starting to focus on its abil-ity to cleave host cell proteins, based on recent advances in proteomics and genomics technologies. Such findings are apparently in contrast with the dogma of HIV-1 PR activity being restricted to the interior of nascent virions, and suggest catalytic activity within the host cell environment. Given the limited amount of PR present in the virion at the time of infection, it is tempting to specu-late that such events mainly occur during viral late gene expression, mediated by newly synthe-sized Gag-Pol polyprotein precursors, rather than at a very early stage of infection, before pro-viral integration. Among cellular targets of HIV-1 PR, three major clusters can be identified: pro-teins involved in viral and cellular translation, those controlling cell survival, and restriction fac-tors responsible for innate/intrinsic antiviral responses. Indeed, by cleaving host cell translation initiation factors HIV-1 PR can impair cap-dependent translation, thus promoting IRES-mediated translation of late viral transcripts and viral production, while by targeting several apoptotic fac-tors it modulates cell survival, thus promoting immune evasion and viral dissemination. Addi-tionally, HIV-1 PR counteracts restriction factors incorporated in the virion that would otherwise interfere with nascent virus vitality. Thus, HIV-1 PR appears to modulate host cell function at dif-ferent times and locations during its life cycle, to ensure efficient viral persistency and propaga-tion. This kind of PR-mediated host cell modulation is found in a plethora of different viruses and HIV-1 is no exception, and although we are far from having a complete picture, it is clear that the PR has a multifaceted role in interfering with host machineries to better suit viral replication, and is a field that needs to be explored further.

Working farm dogs are essential to many livestock farmers. Little is known about factors that influence dogs’ risk of being lost from work. This paper explores risk factors for farm dogs being lost through death, euthanasia and retirement. All enrolled dogs were working and minimum 18 months old. Five data collection rounds were done over four years. Data about dogs were collected from owners and dogs were given physical examinations by veterinarians. Dogs that were lost from work were counted and owner-reported reasons for loss were recorded. Multivariable logistic regression modelling was used to investigate risk factors for loss. Of 589 dogs, 81 were lost from work. Of these, 59 dogs died or were euthanized and 22 were retired. Farm dogs tended to reach high ages, with 38% being 10 years or older when last examined. Acute injury or illness was the most commonly owner-reported reason for loss. Age group (P < 0.0001) and lameness (P = 0.04, OR = 1.8) significantly affected dogs’ risk being lost. These results expand our knowledge about factors that affect health, welfare and work in farm dogs. Further investigation into reasons for lameness may help improve health and welfare in working farm dogs.

Foliage-feeding fall armyworm (Spodoptera frugiperda) and root-feeding western corn rootworm (Diabrotica virgifera virgifera) are maize (Zea mays L.) pests that cause significant yield losses. Jasmonic acid (JA) play pivotal defense role against insects. 12-oxo-phytodienoic acid (12-OPDA) is converted into JA by peroxisome-localized OPDA reductases (OPR). However, little is known about the physiological functions of cytoplasmic OPRs. Here, we show that disruption of ZmOPR2 reduced wound-induced JA production and defense against FAW while accumulating more JA catabolites. Overexpression of ZmOPR2 in Arabidopsis enhanced JA production and defense against beet armyworm (Spodoptera exigua). In addition, lox10opr2 double mutants were more susceptible than either single mutant, suggesting that ZmOPR2 and ZmLOX10 uniquely and additively contributed to defense. In contrast to the defensive role of ZmOPR2 and ZmLOX10 in leaves, single mutants did not display any alteration in root herbivory defense against WCR. Feeding on lox10opr2 double mutants resulted in increased WCR mortality associated with greater herbivory-induced production of insecticidal death acids and ketols. Thus, ZmOPR2 and ZmLOX10 cooperatively inhibit synthesis of these metabolites during herbivory by WCR. We conclude that ZmOPR2 and ZmLOX10 regulate JA-mediated resistance in leaves against FAW while suppressing insecticidal oxylipin synthesis in roots during WCR infestation.

Organ transplantation remains the only treatment option for patients with end-stage organ dysfunction. However, there are numerous limitations that challenge its clinical application, including the shortage of organ donations, the quality of donated organs, injury during organ preservation and reperfusion, primary and chronic graft dysfunction, acute and chronic rejection, infection, and carcinogenesis in post-transplantation patients. Acute and chronic inflammation and cell death are two major underlying mechanisms for graft injury. Necroptosis is a type of programmed cell death involved in many diseases and has been studied in the setting of all major solid organ transplants, including the kidney, heart, liver, and lung. It is determined by the underlying donor organ conditions (e.g., age, alcohol consumption, fatty liver, hemorrhage shock, donation after circulatory death, etc.), preservation conditions and reperfusion, as well as allograft rejection. Specific molecular mechanisms of necroptosis have been uncovered in the organ transplantation setting, and potential targeting drugs have been identified. We hope this review article will promote more clinical research to determine the role of necroptosis and other types of programmed cell death in solid organ transplantation to alleviate the clinical burden of ischemia-reperfusion injury and graft rejection.

Previously, we reported that MTH1 inhibitors TH588 and TH1579 selectively induce oxidative damage and kill Ras expressing or transforming cancer cells, as compared to non-transforming immortalized or primary cells. While this explains the impressive anti-cancer properties of the compounds, the molecular mechanism remains elusive. Oncogenes induce replication stress, re-sulting in under replicated DNA and replication continuing into mitosis, where TH588 and TH1579 treatment cause toxicity and incorporation of oxidative damage. Hence, we hypothesized that oncogene-induced replication stress explains the cancer selectivity. To test this, we overex-pressed c-Myc in human epithelial kidney cells (HA1EB), resulting in increased proliferation, polyploidy and replication stress. TH588 and TH1579 selectively kill c-Myc overexpressing clones, enforcing the cancer cell selective killing of these compounds. Moreover, the toxicity of TH588 and TH1579 in c-Myc overexpressing cells is rescued by transcription, proteasome or CDK1 inhibitors, but interestingly not by nucleoside supplementation. This suggest that cancer selectivity is unrelated oncogene-induced replication stress. We conclude that the molecular toxi-cological mechanisms how TH588 and TH1579 kill c-Myc overexpressing cells have several com-ponents and involves MTH1-independent proteosomal degradation of c-Myc itself, c-Myc driven transcription and CDK activation, and is likely unrelated to oncogene-induced replication stress.

Apoptosis, the programmed and intentional death of senescent, damaged, or otherwise superfluous cells, is the natural end-point for most cells within multicellular organisms. Apoptotic cells are not inherently damaging, but if left unattended they can lyse through secondary necrosis. The resulting release of intracellular contents drives inflammation in the surrounding tissue and can lead to autoimmunity. These negative consequences of secondary necrosis are avoided by efferocytosis—the phagocytic clearance of apoptotic cells. Efferocytosis is a product of both apoptotic cell and efferocyte mechanisms, which cooperate to ensure the rapid and complete removal of apoptotic cells. Herein, the processes used by apoptotic cells to ensure their timely removal, and the receptors, signaling, and cellular processes used by efferocytes to identify, remove, and process the apoptotic cells, are reviewed.

We evaluated the mono- and combination-therapy effects of valproic acid (VPA) and doxorubicin (DOX) in hepatocellular carcinoma (HCC) and identified a specific and efficient, synergistic anti-proliferative effect of the VPA and DOX combination in HCC cells, especially HepG2 cells; this effect was not apparent in MIHA cells, a normal hepatocyte cell line. The calculation of the coefficient of drug interaction confirmed the significant synergistic effect of the combination treatment. Concurrently, the synergistic apoptotic cell death caused by the VPA and DOX combination treatment was confirmed by Hoechst nuclear staining and western blot analysis of caspase-3 and poly (ADP-ribose) polymerase (PARP) activation. Co-treatment with VPA and DOX enhanced reactive oxygen species (ROS) generation and autophagy, which were clearly attenuated by ROS and autophagy inhibitors, respectively. Furthermore, as an indication of the mechanism underlying the synergistic effect, we observed that DOX internalization, which was induced in the VPA and DOX combination-treated group, occurred via by the caveolae-mediated endocytosis pathway. Taken together, our study uncovered the potential effect of the VPA and DOX combination treatment with regard to cell death, including induction of cellular ROS, autophagy, and the caveolae-mediated endocytosis pathway. Therefore, these results present novel implications in drug delivery research for the treatment of HCC.

The effects of hypothermia on neonatal encephalopathy may vary regionally, spatially, and cytopathologically in the gyrencephalic neocortex with manifestations potentially influenced by seizures that alter the severity and distribution of neuropathology. We developed a neonatal piglet survival model of hypoxic-ischemic (HI) encephalopathy and hypothermia with continuous encephalographic (cEEG) monitoring for seizures to study injury in neocortex. Neonatal piglets were randomized to naïve, HI-normothermia (NT), overnight hypothermia (HT) initiated 2 hours after HI, sham-NT, or sham-HT treatments. Some piglets within sham and HI groups received cEEG monitoring during recovery. Survival was 2-7 days (piglets were unmedicated and those with poor recovery and unresolving seizures were euthanized early); there was no differences in survival among groups (p>0.078). Neuropathology was assessed by hematoxylin and eosin staining and immunohistochemistry for RNA Binding FOX-1 Homolog 3 (Rbfox3/NeuN). Normal and ischemic-necrotic neurons were counted (layers II-VI collectively) in somatosensory, motor, and prefrontal cortices, identified by cytoarchitecture and connectomics, and in inferior parietal cortex by layer. Seizure burden was determined. HI-NT piglets had reduced normal/total neuron ratio and increased ischemic-necrotic/total neuron ratio relative to naïve, sham-NT, and sham-HT piglets in anterior and posterior motor and somatosensory cortices. Frontal cortex was vulnerable in the prefrontal lateral bank after HI-NT with ischemic-necrosis. HI-HT piglets had higher normal/total neuron ratios and lower ischemic-necrotic/total neuron ratios than HI-NT piglets in anterior/posterior motor and somatosensory cortices. Total normal neuron density in layer III of inferior parietal cortex was reduced in HI-NT piglets compared to sham piglets and was protected by HT. Laminar analysis of Rbfox3 in somatosensory cortex revealed three types of neurons: Rbfox3-positive/normal, Rbfox3-positive/ischemic-necrotic, and Rbfox3-depleted. HI piglets had increased Rbfox3-depleted/total neuron ratio in layers II and III compared to sham-NT. Cortical neuron Rbfox3-depletion was partly rescued by HT. Seizure burden was more severe in HI piglets compared to sham piglets, but HI-NT and HI-HT piglets were similar. We conclude that 1) the neonatal piglet neocortex has a suprasylvian spatial vulnerability to HI and seizures; 2) HT protects against neuropathology in functionally different regions of the neonatal gyrencephalic neocortex; 3) neurons in neonatal neocortex have a limited cytopathology repertoire seen by H&E staining; 4) higher seizure burden correlates with more ischemic-necrotic neurons in somatosensory cortex; 5) seizure presence associates with damage spread to inferior parietal cortex; 6) seizure presence is insensitive to HT, and 7) Rbfox3 immunophenotyping identifies a novel neuronal RNA splicing protein nuclear-depletion pathology that appears reversible by HT. This work demonstrates that HT protection of neocortex in neonatal HI is topographic and laminar, seizure unmitigating, and restores depleted neuronal RNA splicing factor.

Apoptosis, necroptosis, and autophagy are cellular mechanisms by which cells are programmed to die under a wide range of physiological and developmental stimuli. A multitude of protein mediators of programmed cell death have been identified and apoptosis, necroptosis, and autophagy signals have been found to utilize common pathways elucidating the proteins involved. This narrative review focuses on caspase-dependent and caspase-independent programmed cell death systems. Included studies of caspase-dependent programmed cell death include extrinsic pathway apoptotic mechanisms including phosphatidylserine (PS), FAS (APO-1/CD95), Tumor Necrosis Factor (TNF) Receptor type 1 (TNF-R1) and TNF-Related Apoptosis-Inducing Ligand (TRAIL) and intrinsic or mitochondrial pathway such as Cytochrome C, the Bcl-2 family of proteins and Smac/Diablo. The Bcl-2 family has apoptotic mediators Bcl-2-associated X protein (Bax) and Bcl-2 homologous antagonist/killer (Bak), Bcl-2-Interacting Protein BIM (Bim), Bcl-2 agonist of cell death (Bad), Bid, Bcl-2 adenovirus E1B 19kDa-interacting protein 1 NIP3 (Bnip3), BMF, HRK, Noxa and PUMA and anti-apoptotic proteins such as Bcl-2 itself, Mcl-1, Bcl-w, A1, and Bcl-XL. Moreover, caspase-independent programmed cell death pathways include the mitochondrial pathway with the protein mediators Apoptosis Inducing Factor (AIF), and Endonuclease G, the pathways Necroptosis, and Autophagy. Understanding programmed cell death from those reported in this review could shed substantial light on the processes of biological homeostasis. In addition, identifying specific proteins involved in these processes is mandatory to identify molecular biomarkers as well as therapeutic targets. This knowledge could provide the ability to modulate the programmed cell death response and could lead to new therapeutic interventions in a wide range of diseases.

Our study explores the genetic mechanisms underlying the spotted leaf phenotype in rice, focusing on the rpt5a mutant characterized by persistent reddish-brown leaf spots from seedling stage to maturity, leading to extensive leaf necrosis. Through map-based cloning, we localized the responsible locus to a 330Kb region on chromosome 2 and identified LOC_Os02g56000 (named OsRPT5A) as the causative gene. A point mutation in OsRPT5A, substituting valine for glutamic acid, was identified as the critical factor for the phenotype. Functional complementation and generation of knockout lines in the IR64 background confirmed the central role of OsRPT5A in controlling this trait. Our study also revealed that OsRPT5A is constitutively expressed across various tissues, with its subcellular localization unaffected by mutations. Notably, we observed an abnormal accumulation of reactive oxygen species (ROS) in rpt5a mutants, suggesting a disruption in the ROS system. Complementation studies indicated OsRPT5A's involvement in ROS homeostasis and catalase activity regulation. Moreover, the rpt5a mutant exhibited enhanced resistance to Xanthomonas oryzae pv. oryzae (Xoo), highlighting OsRPT5A's role in rice's pathogen resistance mechanisms. These findings elucidate the genetic basis of the spotted leaf phenotype and emphasize the intricate interplay between plant defense responses and developmental pathways.

This study evaluated gas mixtures of carbon dioxide (CO2) associated with nitrogen (N2) as al-ternatives to the use of CO2 in two phases to improve the welfare of broiler chickens at slaugh-ter. Broilers were exposed to one of three treatments: 40C90C (1st phase: <40% CO2 for 2 min; 2nd phase: >90% CO2 and <2% O2 for 2 min, n=92), 40C60N (40% CO2, 60% N2 and <2% O2 for 4 min, n=79), or 20C80N (20% CO2, 80% N2 and <2% O2 for 4 min, n=72). The time to onset of loss of consciousness (LOC) and death was assessed by brain activity (EEG) and behaviour. Behaviour also allowed characterisation of the aversive response to the treatments. Exposure to 40C60N and 20C80N induced LOC faster (19 s [14 – 30 s] and 21 s [16 – 37 s], respectively) but also with less inter-individual variability compared to 40C90C (53 s [26 – 156 s], P < 0.001) and birds took less time to die (40C60N: 64 s [43 – 108 s]; 20C80N: 70 s [45 – 88 s]; 40C90C: 177 s [89 – 212 s], P < 0.001). The 40C90C birds not only experienced more aversion during induction to LOC but are at risk of remaining conscious when the CO2 concentration is increased in the 2nd phase. From an animal welfare point of view, 40C60N provided the highest welfare, followed by 20C80N and 40C90C.

We document for the first time epsilon waves on the electrocardiogram of a patient with Dravet syndrome (DS) who does not exhibit structural cardiac pathology. DS, a severe form of pediatric epilepsy, involves mutations in the SCN1A gene, which disrupt sodium ion flow and increase the risk of sudden unexpected death in epilepsy. The epsilon waves, typically associated with arrhythmogenic right ventricular dysplasia, may also suggest a link between neuronal and cardiac dysfunctions. In our case, the epsilon waves appear to originate from abnormalities in sodium channels rather than structural changes in the myocardium. This finding underscores the importance of assessing both neurological and cardiac manifestations in patients with severe epilepsy, opening new avenues for the research and treatment of these interactions in DS.

This article introduces existential wellbeing (EWB) as one of the most ignored but also the most important kind of wellbeing, especially for people who experience life-limiting diseases and need palliative care (Wong & Yu, 2021). This article will not only review the literature regarding the nature and practice of existential wellbeing in palliative care, but also propose a preliminary Existential Wellbeing Scale. EWB is defined as the quality-of-life characterized by living well and dying well in spite of pain, obstacles, and the shadow of death; wellbeing within the context of human suffering can only be fully understood from the perspective of existential positive psychology (EPP), dedicated to the study of sustainable wellbeing based on the foundation of transcending suffering. The basic tenets of EPP are (1) redefining positivity or wellbeing in terms of seeing and being the light in the darkness; (2) focusing on the dialectical process of navigating an adaptive balance; and (3) re-orienting one’s life attitude from egotism to self-transcendence (Wong, 2023a). More specifically, EWB depends on some combination of the following experiences: (1) Prior experience of overcoming adversity; (2) Existential intelligence (Gardner, 2020) in addressing existential concerns; (3) Existential wisdom of the soul (Wong 2022a; Wong, Ho, et al, 2023a) to achieve existential wellbeing and sustainable flourishing; (4) Spiritual wellbeing based on spiritual values such as faith, hope, and love (Wong, 2023); (5) Knowledge of meaning-focused coping (Eisenbeck et al., 2021); and (6) The new paradigm of self-transcendence (Reed & Haugan, 2021; Wong, Arslan et al., 2021; Wong, Ho et al., 2023b) to transcend and transform suffering into wellbeing and triumph.

Graphene-based nanomaterials (GNMs), including graphene, graphene oxide, reduced graphene oxide, and graphene quantum dots, may have direct anticancer activity or be used as nanocarri-ers for antitumor drugs. GNMs usually enter tumor cells by endocytosis and can accumulate in lysosomes. This accumulation prevents drugs bound to GNMs from reaching their targets, sup-pressing their anticancer effects. A number of chemical modifications are made to GNMs to facili-tate the separation of anticancer drugs from GNMs at low lysosomal pH and to enable lysosomal escape of drugs. Lysosomal escape may be associated with oxidative stress, permeabilization of the unstable membrane of cancer cell lysosomes, release of lysosomal enzymes into the cytoplasm, and cell death. GNMs can prevent or stimulate tumor cell death by inducing protective autopha-gy or suppressing autolysosomal degradation, respectively. Furthermore, because GNMs prevent bound fluorescent agents from emitting light, their separation in lysosomes may enable tumor cell identification and therapy monitoring. In this review, we explain how the characteristics of the lysosomal microenvironment and the unique features of tumor cell lysosomes can be exploited for GNM-based cancer therapy.

Hsp70.1 has dual functions as chaperone protein and lysosomal stabilizer. Previously, we reported that calpain-mediated cleavage of carbonylated Hsp70.1 causes ischemic neuronal death by inducing lysosomal rupture. Recently, we found that the consecutive injections of vegetable oil-peroxidation product ‘hydroxynonenal’ induces hepatocyte death via the similar cascade. As Hsp70.1 is related also to fatty acid β-oxidation in the liver, its deficiency is known to cause accumulation of fat. Genetic deletion of betaine-homocysteine S-methyltransferase (BHMT) was reported to perturb choline metabolism, inducing decrease of phosphatidylcholine with the resultant hepatic steatosis. Here, focusing on disorders of Hsp70.1 and BHMT, we studied the mechanism of hepatocyte degeneration and steatosis, using monkeys after the consecutive injections of synthetic hydroxynonenal. As these monkeys showed a significant impairment of liver functions, the liver tissues without and with hydroxynonenal injections were compared by proteomics, immunoblotting, immunohisto-chemical and electron microscopic analyses. Western blotting showed upregulation of neither Hsp70.1 nor BHMT, but an increased cleavage of both proteins. Proteomics showed downregulation of Hsp70.1, while 2-fold increments of carbonylated BHMT. Hsp70.1 carbonylation was negligible, showing a marked contrast to ischemic neurons which were associated with ~10-fold increments. The control liver histologically showed lipid droplets in Ito cells, but lipid depositions within hepatocytes were very little. In contrast, after hydroxynonenal injections, widespread fatty degeneration and focal coagulation necrosis were observed with accumulation of numerous tiny lipid droplets within and around the degenerating/dying hepatocytes. Electron microscopy showed lysosomal membrane permeabilization/rupture, remarkable dissolution of mitochondria and rough ER membrane, and proliferation of abnormal peroxisomes. It is probable that disruptions of rough ER caused impaired synthesis of Hsp70.1 and BHMT proteins, while impairments of mitochondria and peroxisomes presumably contributed to the sustained generation of reactive oxygen species. Since both Hsp70.1 and BHMT are vulnerable to the long-standing oxidative stressor, hydroxynonenal-induced disorders facilitated degeneration and steatosis of hepatocytes, respectively.

Nonhost disease resistance is the most common type of plant defense mechanism against potential pathogens. In this study, the metabolic enzyme formate dehydrogenase (FDH1) was identified to be involved in nonhost disease resistance in Nicotiana benthamiana and Arabidopsis thaliana. In Arabidopsis, AtFDH1 was highly upregulated in response to both host and nonhost bacterial pathogens. Arabidopsis Atfdh1 mutants were compromised in nonhost resistance, basal resistance, and gene-for-gene resistance. The expression patterns of salicylic acid (SA) and jasmonic acid (JA) marker genes after pathogen infections in Atfdh1 mutant indicated that SA is most likely involved in the FDH1-mediated plant defense response to both host and nonhost bacterial pathogens. Previous studies reported that FDH1 localizes to only mitochondria, or both mitochondria and chloroplasts. Our results showed that the AtFDH1 localized to mitochondria and the amount of FDH1 localized to mitochondria increased upon infection with host or nonhost pathogens. Interestingly, the subcellular localization of FDH1 was observed in both mitochondria and chloroplasts after infection with a nonhost pathogen in Arabidopsis. We speculate that FDH1 plays a role in cellular signaling networks between mitochondria and chloroplasts to produce coordinated defense responses such as SA-induced reactive oxygen species (ROS) generation and hypersensitive response (HR)-induced cell death against nonhost bacterial pathogens.

The current COVID-19 pandemic is one of the most devastating events in recent history. The virus causes relatively minor damage to young, healthy populations, imposing life-threatening danger to the elderly and people with diseases of chronic inflammation. Therefore, if we could reduce the risk for vulnerable populations, it would make the COVID-19 pandemic more similar to other typical outbreaks. Children don’t suffer from COVID-19 as much as their grandparents and have a much higher melatonin level. Bats are nocturnal animals possessing high levels of melatonin, which may contribute to their high anti-viral resistance. Viruses induce an explosion of inflammatory cytokines and reactive oxygen species, and melatonin is the best natural antioxidant that is lost with age. The programmed cell death coronaviruses cause, which can result in significant lung damage, is also inhibited by melatonin. Coronavirus causes inflammation in the lungs which requires inflammasome activity. Melatonin blocks these inflammasomes. General immunity is impaired by anxiety and sleep deprivation. Melatonin improves sleep habits, reduces anxiety and stimulates immunity. Fibrosis may be the most dangerous complication after COVID-19. Melatonin is known to prevent fibrosis. Mechanical ventilation may be necessary but yet imposes risks due to oxidative stress, which can be reduced by melatonin. Thus, by using the safe over-the-counter drug melatonin, we may be immediately able to prevent the development of severe disease symptoms in coronavirus patients, reduce the severity of their symptoms, and/or reduce the immuno-pathology of coronavirus infection on patients’ health after the active phase of the infection is over.

PURPOSE: Our research interrogates Professor Peter Doherty’s warning to Australians in April 2020 that ‘COVID-19 is just as lethal as the Spanish flu’. METHODS: We identified the epicentres of both pandemics, namely metropolitan Sydney in 1919 and metropolitan Melbourne in 2020. Using original sources, we compared the lethality of COVID-19 in these two cities. Lethality was measured by the number and rate of hospitalisations and deaths per 100,000 of population. Using these two measures, we diagnosed the waves of infection, their severity at various points in time and the cumulative impact of the viruses by the end of our in-depth study period, i.e. 30 September in 1919 and 2020. RESULTS: Spanish Flu in 1919 was more than 30 times more lethal than COVID-19 in 2020. The hospital admission and death rates of COVID-19 in Melbourne in 2020 constituted a small fraction of the devastation wrought by the Spanish Flu in Sydney in 1919. The patterns and lethality of the pandemic waves were also strikingly different. DISCUSSION AND CONCLUSION: Both pandemics broke out with the arrival of unknown pathogens against which vaccines and antivirals did not exist. Professor Doherty’s warning was perhaps taken seriously and that partly explains the findings of this study. Containing infection in 1919 and 2020 threw the burden on nonpharmaceutical interventions (NPIs) such as ‘protective sequestration’ (quarantine), contact tracing, lockdowns and masks. We discuss the effectiveness of these. Despite the failures of genomic analysis and the weaknesses of the contact tracing system due to mismanagement, it was persistent and detailed contact tracing that provided the best explanation for why NPIs in 2020 were more effective than in 1919 and therefore contributed to the lower lethality of the COVID-19 pandemic in its first year.

Wingless-type MMTV integration site (Wnt) signaling is one of the most critical pathways in developing and adult tissues. In the brain, Wnt signaling contributes to different neurodevelopmental aspects ranging from differentiation, axonal extension, synapse formation, neurogenesis and neuroprotection. Canonical Wnt signaling is mediated mainly by the multifunctional β-catenin protein which is a potent co-activator of transcription factors such as Lymphoid Enhancer Factor (LEF) and T Cell Factor (TCF). Accumulating evidence points to dysregulation of Wnt/β-catenin signaling in major neurodegenerative disorders. Here I focus on a “Wnt/β-catenin-glial connection” in Parkinson’s disease (PD), the most common movement disorder characterized by the selective death of midbrain dopaminergic (mDAergic) neuronal cell bodies in the subtantia nigra pars compacta (SNpc) and gliosis. I will summarize the work of the last decade documenting that Wnt/β-catenin signaling in partnership with glial cells is critically involved in each step and at every levels in the regulation of nigrostriatal DAergic neuronal health, protection and regeneration in the MPTP mouse model of PD, focusing on Wnt/β-catenin signaling to boost a full neurorestorative program in PD.

The mortality of birds resulting from collisions and electrocutions with overhead lines, such as power lines, and phone line among others, has been implicated in the decline of various avian species globally. Specifically, overhead line collisions pose a significant threat to the conserva-tion of the Canarian houbara bustard (Chlamydotis undulata fuertaventurae), an endangered sub-species endemic to the Canary Islands. This study centres on the postmortem findings of Canarian houbara bustards that have collided with overhead lines, providing insights into the post-collision outcomes for these birds. A com-plete standardized necropsy of nine Canarian houbara bustards revealed that polytrauma was the cause of death in all cases. The most notable gross lesions associated with trauma included bone fractures, soft tissue lacerations, haemorrhages, luxations, and hemocoelom, with certain body regions being more frequently affected. Histopathology, immunohistochemistry, and en-tomology analysis confirmed that numerous birds survived the initial trauma, exhibiting varia-ble survival intervals before succumbing to their injuries. We concluded that when a houbara bustard collide with an overhead line it frequently survives the initial trauma. The histopathology, immunohistochemistry, or entomologic analysis may be helpful to approximate the timing interval between trauma and death.

The multifarious internal workings of organisms are difficult to reconcile with a single feature defining a state of ‘being alive’. Indeed, definitions of life rely on emergent properties (growth, capacity to evolve, agency) only symptomatic of intrinsic functioning. Empirical studies demonstrate that biomolecules including ratcheting/rotating enzymes, ribozymes and pigment molecules undergo repetitive conformation state changes driven by energy absorption, excitation and relaxation. They exhibit disparate structures, but govern processes relying on directional physical motion (DNA transcription, translation, ATP synthesis, cytoskeleton transport, photosynthetic resonance energy transfer) and share the principle of repetitive uniplanar conformation changes driven by thermodynamic gradients, producing dependable unidirectional motion: ‘heat engines’ exploiting thermodynamic disequilibria to perform work. Recognition that disparate biological molecules share a heat engine principle governing directional motion, working in self-regulating networks, allows a mechanistic definition: life is a self-regulating process whereby matter undergoes cyclic, uniplanar conformation state changes that convert thermodynamic disequilibria into directed motion, performing work that locally reduces entropy. ‘Living things’ are structures including autonomous networks of units operating on the heat engine principle. Death is loss of integrated heat engine function. These principles are independent of any specific chemical environment, and can be applied to other biospheres.

Conventional chemotherapy for colorectal cancer (CRC) gives only a small increase in patient survival, since it is often diagnosed in late stages, when tumor has disseminated to other organs. Besides, it is common to observe that malignant cells acquire tumor escape mechanisms which leads to therapy resistance. Considering these facts, the discovery of new molecules with therapeutic potential has become an invaluable tool in chemoprevention. In this context, we previously evaluated two hybrids (SAC-CAFA-MET and SAC-CAFA-PENT) which exhibited selective cytotoxicity against SW480, with better results than the conventional chemotherapeutic agent (5-fluorouracil; 5-FU). Here, we investigated a little deeper in the possible mechanism of these molecules to identify potential therapeutic alternatives for the treatment of CRC. Both compounds induced cell damage and reduced ROS formation. Further evaluations showed that SAC-CAFA-MET induces cell death independent from caspases and p53, but probably mediated by the negative regulation of the proapoptotic Bcl-2. In addition, the lack of activation of caspase 8 and the positive regulation of caspase 3 induced by SAC-CAFA-PENT suggest this compound acts through an apoptotic mechanism, probably initiated by intrinsic pathway. Besides, the down regulation of IL-6 by SAC-CAFA-PENT suggests it also induces a significant anti-inflammatory process. In addition, docking studies would suggest caspase-3 modulation as the primary mechanism by which hybrids elicits apoptosis in human colorectal adenocarcinoma SW480. Meanwhile, DFT calculations suggest that hybrids would produce effects in modulation of ROS in SW480 cells via hydrogen atom transfer pathway (HAT). Finally, both, SAC-CAFA-MET and SAC-CAFA-PENT displayed a favorable pharmacokinetic profile. The current work highlights the potential of the lead compounds SAC-CAFA-MET and SAC-CAFA-PENT as potential agents for colorectal cancer chemoprevention.

The resistance of cancer cell subpopulations, including cancer stem cell (CSC) populations, to apoptosis-inducing chemotherapeutic agents is a key barrier to improved outcomes for cancer patients. The cationic amphiphilic drug hexamethylene amiloride (HMA) has been previously demonstrated to efficiently kill bulk breast cancer cells independent of tumor subtype or species, but acts poorly toward non-transformed cells derived from multiple tissues. Here we demonstrate that HMA is similarly cytotoxic toward breast CSC-related subpopulations that are resistant to conventional chemotherapeutic agents, but poorly cytotoxic toward normal mammary stem cells. HMA inhibits the sphere-forming capacity of FACS-sorted human and mouse mammary CSC-related cells in vitro, specifically kills tumor but not normal mammary organoids ex vivo, and inhibits metastatic outgrowth in vivo, consistent with CSC suppression. Moreover, HMA inhibits viability and sphere formation by lung, colon, pancreatic, brain, liver, prostate and bladder tumor cell lines, suggesting that its effects may be applicable to multiple malignancies. Mechanistically, HMA elicits the permeabilization of the limiting lysosomal membrane, a hallmark feature of the lysosome-dependent cell death pathway. Our observations expose a key vulnerability intrinsic to cancer stem cells, and point to novel strategies for the exploitation of cationic amphiphilic drugs in cancer treatment.

Studies performed at single-cell resolution have demonstrated the physiological significance of cell-to-cell variability. Various types of mathematical models and systems analyses of biological networks have further been used to gain a better understanding of the sources and regulatory mechanisms of such variability. In this work, we present a novel sensitivity analysis method, called molecular density function perturbation (MDFP), for the dynamical analysis of cellular heterogeneity. The proposed analysis is based on introducing perturbations to the density or distribution function of the cellular state variables at specific time points, and quantifying how such perturbations affect the state distribution at later time points. We applied the MDFP analysis to a model of signal transduction pathway involved in TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)-induced apoptosis in HeLa cells. The MDFP analysis showed that caspase-8 activation regulates the timing of the switch-like increase of cPARP (cleaved poly(ADP-ribose) polymerase), an indicator of apoptosis. Meanwhile, the cell-to-cell variability in the commitment to apoptosis depended on mitochondrial outer membrane permeabilization (MOMP) and events following MOMP, including the release of Smac (second mitochondria-derived activator of caspases) and cytochrome-C from mitochondria, the inhibition of XIAP (X-linked inhibitor of apoptosis) by Smac and the formation of apoptosome.

(1) Background: In patients suffering from heart failure, the main causes of death are either he-modynamic failure, or ventricular arrhythmias. The only tool to significantly reduce arrhythmic sudden death is the implantable cardioverter defibrillator (ICD), but not all patients benefit to the same extend of these devices. (2) Methods: The primary outcome of this single center study was defined as cardiovascular death in patients with ischemic and non-ischemic heart failure who have benefited from ICD therapy. The secondary outcomes were death from any cause, sudden cardiac death, ICD-related therapies (appropriate antitachycardia pacing or shock therapy for ventricular tachycardia or fi-brillation) and recurrences of ventricular tachyarrhythmias. (3) Results: A total of 403 consecutive ICD recipients – symptomatic heart failure patients with ICD for the primary prevention of sudden cardiac death – were included retrospectively: 59% is-chemic cardiomyopathy (ICMP) and 41% non-ischemic cardiomyopathy (NICMP). Within a median follow-up period of 36 months, the incidence of cardiovascular mortality was not signif-icantly different in patients with NICMP and ICMP: the primary outcome had occurred in 9 pa-tients (5.4%) in the NICMP group and in 14 patients (5.9%) in the ICMP group (hazard ratio 1; 95%confidence interval [CI] 0.45 to 2.28; p =0.97). All-cause mortality occurred in 14 of 166 pa-tients (8.4%) in NICMP group and 18 of 237 patients (7.6%) in ICMP group. Sudden cardiac death occurred in 2 patients (1.2%) in the NICMP group and in 4 patients (1.7%) in the ICMP group (hazard ratio 0.71; 95% CI, 0.13 to 3.88; P=0.69). The rate of appropriate device therapies was comparable in both groups. (4) Conclusion: In this study, ICD implantation for primary prevention of sudden cardiac death in patients with symptomatic systolic heart failure was associated with similar rates of cardiovas-cular and all-cause mortality in patients with ischemic heart disease, and in patients with heart failure from other causes. NICMP and ICMP showed comparable rates of recurrent ventricular tachyarrhythmias and appropriate ICD therapies.

Background: Substance use continues to be on the rise in the United States and has been linked to new onset cardiovascular (CVDs) and cerebrovascular disorders (CeVDs) leading to hospitalizations. We aimed to study the association of different subtypes of substance use disorders (SUDs) among hospitalized patients, with the different subtypes of CVDs and CeVDs, using the National Inpatient Sample (NIS) Database. Additionally, we aimed to assess the odds of hospitalizations with new onset CVDs and CeVDs among patients with different types of SUDs. Methods: A retrospective study of the NIS database (2016-2017) using the ICD-10-CM codes was performed. The hospitalizations with a secondary diagnosis of SUDs were identified. Weighted univariate analysis using the chi-square test and multivariate survey logistic regression analysis was performed to evaluate for the incidence, prevalence, and odds of association between vascular events and SUDs. Results: There were a total of 58,259,589 hospitalizations, out of which 21.42% had SUDs. Out of all the hospitalized patients between the age 18-50, more patients had SUDs than not (31.83%, p< 0.0001). This difference existed for all the different subtypes of SUDs including alcohol related disorder (42.61%), amphetamine dependence (76.17% vs 31.83%), cannabis related disorder (75.17%), cocaine related disorders (57.87%), hallucinogen related disorder (82.91%), inhalant related disorders (67.25%), opioid related disorders (52.86%), and nicotine dependence (35.72%). We found a significant association of acute ischemic stroke with amphetamine dependence (OR 1.23, 95%CI 1.14-1.33), cocaine related disorders (1.17, 1.12-1.23) and nicotine dependence (1.42, 1.40-1.43). Similarly, the association of intracerebral hemorrhage was higher with amphetamine dependence (2.58, 2.26-2.93), and cocaine related disorders (1.62, 1.46-1.79). The association of subarachnoid hemorrhage was noted to be higher with amphetamine dependence (1.82, 1.48-2.24) and nicotine dependence (1.47, 1.39-1.55). In terms of association of cardiovascular disorders with SUDs,the patients with myocardial infarction had higher odds of nicotine dependence (1.85, 1.83-1.87) than not, Similarly, the patients with angina pectoris were noted to have a higher association with cocaine related disorders (2.21, 1.86-2.62), and those with atrial fibrillation had a higher association alcohol related disorders (1.14, 1.11-1.17). Conclusion: Our study demonstrates the variability of CVD and CeVD in patients hospitalized for SUD. Findings from our study may help promote increased awareness and early management of these events. Further studies are needed to evaluate specific effects of frequency and dose on the incidence and prevalence of CVD and CeVD in patients with SUD.

Silicified ostracods from the Lower Carboniferous (Lower Tin Mountain Limestone; Kinderhookian-early Osagean; 350-358.9 Ma) of Lost Burro Gap, Death Valley region, Inyo County, California, USA augment the diversity of Paleozoic ostracods of western North America. Acid maceration of pelmatozoan, micritic and silicate clay-rich micritic marine limestones yielded the following palaeocopid and podocopid ostracods: Acratia spp., Bairdia quasilecta Bushmina, 1975, Bairdia sp. cf. B. orientalis, Ceratobairdia sp., Kirkbya panamintensis sp. nov., Rectobairdia sp. cf. R. legumen, and Silenites sp. This is the first report of Ceratobairdia and Silenites from the Tin Mountain Limestone. These ostracods occupied a Panthalassan carbonate ramp environment, and represent part of a fauna that was widespread in shallow marine waters of Panthalassa.

Background: All Payer Claims Databases (APCD) are a rich source of health information, however, race and ethnicity (R&E) data are largely missing. Bayesian Improved Surname Geocoding (BISG) is a common R&E imputation method, yet, validation of BISG in APCDs is lacking. We used the BISG to impute missing R&E in the Oregon APCD. Methods: BISG imputed R&E for Asian Pacific Islanders (API), Blacks, Hispanics and Whites were contrasted to the gold standard (vital statistics) and sensitivity and specificity improvements were assessed. Logistic regression examined whether missing R&E was random across patient characteristics. Results: Among 85,857 individuals in the study, 32.1% (n=27,594) had missing R&E. Missing R&E was not randomly distributed. There were higher odds of missingness among males, Whites, those age 65 and older, and commercially insured individuals. Differences in the percent missing were also found by co-morbid conditions and mortality causes. Imputing the missing R&E with BISG method improved the sensitivity to identify White, Black, API, and Hispanics. Conclusions: APCDs can benefit from enhancing missing R&E with BISG imputation to perform more robust population-health level analyses and identify inequities according to R&E without losing power or dropping non-random records with missing R&E data.

Extracellular vesicles (EVs) have been identified as novel mediators of intercellular communication. They work via delivering the sequestered cargo to cells in close vicinity as well as distant sites in the body, regulating pathophysiological processes. Cell death and inflammation are biologically crucial processes in both normal physiology and pathology. These processes are indistinguishably linked with their effectors modulating the other process. For instance, during an unresolvable infection, the upregulation of specific immune mediators leads to inflammation causing cell death and tissue damage. EVs have gained considerable interest as mediators of both cell death and inflammation during conditions such as sepsis. This review summarizes the types of extracellular vesicles known to date and their roles in mediating immune responses leading to cell death and inflammation with specific focus on sepsis and lung inflammation.

Breast cancer is the most common cause of mortality due to cancer for woman both in Lithuania and worldwide. Chances of survival after diagnosis differ significantly depending on the stage of disease at the time of diagnosis and other factors. One way to estimate survival is to construct a Kaplan-Meier estimate for each factor value separately. However, in cases when it is impossible to observe a large number of patients (for example, in case of countries with lower numbers of inhabitants) dividing data into subsets, say, by stage at diagnosis may lead to results where some subsets contain too little data so that results of Kaplan Meier (or any other) method will become statistically incredible. The problem may become even more acute if the researcher would like to use more risk factors, such as stage at diagnosis, sex, place of living, treatment method, etc. Alternatively, Cox models are used to analyse survival data with covariates, and they don’t require dividing the data into subsets according to chosen risks factors (hazards).

Background: Over 900,000 cases of COVID-19 and 23,000 deaths have been reported till 13 July in India. Preserving the limited healthcare workforce is part of the strategy against the pandemic. Mortality and morbidity data have a role in customising this strategy. At this time, there is no published study on COVID-related mortality among doctors or other healthcare workers in India. Methods: A multi-pronged search was made for all reported deaths linked with COVID-19 among doctors in India. Details of COVID-linked deaths reported by mainstream media and by multiple professional social media sources were collected, screened, verified and analysed. Violent deaths occurring in the setting of pandemic-related work were separately listed. Deaths from other diseases were excluded. Results: Among 108 COVID-linked deaths among doctors, there were four pandemic-related violent deaths including three road accidents and a suicide. Of the 104 non-violent deaths, 55.5% were below 60 years of age, while 29.6% and 21% were below the age of 50 and 40 respectively. The average age at death was 56.3 (range 22 - 96). Over half of the deaths occurred among general practitioners, while surgical specialties accounted for 27% of the mortality. The geographic distribution of deaths of doctors correlated with the reported number of COVID-19 patients in each state. The total number of COVID-related healthcare worker deaths was 136, out of which eight (5.8%) were violent, and occurred in young individuals with an average age of 27.8 years. Conclusions: The majority of the 104 COVID-related non-violent deaths among doctors (55.5%) occurred below the age of 60. The average at death was 56.6 years. The states with highest number of COVID-19 cases had greater number of doctor deaths. Violent deaths among young healthcare workers in the setting of the pandemic requires special attention.

Programmed cell death protein 1 (PD-1) is a biomarker on the surface of cells that has a role in promoting self-tolerance by suppressing the inflammatory activity of T cells. In this work, one peptide of PD-1 was used as the template in molecular imprinting. The magnetic peptide-imprinted poly(ethylene-co-vinyl alcohol) composite nanoparticles (MPIP NPs) were characterized by dynamic light scattering (DLS), high-performance liquid chromatography (HPLC), Brunauer-Emmett-Teller (BET) analysis and superconducting quantum interference device (SQUID) analysis. Natural killer-92 (NK-92) cells were added to these composite nanoparticles and then incubated with human hepatoma (HepG2) cells. The viability and apoptosis pathway of HepG2 were then studied using cell counting kit-8 (CCK8) and the quantitative real-time polymerase chain reaction (qRT-PCR), respectively. These nanoparticles were found significantly enhance the activity of natural killer cells toward HepG2 cells by increasing expression of NK-kB, caspase 8 and especially caspase 3.

Stress Granules formation is a pro-survival mechanism helping cells to cope with environmental challenges. Stress Granules have been studied for two decades in fundamental research, and are now being examined in the context of human pathogenesis. Here, we review studies highlighting stress granules’ involvement in cancer development through translational pattern modification.

Extracellular vesicles (EV) are a very heterogeneous group of cell-derived vesicles released by almost all kind of living cells. EV are involved in intercellular communication, both locally and systemically, since they induce signals and transfer their contents (proteins, lipids, RNAs) to other cells, which subsequently trigger a wide variety of biological responses in the target cells. How-ever, cell surface receptor-induced EV release is limited to cells from the immune system, includ-ing T lymphocytes. T cell receptor activation of T lymphocytes induces secretion of EV containing T cell receptor for antigen and several bioactive molecules, including proapoptotic proteins. These EV are thus specific for antigen-bearing cells, which make them ideal candidates for a cell-free, EV-dependent cancer therapy. In this review we discuss the generation of EV by T lymphocytes and some potential therapeutic approaches of these EV.

Immunotherapy has been considered for years as a viable and attractive treatment option for patients with cancer. Among immunotherapy arsenal, the targeting of intratumoral immune cells by immune-checkpoint inhibitory agents has recently revolutionized the treatment of several subtypes of tumours. These approaches aimed at restoring an effective anti-tumour immunity, rapidly reached the market thanks to the simultaneous identification of inhibitory signals that dampen an effective antitumor response in a large variety of neoplastic cells, and the clinical development of monoclonal antibodies targeting checkpoint receptors. Leading therapies in solid tumours are mainly focused on the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed-death 1 (PD-1) pathways. These approaches have found a promising testing ground in both Hodgkin lymphoma and non-Hodgkin lymphoma, mainly because in these diseases the malignant cells interact with the immune system and commonly provide signals that regulate immune function. Although several trials have already demonstrated evidence of therapeutic activity with some checkpoint inhibitors in lymphoma, many of the immunologic lessons learned from solid tumours may not directly translate to lymphoid malignancies. In this sense, the mechanisms of effective antitumor responses are different between the different lymphoma subtypes, while the reasons for this substantial difference remain partially unknown. This review will discuss the current advances of immune-checkpoint blockade therapies in B-cell lymphoma and will build a projection of how the field may evolve in the near future. In particular, we will analyze the current strategies being evaluated both preclinically and clinically with the aim to foster the use of immune-checkpoint inhibitors in non-Hodgkin lymphoma, including combination approaches with chemotherapeutics, biological agents and/or different immunologic therapies.

Arrhythmic sudden cardiac death (SCD) has an annual prevalence of 1 per 1000 while 75% of the victims suffer from ischemic and 10% from non-ischemic or hypertrophic cardiomyopathy. Altogether, these three entities account for more than 80% of the total SCD victims. Guidelines for implantable cardiac defibrillators are still dominated by LVEF<30% from the MADIT II study. In terms of arrhythmic risk stratification, the PRESERVE-EF study restored in clinical practice the two-step arrhythmic risk stratification approach based on Electrocardiographic non-invasive risk factors (NIRFs) guiding to electrophysiological study. In our times with the multiple cardiac imaging methods and artificial intelligence applications availability, this two-step approach based on integrated arrhythmia mechanisms detection, emerges as an efficient SCD risk stratification paradigm for these three entities but also for the patients with congenital heart disease.

The COVID-19 pandemic has exposed the inadequacies of the current healthcare system and needs a paradigm change, which is holistic, and community based illustrated by the healing wheel. The present paper proposes that existential positive psychology (PP 2.0) represents a promising approach to meet the rising needs in palliative care. This framework has a twofold emphasis on (a) How to transcend and transform suffering as the foundation for wellbeing, and (b) how to cultivate our spiritual and existential capabilities to achieve personal growth and flourishing. We propose that these objectives can be achieved simultaneously through dialectical palliative counselling, as illustrated by Wong’s integrative meaning therapy (Wong, 2020) and Lo’s Conceptual Model of CALM Therapy in palliative care (Lo et al., 2014). We then discuss existential suffering in general and at the last stage of life in particular; we also review recent research and interventions on existential suffering in palliative patients. Finally, we outline the objectives and the strategies of IMT in providing palliative counselling for palliative care and hospice patients.

Neuronal cell fate is predominantly controlled by the effects of growth factors, such as neurotrophins, and the activation of a variety of signaling pathways acting through neurotrophin receptors, namely Trk and p75 (p75NTR). Despite their beneficial effects on brain function, their therapeutic use is compromised, due to their polypeptidic nature and blood–brain-barrier impermeability. To overcome these limitations, our previous studies have proven that DHEA-derived synthetic analogs can act like neurotrophins, lacking endocrine side effects. The present study focuses on the biological characterization of a newly synthesized analog, ENT-A044, and its role on inducing cell specific functions of p75NTR. We show that ENT-A044 can induce cell death and phosphorylation of JNK protein by activating p75NTR. Additionally, ENT-A044 can induce the phosphorylation of TrkB receptor, indicating that our molecule can activate both neurotrophin receptors, leading towards the protection of neuronal populations that express both receptors. Furthermore, the present study demonstrates for the first time the expression of p75NTR in human induced Pluripotent Stem Cells - derived Neural Progenitor Cells (hiPSCs - derived NPCs) and receptor-dependent cell death induced by ENT-A044 treatment. In conclusion, ENT-A044 could be proven a lead molecule for the development of novel pharmacological agents, aiming on new therapeutic approaches and research tools, by controlling p75NTR actions.

Decisions affecting the COVID-19 pandemic, by the individual and those with highest authority, are being made on the basis of unreliable data. Data about cases and deaths are collected daily but represent only a sample of reality. Statistics convert sample data into more reliable estimates. However, statistics have no magical powers; reliability requires dependable data. It is futile to rail against this darkness; COVID-19 is not a scientific experiment. However, we must do better both with data collection and data analysis. In this review, I focus on one element of the data, the asymptomatic case of COVID-19. Without reliable information about this number, decision makers are significantly blinded. By its nature, the asymptomatic case is hidden but contaminating to understanding COVID-19. The true case rate and death rate per case are unknowable without knowing the fraction of cases that are asymptomatic. The best estimate of asymptomatic cases is in the CDC document: COVID-19 Pandemic Planning Scenarios. For four different scenarios the estimates range from 10% to 70%, with the best estimate of 40% for asymptomatic cases. However, even the definition of the asymptomatic case is problematic. In simplest terms, two elements are required: an infection and no symptoms. How is “no symptoms” to be usefully defined? It appears to be analogous to pontificating about black swans from studying only white swans. It implies infection, but how is infection defined? Is it presence of the virus, replication of the virus, or presence of antibodies? Is asymptomatic disease an oxymoron? Without extensive, purposeful screening for specifically defined, essential symptoms and appropriate virus and antibody testing over time, the class of asymptomatic cases remains unknown. Current estimates range from <20% to ˃80%. If low, it can be ignored; if high, it dramatically and proportionately lowers the case rate and the death rate per case. Consequentially, the asymptomatic rate dramatically affects our societal and political responses. In this focused review, we assess the limitations of the published estimates, bring attention to the importance of obtaining accurate data, and exhort that high priority be given in the scientific community to understanding the issue, asymptomatic COVID-19 cases.

Background: This study retrospective evaluates patients with stage IV melanoma treated with Nivolumab and Ipilimumab combination therapy from two regional oncology centers from Romania between the years of 2019 up to the end of 2022. Methods: The data were analyzed in SAS for Windows, V9.4. The survival curves were estimated using the Kaplan-Meier method, and survival distributions were compared with log-rank test. The effects of the main clinical and pathological variables on OS and PFS were investigated with Cox regression. Results: Kaplan-Meier curve of OS in all evaluable patients enrolled in the study resulted in a median OS of 346 days (95% CI: 150-NA) and a median PFS of 211 days (95% CI: 113-430). 45.3% of the patients experienced adverse events during the Nivolumab + Ipilimumab treatment with some of them having multiple organ systems involved. Discussion: The OS values were lower than that reported in approval clinical trials, but the results show a marked improvement when comparing to results obtained by chemotherapy regimens previously used in these scenarios. Conclusion: This study provides real-world insights into the survival data and safety profiles of combination therapy with anti-PD-1 antibodies and anti-CTLA-4 antibodies.

Tumour microenvironment, composed of pro- and anti-tumour immune cells, affects cancer cells behaviour. We aimed to evaluate if tumour-infiltrating lymphocyte (TIL) density and TILs subtypes in core biopsies at diagnosis of breast cancer patients could predict pathologic complete response (pCR; ypT0/is ypN0) from neoadjuvant systemic therapy (NST). The TIL subtypes were determined based on the proportions of presumably anti-tumour (CD8+, CXCL13+) and pro-tumour (PD-1+, FOXP3+) immune cells. A prospective, non-interventional study including 171 participants undergoing NST was performed. The median TIL density for the entire cohort was 10% (IQR: 3.5-23.8), and 59 (35%) patients achieved pCR. TIL density was positively associated with pCR (univariately and multivariably). In the multivariable logistic regression model, TIL density was an independent predictor of pCR (p=0.012, OR 1.27; 95% CI 1.05-1.54) when controlled for age (p=0.232), Ki-67 (p=0.001), node-negative status (p=0.024), and HER2+/triple negative vs luminal B-like subtype (p&lt;0.001). In our sample, higher proportions of PD-1+ TILs and FOXP3+ TILs were associated with a higher probability of pCR but the association was not statistically significant. In the exploratory multivariable analysis, we showed that only higher CD8+ TILs were associated with pCR. In conclusion, TIL density and its subtypes are associated with pCR.

Ferroptosis is a unique variety of non-apoptotic cell death, driven by massive lipid oxidation in an iron-dependent manner. Since Ferroptosis was introduced as a concept in 2012, it was shown it's essential role in the pathogenesis in neurodegenerative diseases and an important role in therapy-resistant cancer cells. Thus, a detailed molecular understanding of both canonical and alternative ferroptosis pathways are required. There is a set of widely used chemical agents to modulate ferroptosis using different pathway targets: Erastin blocks cystine-glutamate antiporter, system xc-; ML210 directly inactivate GPX4; L-buthionine sulfoximine (BSO) inhibits γ-glutamylcysteine synthetase, an essential enzyme for glutathione synthesis de novo. Most studies were focused on lipidomic profiling of model systems undergoing death in a ferroptotic modality.

Objectives to assess COVID-19 mortality rates per country population. To determine what if any independent country-specific variables from 9 different databases were correlated. Design population based retrospective cohort study. Setting analysis of global COVID-19 treatment and containment strategies using data from 9 worldwide websites. Participants 108 countries worldwide. Interventions none. Main Outcome Measures were COVID-19 death rates per country population analyzed by univariate and multivariate analysis. The main outcome parameters were to determine if there are any correlations between the percentage of countrywide COVID-19 deaths/population by the countries’ percent vaccinated. Secondary outcome measures include the effect of other independent variables on COVID-19 death rates per country population including: health expenditures per capita, annual income per capita, COVID-19 tests per 1000 people, stringency index (a measure of each countries containment strategies), hydroxychloroquine score (a measure of each countries use), ivermectin score (a measure of each countries use), hypertension, obesity, diabetes, and specific countries and geographic locations. Results COVID-19 vaccination rates ranged from 0-99% in 108 countries. Univariate analysis demonstrates the following independent variables to correlate with COVID-19 deaths/population (correlation coefficient, p value): countrywide COVID-19 vaccination rates (+0.2936, p=0.002); healthcare costs per capita (+0.3212, p=0.0007), income per capita (+0.3051, p=0.0013), COVID-19 tests per 1000 population (+0.6981 p=0.0307); stringency index (+0.3098, p=0.0011); hydroxychloroquine index (-0.1337, p=0.0678); and ivermectin index (-0.1383, p=0.1535). Conclusions Increasing rates of COVID-19 vaccination are associated with increase COVID-19 death rates per country population (p=0.002). Other variables associated include healthcare costs per capita (+0.3212, p=0.0007), income per capita (+0.3051, p=0.0013), COVID-19 tests per 1000 population (+0.6981 p=0.0307); and stringency index (+0.3098, p=0.0011).

Ontological premises have profound theoretical implications. This analysis posits a single, universal structure composed of two ontic entities: discrete, quantized units of space ("Planck Spheres") and a State of Absolute Nothingness (the "SOAN"). Planck Spheres and the SOAN form a physical, ultra-high (3 x N) dimensional space ("Planck Space") and a discrete 3D space (or "4D spacetime"). Together, Planck Space and 4D spacetime form a tightly integrated ((3 x N) + 3) hyperspace (the "Dual Ontology"). Critically, a one-to-one mapping and identity exists between the Planck Spheres comprising 4D spacetime and Planck Space. The Dual Ontology conjecture supports radically simplified physical explanations for three distinct areas of theoretical physics: First, the conjecture reconciles fundamental issues in Special Relativity and quantum mechanics by explaining why single and N-body quantum states (a) dynamically evolve in 4D spacetime subject to the speed of light and (b) instantaneously collapse in a physical Planck Space that is not subject to Special Relativity. Second, the temporal and physical asymmetry between the dynamic evolution of quantum states in 4D spacetime subject to Special Relativity and the instantaneous collapse of quantum states in a Planck Space where Special Relativity is inapplicable explains quantum path irreversibility and the arrow of time. Third, at or near the heat death of 4D spacetime, the instantaneous collapse of the energy content of Planck Space and the simultaneous transition of 4D spacetime's extremely widely dispersed energy content to a non-singular, generally localized volume at t = 0 explains 4D spacetime's isotropy, homogeneity, extremely high energy, pressure, and temperature, flatness, and low gravitational entropy. It also explains the horizon and fine-tuning problems.

Chronic lymphocytic leukemia (CLL) is characterized by dysfunctional B cells. Immune checkpoint molecules such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and programmed death-1 (PD-1) are upregulated in patients with CLL and may correlate with prognostic markers such as beta-2 microglobulin (B2M). The aim of this study was to evaluate the levels of immune checkpoints on B-cell subsets and to further correlate them with B2M levels in patients with CLL. We recruited 21 patients with CLL and 12 controls. B cell subsets and the levels of immune checkpoint expression were determined using conventional multi-color flowcytometry. Basal levels of B2M in patients with CLL were measured using an Enzyme-linked immunosorbent assay. Patients with CLL had increased levels of activated B cells when compared to the control group, p< 0.001. The expression of PD-1 and CTLA-4 were increased on activated B cells and memory B cells, p< 0.05. There were no associations between B2M levels and the measured immune checkpoints on B cell subsets, after adjusting for sex and age. African patients with CLL express elevated levels of PD-1 and CTLA-4 immune checkpoints on activated and memory B cell subsets. However, there is no correlation between these immune checkpoint expressions and B2M levels.

Navigating growth cones are exposed to multiple signals simultaneously and have to integrate competing cues into a coherent navigational response. Integration of guidance cues is traditionally thought to occur at the level of cytoskeletal dynamics. Drosophila studies indicate that cells exhibit a low level of continuous caspase protease activation, and that axon guidance cues can activate or suppress caspase activity. We base a model for axon guidance on these observations. By analogy with other systems in which caspase signaling has non-apoptotic functions, we propose that caspase signaling can either reinforce repulsion or negate attraction in response to external guidance cues by cleaving cytoskeletal proteins. Over the course of an entire trajectory, incorrectly navigating axons may pass the threshold for apoptosis and be eliminated, whereas axons making correct decisions will survive. These observations would also explain why neurotrophic factors can act as axon guidance cues and why axon guidance systems such as Slit/Robo signaling may act as tumor suppressors in cancer.

In the past decade, targeted therapies for solid tumors, including non-small cell lung cancer (NSCLC), have advanced significantly, offering tailored treatment options for patients. However, individuals without targetable mutations pose a clinical challenge, as they may not respond to standard treatments like immune-checkpoint inhibitors (ICIs) and novel targeted therapies. While the mechanism of action of ICIs seems promising, the lack of a robust response limits their widespread use. Although the expression levels of programmed death ligand 1 (PD-L1) on tumor cells are used to predict ICI response, identifying new biomarkers, particularly those associated with the tumor microenvironment (TME), is crucial to address this unmet need. Recently, inflammatory cytokines such as interleukin-1 beta (IL-1β) have emerged as a key area of focus and hold significant potential implications for future clinical practice. Combinatorial approaches of IL-1β inhibitors and ICIs may provide a potential therapeutic modality for NSCLC patients without targetable mutations. In this review, we discuss the role of IL-1β in NSCLC, its involvement in inflammatory pathways, and explore its potential role in the treatment of NSCLC.

Increased screen time during the COVID-19 pandemic and the accelerated incorporation of technology into daily practices have directly contributed to the increased prevalence of eye disease. The human eye is not built for continual technological use and must adjust to exposure to digital screens. Overexposure to technology can result in eye strain and an increased risk of eye diseases such as myopia with complications later in life, including retinal tears, cataracts, and macular degeneration. As vision and ocular diseases become more prevalent, the study of eye diseases, including their causes and treatments, is especially relevant. There is a need to prevent ocular diseases before they become a burden to individuals, their families, and their communities by better understanding the pathophysiology of ocular diseases. Several ocular diseases are thought to be caused by imbalances in reactive oxygen species (ROS) and autophagy. ROS refers to a class of highly reactive oxygen-containing molecules that can undergo damaging reactions with other molecules in the cell. Autophagy is a cellular process of self-eating whereby damaged, harmful, or dead material in cells is broken down to maintain cellular homeostasis. This paper discusses the role of ROS and autophagy in the pathogenesis of computer vision syndrome (CVS), digital eye strain (DES), myopia, cataracts, glaucoma, diabetic retinopathy (DR), age-related macular degeneration (AMD), optic nerve crush injury (OCN), optic nerve gliomas, and retinoblastoma. Lifestyle changes such as limiting screen time, ensuring adequate exposure to evening sunlight, and using blue light protection measures or protective eyewear are important in the prevention of eye disease. Nutrition also contributes significantly to eye health. A balanced diet rich in vitamins and antioxidants may help to prevent ROS and autophagy imbalance-induced eye disease. Medical and surgical treatments become necessary when preventative measures fail. This paper also addresses how government measures to decrease the onset of eye disease, including targeted programs to increase access to fresh vegetables and fruits in food deserts, are a critical macro-level avenue to reduce eye disease prevalence in the US, which according to the National Eye Institute, costs $139 billion yearly.

Background: Despite tremendous efforts to reduce neonatal mortality worldwide and in 24 Ethiopia, there is the country is one of the countries with highest neonatal morbidity and health 25 losses. Never the less, the past three decades’ national trend and subnational distribution of 26 neonatal morbidity and mortality and its health loss in Ethiopia, was not well documented. 27 Hence, this study had aimed to analyze the trend and distributions as well as health losses 28 resulting from neonatal morbidity in the past three decades in Ethiopia, 2019. 29 Objective: To assess the national trend and sub national distributions of neonatal morbidity and 30 neonatal mortality in the previous three decades by using Global Burden of Diseases, 2019 data. 31 Methods: The data sources were primary and secondary data related to risk factors, morbidity, 32 disability, deaths, Disability Adjusted Life Years, Years Lived with Disability and Years Life Lost 33 were collected form case studies and case series, household surveys, socio-demographic surveys 34 and surveillances, health facilities surveys, Health facility observations and interviews and 35 published and unpublished literatures. The prevalence, deaths and health losses were calculated 36 by using embedded model. The study period covered from 1990 to 2019. Results were presented 37 buy using texts, tables and graphs. 38 Results: Seventy percent of neonatal disorders had occurred among early neonates aged 0 to 6 39 days. Between 1990 and 2019, the national prevalence of neonatal disorders had increased by 40 47% in to 28,319 (95% UI, 25646-30,361). Bet Similarly, the highest number of neonatal deaths 41 caused by neonatal sepsis had shifted from Southern Nations Nationalities and Peoples region to 42 Oromia region while Harari remains to bear the lowest burden in the last three decades. The 43 highest and the lowest YLL as a result of neonatal disorders had occurred in Oromia 44 [(2,753,038,95% UI, 2,184,142-3,497-926) and Amhara 1,360,847 [(95% UI, 95% UI, 45 1,062,660-1,762,028)] regions respectively. Unlike other regions, Addis Ababa had the highest 46 (52%) prevalence of preterm birth in 2019 47 Conclusion and Recommendation: About seven in ten of neonatal death had occurred among 48 early neonates indicating narrowed occurrence of the event. The highest and the lowest number 49 of neonatal death and health loss had occurred in Oromia and Harari regions respectively. The 50 main causes of death were neonatal sepsis and other infections, neonatal preterm, hemolytic 51 disease and other jaundice and neonatal encephalopathy and trauma. Hence, Contextualized, 52 locally accepted innovative early neonatal care is crucial to avert the event.

Individuals residing in more deprived areas have a lower diet quality. While several studies have shown that individuals with a lower diet quality have a higher mortality risk, a low quality diet might also lead to poor health in highly deprived areas. We aimed to examine the association between deprivation within an area and all-cause mortality risk according to diet quality. Methods: We conducted a population-based prospective study on 27994 men and 33273 women aged 45–75 years. Neighborhood deprivation was assessed using the Japanese areal deprivation index (ADI). Dietary intakes were assessed using a validated 147-item food frequency questionnaire. Subsequently, Japanese Food Guide Spinning Top scores were calculated. Hazard ratios (HR) and 95% confidence intervals (CI) of mortality were calculated according to tertiles of ADI by diet quality score. Results: Individuals residing in the most deprived area had the lowest dietary scores. During the 16.7-year follow-up, compared to individuals with a high quality diet residing in the least deprived area, individuals with a low quality diet had a higher risk of mortality according to increment of ADI (P trend = 0.02); the multivariate adjusted HR (95% CI) was 1.07 (1.00-1.15), 1.15 (1.07-1.24), and 1.18 (1.08-1.29) in those residing in the lowest through the highest third of ADI, respectively. However, individuals with a high quality diet had no significant association between ADI and mortality (P trend =0.87). Conclusion: A well-balanced diet may prevent early death associated with neighborhood socioeconomic status among those residing in highly deprived areas.

This study presents the interaction with human host metabolism of SARS-CoV-2 ORF7b protein (43 aa), using a Protein-Protein-Interaction Networks analysis. After pruning, we selected from BioGRID the 51 most significant proteins among 2,753 proven interactions and 1,708 interactors, specific to ORF7b. We used these proteins as functional seeds and we got a significant network of 551 nodes via STRING. We performed topological analysis and calculated topological distributions by Cytoscape. Seven high ranked proteins as hub and seven as bottleneck following a hub-and-spoke network-architectural-model were found. Through this interaction model, we identified significant GO-processes (5,057 terms in 15 categories) induced in human metabolism by ORF7b. High statistical significance processes of dysregulated molecular cell mechanisms by the action of ORF7b were discovered. We detected disease-related human proteins and their involvement in metabolic roles, how they relate in a distorted way to signaling and/or functional systems, in particular intra- and inter-cellular signaling systems and the molecular mechanisms that supervise to programmed cell death, with mechanisms similar to that of cancer metastasis diffusion. A cluster analysis showed 10 compact and significant functional clusters, where two of them overlap in a Giant-Connected-Components core of 206 total nodes. These two clusters contain most of the high-rank nodes. ORF7b mainly acts through these two clusters, inducing most of the metabolic dysregulation. We conducted a co-regulation, transcriptional analysis by hub and bottleneck proteins. This analysis allowed us to define the transcription factors and miRNAs that control the high-ranking proteins and the dysregulated processes, within the limits of the poor knowledge that these sectors still impose.

One of the earliest hallmarks of plant immune response is production of reactive oxygen spe-cies (ROS) in different subcellular compartments, which regulate plant immunity. A suitable equilibrium, which is crucial to prevent ROS over-accumulation leading to oxidative stress, is maintained by salicylic acid (SA), a chief regulator of ROS. However, ROS are not only acting downstream of SA signaling, but were also proposed to be a central component of a self-amplifying loop that regulates SA signaling as well as the interaction balance between dif-ferent phytohormones. The exact role of this crosstalk, the position where SA interferes with ROS signaling and ROS interferes with SA signaling and the outcome of this regulation depend on the origin of ROS but also on the pathosystem. The precise spatiotemporal regulation of or-ganelle specific ROS and SA levels determine the effectiveness of pathogen arrest and is there-fore crucial for a successful immune response. However, the regulatory interplay behind still remain poorly understood, as up till now, the role of organelle specific ROS and SA in HR-conferred resistance has mostly been studied by altering the level of a single component. In order to address these aspects, a sophisticated combination of research methods for monitoring the spatiotemporal dynamics of key players and transcriptional activity in plants is needed, and will most probably consist of biosensors and precision transcriptomics.

Cisplatin (CDDP), carboplatin (CP), and oxaliplatin (OXP) are three platinating agents clinically approved worldwide for use against a variety of cancers. They are canonically known as DNA damage inducers; however, that is only one of their mechanisms of cytotoxicity. CDDP mediates its effects through DNA damage-induced transcription inhibition and apoptotic signalling. In addition, CDDP targets the endoplasmic reticulum (ER) to induce ER-stress, the mitochondria via mitochondrial DNA damage leading to ROS production, and the plasma membrane and cytoskeletal components. CP acts in a similar fashion to CDDP by inducing DNA damage, mitochondrial damage, and ER stress. Additionally, CP is also able to upregulate micro-RNA activity, enhancing intrinsic apoptosis. OXP, on the other hand, at first induces damage to all the same targets as CDDP and CP, yet it is also capable of inducing immunogenic cell death via ER stress and can decrease ribosome biogenesis through its nucleolar effects. In this comprehensive review, we provide detailed mechanisms of action for the three platinating agents, going beyond their nuclear effects to include their cytoplasmic impact within cancer cells. In addition, we cover their current clinical use and limitations, including side effects and mechanisms of resistance.

According to Swiss-American Doctor of Sciences and Agricultural Engineer Jean-Pierre Jost, "plants communicate with each other by the quality of light emitted by their leaves or by means of stress hormones and other volatile chemicals. They also make use of cocktails of chemicals, pheromones, shape and colors to attract pollinators whereas other signals repel unwanted organisms. Insects are able to decode such messages and respond accordingly. Plants are apparently also communicating by sounds and electric signals." (1) How do plants do these things? Of course, it's easy to imagine it's all purely mechanical. But at the risk of sounding like a mysticism fanatic, I wonder if plants' activities are part of a spectrum of consciousness that pervades the entire universe. This spectrum would result from everything in the universe having the BITS or BInary digiTS of electronics as their ultimate composition. As explained in this hypothesis, something I call vector-tensor-scalar geometry is essential to my hypothesis. VTS geometry produces the particles of chemicals and pheromones, and refers to communication via electric signals when it speaks of electromagnetic-gravitational interaction. There's another consequence if everything in the universe is ultimately composed of electronic BITS and the cosmos is a spectrum of consciousness/artificial intelligence. It's impossible for an absence of consciousness to exist, either after death or before conception.

The SARS-CoV-2 virus that causes the COVID-19 disease has wreaked havoc on the world community in terms of every imaginable parameter. The research output on COVID-19 has been nothing short of phenomenal, especially in the medical and biomedical sciences, where the search for a potential vaccine is being conducted in earnest. Much of the advanced research has been distributed in the leading medical journals, including the Journal of the American Medical Association (JAMA), where the latest research is distributed on a daily basis. The purpose of this paper is to provide some perspectives on 44 interesting and highly topical research papers that have been published in JAMA, at the time of writing, within the past two weeks. The diverse topics include public health, general medicine, internal medicine, oncology, paediatrics, geriatrics, and biostatistics.