Background: Although rarely indicated, antibiotics are commonly used for acute diarrhoea in China. We conducted a randomized, double blind exploratory clinical trial of loperamide, berberine and turmeric for treatment of acute diarrhoea. Methods: Adults with acute uncomplicated diarrhoea were randomized to 4 groups: (A) loperamide; (B) loperamide and berberine; (C) loperamide and turmeric; (D) loperamide, berberine and turmeric. All participants were given rescue ciprofloxacin for use after 48 hours if symptoms worsened or were unimproved. Primary endpoints were feasibility and ciprofloxacin use during the 2 week follow-up period. Semi-structured interviews were conducted following recruitment. Results: Only 21.5% (278/1295) of patients screened were deemed eligible, and 49% (136/278) of these consented and entered into the final analysis. Most participants had mild symptoms, because most patients with moderate or severe symptoms wanted to be given antibiotics. Follow-up was good (94% at 2 weeks). Only two participants used rescue antibiotics compared to 65% of acute diarrhoea patients in the hospital during the recruitment period. The median symptom duration was: 14 hours in group B (IQR 10-22), 16 hours in group D (IQR 10-22), 18 hours in group A (IQR 10-33), 20 hours in group C (IQR 16-54). Re-consultation rates were low. There were no serious treatment-related adverse events. Most interviewed participants said the treatment was effective. Conclusion: Although recruitment was challenging because of widespread expectations for antibiotics, patients with mild diarrhoea accepted to try an alternative. This therapy requires further evaluation in a fully powered, randomised controlled trial among a broader sample.

Wall–stabilized arcs dominated by nozzle–ablation are key elements of self–blast circuit breakers. In the present study, high–current arcs were investigated using a model circuit breaker (MCB) in CO2 as gas alternative to SF6 and in addition a long polytetrafluoroethylene nozzle under ambient conditions for stronger ablation. The assets of different methods for optical investigation were demonstrated, e.g. high-speed imaging with channel filters and optical emission spectroscopy. Particularly the phase near current zero (CZ) crossing was studied in two steps. In the first step using high-speed cameras, radial temperature profiles have been determined until 0.4 ms before CZ in the nozzle. Broad temperature profiles with a maximum of 9400 K have been obtained from analysis of fluorine lines. In the second step, the spectroscopic sensitivity was increased using an intensified CCD camera, allowing single-shot measurements until few microseconds before CZ in the MCB. Ionic carbon and atomic oxygen emission were analyzed using absolute intensities and normal maximum. The arc was constricted and the maximum temperature decreased from >18000 K at 0.3 ms to about 11000 K at 0.010 ms before CZ. The arc plasma needs about 0.5-1.0 ms after both the ignition phase and the current zero crossing to be completely dominated by the ablated wall material.

Complementary and alternative treatment approaches are becoming more common among children with chronic conditions. The pravelance of CAM use among US adults was estimated to be around 42% in 2015, and around 44% to 50% among adults with neurologic disorders. Studies report children with chronic illnesses such as cancer, asthma, attention-deficit/hyperactivity disorder (ADHD), genetic disorders, and other neurodevelopmental disorders are treated with complementary and alternative treatments at higher rates. Dietary therapies are gaining increasing popularity in the mainstream population, due to the heavy media involvement. Although, majority of “fad” diets do not have enough supporting evidence, some dietary therapies have been utilized for decades and have numerous published studies. The objective of this review is to describe the dietary interventions used in children with the specific chronic conditions, to evaluate their efficacy based on published data, and to encourage pharmacist involvement in the management and care of such patients.

Alternative splicing (AS) is a gene regulatory mechanism modulating gene expression in multiple ways. AS is prevalent in all eukaryotes including plants. AS generates two or more mRNAs from the precursor mRNA (pre-mRNA) to regulate transcriptome complexity and proteome diversity. Advances in next-generation sequencing, omics technology and bioinformatics tools, and computational methods provide new opportunities to quantify and visualize AS-based quantitative trait variation associated with plant growth, development, reproduction, and stress tolerance. Domestication, polyploidization and environmental perturbation may evolve novel splicing variants associated with agronomically beneficial traits. To date, pre-mRNAs from many genes are spliced into multiple transcripts that cause phenotypic variation for complex traits, both in model plant Arabidopsis and field crops. Cataloguing and exploiting such variation may provide new paths to enhance climate resilience, resource-use efficiency, productivity, and nutritional quality of staple food crops. This review provides insights into AS variation alongside gene expression analysis to select for novel phenotypic diversity for use in breeding programs. AS contributes to heterosis, enhances plant symbiosis (mycorrhiza and rhizobium), and provides a mechanistic link between the core clock genes and diverse environmental clues.

The fusion of penetrating peptides (PPs), e.g., cell penetration peptides (CPPs), or antimicrobial peptides (AMPs) together with antimicrobial agents is an expanding research field. Specific AMPs, such as lactoferricin B (LfcinB), have demonstrated strong antibacterial, antifungal, and antiparasitic activity, as well as valuable anticancer activity, proving beneficial in the development of anticancer conjugates. The resulting conjugates offer potential dual functionality, acting as both an anticancer and an antimicrobial agent. This is especially necessary in cancer treatment where microbial infections pose a critical risk. Leukemic cells frequently exhibit altered outer lipid membranes compared to healthy cells, making them more sensitive to compounds that interfere with their membrane. In this communication, we revisited and reanalyzed our earlier research on LfcinB and its conjugates. Furthermore, we carried out new experiments with a specific focus on cell proliferation, changes in membrane asymmetric phosphatidylserine location, intracellular reactive oxygen species (ROS) generation, mitochondrial functions, and in vitro bacterial topoisomerase inhibition.

In the event of an abrupt sunlight reduction scenario there is a time window that occurs between when food stores would likely run out for many countries (~6 months or less) and ~1 year when resilient foods are scaled up. A promising temporary resilient food is leaf protein concentrate (LPC). Although it is possible to extract LPC from tree biomass (e.g. leaves and needles), neither the yields nor the toxicity of the protein concentrates for humans from the most common tree species has been widely investigated. To help fill this knowledge gap, this study uses high-resolution mass spectrometry and an open source toolchain for non-targeted screening of toxins on five common North American coniferous species: Western Cedar, Douglas Fir, Ponderosa Pine, Western Hemlock, and Lodgepole Pine. The yields for LPC extraction from the conifers ranged from 1% to 7.5%. The toxicity screenings confirm that these trees may contain toxins that can be consumed in small amounts and additional studies including measuring the quantity of each toxin are needed. The results indicate that LPC is a promising candidate to be used as resilient food, but future work is needed before LPCs from conifers can be used as a wide-scale human food.

PitNETs, although typically benign, comprise a small percentage of therapy-resistant aggressive, occasionally metastatic tumors, underpinning a need to identify novel therapeutic targets. PitNETs carry few mutations but associate with conditions that promote alternative splicing as an oncogenic alternative and express the TrkA neurotrophin receptor, which exhibits oncogenic alternative TrkAIII splicing in other tumors. Alternative TrkAIII splicing was assessed by RT-PCR in 53 PitNETs and compared to HIF1a, HIF2a, SF3B1, SRSF2, U2AF1 and JCPyV large T antigen mRNA expression, unconventional Xbp1 splicing, SF3B1 mutation, and TrkA isoform(s) immunoreactivity by confocal immunofluorescence (IF). Alternative TrkAIII mRNA splicing was detected in all invasive PitNET phenotypes, was significantly elevated in invasive compared to non-invasive PIT1 PitNETs, relatively high in invasive and non-invasive SF1 and TPIT PitNETs, and was associated with IF consistent with intracellular TrkAIII activation but not with hotspot SF3B1 mutations, altered SF3B1, SRSF2 and U2AF1 splice factor mRNA expression, JCPyV large T antigen expression or unconventional Xbp1 splicing. A potential role for hypoxia in TrkAIII mRNA splicing was supported by significant elevation of HIF2a mRNA expression in invasive PIT1 PitNETs. These data demonstrate that alternative TrkAIII splicing, potentially promoted by hypoxia, occurs frequently in PitNETs and may associate with IF consistent with intracellular TrkAIII activation, supporting a potential role for TrkAIII in PitNET pathogenesis and progression, identifying TrkAIII as a novel potential target in refractory PitNETs.

Currently, there is increasing industrial demand for rare earth elements (REE) as these elements are now integral to the manufacture of many carbon-neutral technologies. The depleting REE ores and increasing mining costs are prompting to look for alternative sources for these valuable metals, particularly from waste streams. Although REE concentrations in most of the alternate resources are lower than current REE ores, some sources such as marine sediments, coal ash, and industrial wastes like red mud are looking promising with significant concentrations of REE in them. This review focuses on the alternative resources for REE such as ocean bottom sediments, continental shelf sediments, river sediments, stream sediments, lake sediments, phosphorites deposits, industrial waste products like red mud, and phosphogypsum, coal, coal fly ash, and related materials, waste rock sources from old and closed mines, acid mine drainage, and recycling of e-waste. Possible future Moon exploration and mining for REE and other valuable minerals are also discussed. It is evident that REE extractions from both primary and secondary ores alone are not adequate to meet the current demand, and sustainable REE recovery from the alternative resources described here is also necessary to meet the growing REE demand. An attempt is made to identify the potential of these alternative resources and sustainability challenges, benefits, and possible environmental hazards to meet the growing challenges in meeting the future REE requirements.

Multiple mRNA isoforms of the same gene are produced via alternative splicing, a biological mechanism that regulates protein diversity while maintaining genome size. Alternatively spliced mRNA isoforms of the same gene may sometimes have very similar sequence, but they can have significantly diverse effects on cellular function and regulation. The products of alternative splicing have important and diverse functional roles, such as response to environmental stress, regulation of gene expression, human heritable and plant diseases. The mRNA isoforms of the same gene, such as the apoptosis associated CASP3 gene, can have dramatically different functions. The shorter mRNA isoform product CASP3-S inhibits apoptosis, while the longer CASP3-L mRNA isoform promotes apoptosis. Despite the functional importance of mRNA isoforms, very little has been done to annotate their functions. The recent years have however seen the development of several computational methods aimed at predicting mRNA isoform level biological functions. These methods use a wide array of proteo-genomic data to develop machine learning-based mRNA isoform function prediction tools. In this review, we discuss the computational methods developed for predicting the biological function at the individual mRNA isoform level.

Nucleic acid therapeutics are witnessing an impressive acceleration in recent years. They work through multiple mechanisms of action, including downregulation of gene expression and modulation of RNA splicing. While several drugs based on the former mechanism have been approved, few target the latter, despite the promise of RNA splicing modulation. To improve our ability to discover novel RNA splicing-modulating therapies, we developed HCS-Splice, a robust cell-based High-Content Screening (HCS) assay. By implementing the use of a two-colour (GFP/RFP) fluorescent splicing reporter plasmid, we developed a versatile, effective, rapid, and robust high-throughput strategy for the identification of potent splicing-modulating molecules. The HCS-Splice strategy can also be used to functionally confirm splicing mutations in human genetic disorders or to screen drug candidates. As a proof-of-concept, we introduced a dementia-related splice-switching mutation in Microtubule-Associated Protein Tau (MAPT) exon 10 splicing reporter. We applied HCS-Splice to the wild-type and mutant reporters and measured the functional change in exon 10 inclusion. To demonstrate the applicability of the method to cell-based drug discovery, HCS-Splice was used to evaluate the efficacy of an exon 10-targeting siRNA, which was able to restore the correct alternative splicing balance.

Cyber diplomacy is critical in dealing with evolving cybersecurity dangers and possibilities in the digital era. This article investigates the impact of Artificial Intelligence (AI), the Internet of Things (IoT), Blockchains, and Quantum Computing on cyber diplomacy. AI holds the potential for proactive threat identification and response, while IoT enables international information sharing. Blockchains enable secure data sharing and document verification, but they also pose new threats, such as AI-driven cyber-attacks, IoT privacy breaches, blockchain vulnerabilities, and the potential for quantum computing to break encryption. This article conducts case study reviews, in combination with secondary data analysis, and emphasises the value of international cooperation in developing global norms and frameworks to control responsible technology adoption. Cyber diplomacy can promote cybersecurity, protect national interests, and foster mutual trust among nations in the digital sphere by capitalising on possibilities and reducing threats.

The spillover of a virus from an animal reservoir to humans requires both molecular and ecological risk factors to align. While extensive research both before and after the emergence of SARS-CoV-2 in 2019 implicates horseshoe bats as the significant animal reservoir for the new human coronavirus, it remains unclear why it emerged at this time. One massive disruption to animal-human contacts in 2019 is linked to the on-going African swine fever virus (ASFV) pandemic. Pork is the major meat source in the Chinese diet. We hypothesize that the dramatic shortage of pork following large-scale culling and restrictions of pig movement (resulting in marked price increases) led to alternative sources of meat and unusual animal and meat movements nationwide, e.g., involving wildlife, and thus greatly increased opportunities for human-sarbecovirus contacts. Pork prices were particularly high in southern provinces (Guangdong, Guangxi, Fujian, Jiangxi, Hunan, and Hubei), where wildlife is farmed and more frequently consumed. Major wildlife farming provinces are spread from Northern to Southern China, which overlaps with horseshoe bat host ranges, potential hosts of the proximal SARS-CoV-2 ancestor, and wildlife sourcing provinces of Wuhan Huanan market and possibly other markets. Trading of SARS-CoV-2 susceptible wildlife in these markets, such as minks, raccoon dogs, foxes and palm civets in Wuhan markets, could have increased the risk of SARS-CoV-2 from an intermediary host. Moreover, large quantities of animals raised for fur could have entered the human food chain undetected and significantly increased risks of animal-human contact. Performing retrospective testing of stored susceptible animals and their meat sold before December 2019 may be helpful in the next stage of tracing the animal origin of SARS-CoV-2 as spillover events are more likely to have taken place in 2019 when China was experiencing the worst effects of the ASFV pandemic.

Researchers have reported various impacts of the COVID-19 outbreak on small-scale fishers, such as stagnating market demands, reduction of market price and income, etc. While literature have heeded to these impacts in a relatively short time frame, scant evidence exists on the changing impacts over time and on the detailed processes of how fishers have been coping with the challenges in a longer time period. Furthermore, few studies have comprehensively analysed the impacts and strategies from multiple perspectives. This study aims to explore the perceived impacts of the COVID-19 outbreak on small-scale fishing communities and to highlight the coping strategies adopted by fishers over a year since the initial outbreak, through a case study in Trang Province, Thailand. Analysis of both qualitative and quantitative data obtained through semi-structured interviews indicated that fishers wisely utilised natural, financial and social capitals at the early stages of the outbreak, while human capitals were essential for recovering from the impacts in the later stages. Our findings suggest that the adaptive capacity to flexibly change livelihood strategies are crucial, while alternative income source may not necessarily help small-scale fishers under stagnating global economy.

Agroindustrial by-products constitute an alternative source of feed livestock, and their use contributes to the sustainability of livestock systems and the circular bioeconomy. The effects of replacing cereal (0%, 40% and 80%) with dehydrated orange pulp (DOP) in the diet of goats on the antioxidant and fatty acid (FA) contents of cheeses were evaluated. For a more suitable understanding of the role of coagulant enzymes in establishing the properties of the cheese, the effect of milk-clotting with animal and vegetable rennet was also analysed. The rennet did not substantially affect the FA or the antioxidant compounds, and the use of DOP did not affect the FA contents. However, the α-tocopherol levels, total phenolic compounds (TPC), and total antioxidant capacity (TAC) in cheeses increased as the percentage of DOP replacing cereals increased. Moreover, the high correlation obtained between the TAC and the TPC (r = 0.73) and α-tocopherol (r = 0.62) contents indicated the important role played by these compounds in improving the antioxidant capacity of the cheese. In conclusion, DOP is a suitable alternative to cereals in the diet of goats and improves the antioxidant status of the cheese produced.

Synthetic fuels play an important role in the defossilization of future aviation transport. To reduce the ecological impact of remote airports due to long range transportation of kerosene, a decentralized on-site-production of synthetic paraffinic kerosene is applicable, preferably as near-drop-in fuel or alternatively as blend. One possible solution for such a production of synthetic kerosene is the Power-to-Liquid process. The basic development of a simplified plant layout addressing the specific challenges of a decentralized kerosene production which differ from most current approaches for infrastructural well-connected regions is described. The decisive influence of the Fischer-Tropsch synthesis on the PtL process is shown by means of a steady-state reactor model which was developed in Python and serves as basis for further development of a modular environment able to represent entire process chains. The reactor model is based on reaction kinetics according current literature. The effects of adjustments of the main operation parameters on the reactor behavior are evaluated and the impacts on up- and downstream processes are described. The results prove the governing influence of the Fischer-Tropsch reactor on the PtL process and show its flexibility regarding the desired product fraction output, which makes it an appropriate solution for a decentralized kerosene production.

Background: Recent developments in our understanding of the interactions between long non-coding RNA (lncRNA) and cellular components have improved treatment approaches for various human diseases including cancer, vascular diseases, and neurological diseases. Although investigation of specific lncRNAs revealed their role in the metabolism of cellular RNA, our understanding of their contribution to post-transcriptional regulation is relatively limited. In this study, we explore the role of lncRNAs in modulating alternative splicing and their impact on downstream protein-RNA interaction networks. Results: Analysis of alternative splicing events across 39 lncRNA wildtype and knockout RNA-sequencing datasets from three human cell lines: HeLa (Cervical Cancer), K562 (Myeloid Leukemia), and U87 (Glioblastoma), resulted in high confidence (fdr < 0.01) identification of 4432 skipped exon events and 2474 retained intron events, implicating 759 genes to be impacted at post-transcriptional level due to the loss of lncRNAs. We observed that a majority of the alternatively spliced genes in a lncRNA knockout were specific to the cell type, in agreement with the finding that genes affected by alternative splicing also displayed enriched functions in a cell type specific manner. To understand the mechanism behind this cell-type specific alternative splicing patterns, we analyzed RNA binding protein (RBP)-RNA interaction profiles across the spliced regions. Conclusions: Despite limited RBP binding data across cell lines, alternatively spliced events detected in lncRNA perturbation experiments were associated with RBPs binding in proximal intron-exon junctions, in a cell type specific manner. The cellular functions affected by alternative splicing were also affected in a cell type specific manner. Based on the RBP binding profiles in HeLa and K562 cells, we hypothesize that several lncRNAs are likely to exhibit a sponge effect in disease contexts, resulting in the functional disruption of RBPs due to altered titration of the RBPs from their target loci. We propose that such lncRNA sponges can extensively rewire the post-transcriptional gene regulatory networks by altering the protein-RNA interaction landscape in a cell-type specific manner.

Pathogenicity is unknown for the majority of human gene variants. For prioritization of sequenced somatic and germline mutation variants, in silico approaches can be utilized. In this study, 84 million non-synonymous Single Nucleotide Variants (SNVs) in the human coding genome were annotated using consensus Variant Effect Prediction (cVEP) method. An algorithm, implemented as a stacked ensemble of supervised learners, performed combination of the 39 functional, conservation mutation impact scores from dbNSFP4.0. Adding gene indispensability score, accounting for differences in the pathogenicities of the variants in the essential and the mutation-tolerant genes, improved the predictions. For each SNV the consensus combination gives either a continuous-value pathogenicity score, or a categorical score in five classes: pathogenic, likely pathogenic, uncertain significance, likely benign, benign. The provided class database is aimed for direct use in clinical practice. The trained prediction models were 5-fold cross-validated on the evidence-based categorical annotations from the ClinVar database. The rankings of the scores based on their ability to predict pathogenicity were obtained. A two-step strategy using the rankings, scores and class annotations is suggested for filtering and prioritization of the human exome mutations in clinical and biological applications of NGS technology.

Dietary supplements are widely embraced by cancer patients seeking complementary and integrative approaches to their care. Unfortunately, many patients do not discuss supplement use with physicians, often due to perceptions of physician indifference or negativity toward supplements. This communication gap exposes patients to unreliable information sources and, potentially, unnecessary risk. As the healthcare landscape evolves, patients increasingly value physicians who recognize their pivotal role in shaping healthcare decisions. This patient-centered perspective emphasizes the provision of evidence-based information tailored to individual needs, open discussions on potential risks, and shared decision-making. It underscores the importance of respecting patient autonomy, offering alternative options, documenting preferences, and ensuring ongoing support while coordinating with the healthcare team. To address these needs, healthcare providers should transform their perspectives and become expert guides who embrace patients as informed, empowered participants. This approach prioritizes open dialogue that considers both facts and uncertainties regarding dietary supplement use, allowing for mutually informed decision-making. Here, we review the literature and present a practical approach emphasizing open discussions, transparency, and respect for patient autonomy. Following this approach, healthcare providers can empower patients to navigate the complexities of dietary supplement use in the context of cancer care, ultimately safeguarding patient safety and well-being.

Pieron's and Chocholle’s seminal psychophysical work predicts that human response time to information relative to visual contrast and/or sound frequency decreases when contrast intensity or sound frequency increases. The goal of this study is to bring to the fore the ability of individuals to use visual contrast intensity and sound frequency in combination for faster perceptual decisions of relative depth (“nearer”) in planar (2D) object configurations on the basis of physical variations in luminance contrast. Computer controlled images with two abstract patterns of varying contrast intensity, one on the left and one on the right, preceded or not by a pure tone of varying frequency, were shown to healthy young humans in controlled experimental sequences. Their task (two-alternative forced-choice) was to decide as quickly as possible which of two patterns, the left or the right one, in a given image appeared to “stand out as if it were nearer” in terms of apparent (subjective) visual depth. The results show that the combinations of varying relative visual contrast with sounds of varying frequency exploited here produced an additive effect on choice response times in terms of facilitation, where a stronger visual contrast combined with a higher sound frequency produced shorter forced-choice response times. This new effect is predicted by cross-modal audio-visual probability summation.

The capacitor-mismatch among diverse defects caused by the manufacturing process variations significantly affects the linearity of capacitor-array used to implement the capacitive digital-to-analog converter (CDAC) in the successive-approximation-register (SAR) analog-to-digital converter (ADC). Accordingly, the linearity of the SAR ADC is limited by that of capacitor-array, resulting in serious yield loss. This paper proposes an efficient foreground self-calibration technique to enhance the linearity of the SAR ADCs by mitigating the capacitor-mismatch based on the split ADC architecture along with variable capacitors. In this work, two ADC channels (i.e., ADC1 and ADC2) for the split ADC architecture include their capacitive DACs (CDACs) whose binary-weighted capacitor-arrays consist of variable capacitors. A charge-sharing SAR ADC is used for each ADC channel. In the normal operation mode, their digital outputs are averaged to be the final ADC output, as in a conventional split ADC. In the calibration mode, every single binary-weighted capacitor for the two ADCs is sequentially calibrated by making parallel or/and antiparallel connection among two or thee capacitors from the two channels. For instance, because the capacitors of the CDACs ideally exhibit the binary-weighted relation as Cn=2×Cn−1, variable capacitor Cn of ADC1 can be updated to be closest to the sum of Cn−1 of ADC1 and Cn−1 of ADC2 for the calibration. For the process, the two capacitor-arrays of the two ADCs can be reconfigured to be connected to each other, so that Cn of ADC1 can be connected with two of Cn−1 of ADC1 and ADC2 in antiparallel. The two voltages at the top and the bottom plates of the CDAC are compared by a comparator of ADC1, and the comparison results are used to update Cn. This process is iterated, until Cn is in agreement with the sum of two of Cn−1. Finally, all the capacitors can be calibrated in this way to have the binary-weighted relation. The simulation results based on the proposed work with a split SAR ADC model verified that the proposed technique can be practically used, by showing that the total-harmonic-distortion and the signal-to-noise-and-distortion ratio were enhanced by 21.8-dB and 6.4-dB, respectively.

As a complementary and alternative medicine in the western countries for decades, traditional Chinese medicine (TCM) has been used for more than 2000 years in China. Because of the characteristics of the philosophical style and the unknown mechanism of action, TCM sometimes has been biasedly described as "fraught with pseudoscience". From the scientific basis of the systems biology, here we promoted a novel medical model called the entropic systems medicine which could be applied to scientize TCM in future. In entropic systems medicine, TCM and Western modern biomedicine target the different variables of the entropic system. For instance, while Western modern biomedicine directly targets the phenotypes and its SOCs of macrostates, TCM differently targets the microstates, entropy and entropic force to generate SOTFs gradually causing the differentiated syndromes to be slowly rearranged. The prerequisites to modernize TCM are the entropic systems biology having been well established so that the variables could be precisely monitored and mathematically calculated.