tRNA modifications and tRNA-derived small RNAs: new insights of tRNA in human disease.

tRNAs are codon decoders that convert the transcriptome into the proteome. The field of tRNA research is excited by the increasing discovery of specific tRNA modifications that are installed at specific, evolutionarily conserved positions by a set of specialized tRNA-modifying enzymes and the biogenesis of tRNA-derived regulatory fragments (tsRNAs) which exhibit copious activities through multiple mechanisms. Dysregulation of tRNA modification usually has pathological consequences, a phenomenon referred to as "tRNA modopathy". Current evidence suggests that certain tRNA-modifying enzymes and tsRNAs may serve as promising diagnostic biomarkers and therapeutic targets, particularly for chemoresistant cancers. In this review, we discuss the latest discoveries that elucidate the molecular mechanisms underlying the functions of clinically relevant tRNA modifications and tsRNAs, with a focus on malignancies. We also discuss the therapeutic potential of tRNA/tsRNA-based therapies, aiming to provide insights for the development of innovative therapeutic strategies. Further efforts to unravel the complexities inherent in tRNA biology hold the promise of yielding better biomarkers for the diagnosis and prognosis of diseases, thereby advancing the development of precision medicine for health improvement.

Future in the past: paternal reprogramming of offspring phenotype and the epigenetic mechanisms.

That certain preconceptual paternal exposures reprogram the developmental phenotypic plasticity in future generation(s) has conceptualized the "paternal programming of offspring health" hypothesis. This transgenerational effect is transmitted primarily through sperm epigenetic mechanisms-DNA methylation, non-coding RNAs (ncRNAs) and associated RNA modifications, and histone modifications-and potentially through non-sperm-specific mechanisms-seminal plasma and circulating factors-that create 'imprinted' memory of ancestral information. The epigenetic landscape in sperm is highly responsive to environmental cues, due to, in part, the soma-to-germline communication mediated by epididymosomes. While human epidemiological studies and experimental animal studies have provided solid evidences in support of transgenerational epigenetic inheritance, how ancestral information is memorized as epigenetic codes for germline transmission is poorly understood. Particular elusive is what the downstream effector pathways that decode those epigenetic codes into persistent phenotypes. In this review, we discuss the paternal reprogramming of offspring phenotype and the possible underlying epigenetic mechanisms. Cracking these epigenetic mechanisms will lead to a better appreciation of "Paternal Origins of Health and Disease" and guide innovation of intervention algorithms to achieve 'healthier' outcomes in future generations. All this will revolutionize our understanding of human disease etiology.

Editing microbes to mitigate enteric methane emissions in livestock.

Livestock production significantly contributes to greenhouse gas (GHG) emissions particularly methane (CH4) emissions thereby influencing climate change. To address this issue further, it is crucial to establish strategies that simultaneously increase ruminant productivity while minimizing GHG emissions, particularly from cattle, sheep, and goats. Recent advancements have revealed the potential for modulating the rumen microbial ecosystem through genetic selection to reduce methane (CH4) production, and by microbial genome editing including CRISPR/Cas9, TALENs (Transcription Activator-Like Effector Nucleases), ZFNs (Zinc Finger Nucleases), RNA interference (RNAi), Pime editing, Base editing and double-stranded break-free (DSB-free). These technologies enable precise genetic modifications, offering opportunities to enhance traits that reduce environmental impact and optimize metabolic pathways. Additionally, various nutrition-related measures have shown promise in mitigating methane emissions to varying extents. This review aims to present a future-oriented viewpoint on reducing methane emissions from ruminants by leveraging CRISPR/Cas9 technology to engineer the microbial consortia within the rumen. The ultimate objective is to develop sustainable livestock production methods that effectively decrease methane emissions, while maintaining animal health and productivity.

Mastering tracheostomy care: Refresher programme for tracheostomy training for nurses: Comparison of two training methods based on hands-on simulation-based training alone versus additional complementary self-directed e-learning.

BACKGROUND: Effective clinical education is essential for managing tracheostomy patients safely and efficiently. Simulation-based training has shown greater efficacy than traditional methods in various clinical settings. Our internal training programme, called the Tracheostomy Refresher Program (TRP) was used to enhance nurses' skills in tracheostomy care. AIM/OBJECTIVE: The aim of this study was to evaluate the impact of the TRP on nurses' self-reported knowledge and confidence and psychomotor skills comparing hands-on simulation-based training alone (TRP-S) with both the simulation-based training and the e-learning component (TRP-S + e). METHODS: The study was conducted at a large tertiary hospital in Singapore from February 2022 to October 2022, focussing on the TRP. Participants were divided into two cohorts: those receiving TRP-S and those receiving additional complementary TRP-S + e. All participants completed theory tests and affective questionnaires before and after the training to assess knowledge and attitudes. At the same time, their psychomotor skills were evaluated during the simulation using a standardised checklist. The two cohorts were then compared based on the results of these pretests and post-tests and the psychomotor skills assessment to evaluate the effectiveness of the additional e-learning component. RESULTS: Participants reported significantly enhanced confidence, knowledge, and psychomotor skills in tracheostomy care post training (p < 0.001 for all). The TRP-S + e cohort showed significantly higher knowledge and confidence scores than the TRP-S cohort (p < 0.001 for both). CONCLUSION: Our study suggests that a TRP incorporating hands-on simulation-based training with or without e-learning significantly improved self-reported knowledge, confidence, and psychomotor skills in tracheostomy care. Future research should explore the optimal duration, engagement strategies, and cost-effectiveness of such educational techniques and whether similar approaches can be applied for other clinical skills.

The emerging era of lactate: A rising star in cellular signaling and its regulatory mechanisms.

Cellular metabolites are ancient molecules with pleiotropic implications in health and disease. Beyond their cognate roles, they have signaling functions as the ligands for specific receptors and the precursors for epigenetic or posttranslational modifications. Lactate has long been recognized as a metabolic waste and fatigue product mainly produced from glycolytic metabolism. Recent evidence however suggests lactate is an unique molecule with diverse signaling attributes in orchestration of numerous biological processes, including tumor immunity and neuronal survival. The copious metabolic and non-metabolic functions of lactate mediated by its bidirectional shuttle between cells or intracellular organelles lead to a phenotype called "lactormone." Importantly, the mechanisms of lactate signaling, via acting as a molecular sensor and a regulator of NAD+ metabolism and AMP-activated protein kinase signaling, and via the newly identified lactate-driven lactylation, have been discovered. Further, we include a brief discussion about the autocrine regulation of efferocytosis by lactate in Sertoli cells which favoraerobic glycolysis. By emphasizing a repertoire of the most recent discovered mechanisms of lactate signaling, this review will open tantalizing avenues for future investigations cracking the regulatory topology of lactate signaling covered in the veil of mystery.

Recent advances in chromosome capture techniques unraveling 3D genome architecture in germ cells, health, and disease.

In eukaryotes, the genome does not emerge in a specific shape but rather as a hierarchial bundle within the nucleus. This multifaceted genome organization consists of multiresolution cellular structures, such as chromosome territories, compartments, and topologically associating domains, which are frequently defined by architecture, design proteins including CTCF and cohesin, and chromatin loops. This review briefly discusses the advances in understanding the basic rules of control, chromatin folding, and functional areas in early embryogenesis. With the use of chromosome capture techniques, the latest advancements in technologies for visualizing chromatin interactions come close to revealing 3D genome formation frameworks with incredible detail throughout all genomic levels, including at single-cell resolution. The possibility of detecting variations in chromatin architecture might open up new opportunities for disease diagnosis and prevention, infertility treatments, therapeutic approaches, desired exploration, and many other application scenarios.

Unlocking gut microbiota potential of dairy cows in varied environmental conditions using shotgun metagenomic approach.

Food security and environmental pollution are major concerns for the expanding world population, where farm animals are the largest source of dietary proteins and are responsible for producing anthropogenic gases, including methane, especially by cows. We sampled the fecal microbiomes of cows from varying environmental regions of Pakistan to determine the better-performing microbiomes for higher yields and lower methane emissions by applying the shotgun metagenomic approach. We selected managed dairy farms in the Chakwal, Salt Range, and Patoki regions of Pakistan, and also incorporated animals from local farmers. Milk yield and milk fat, and protein contents were measured and correlated with microbiome diversity and function. The average milk protein content from the Salt Range farms was 2.68%, with an average peak milk yield of 45 litters/head/day, compared to 3.68% in Patoki farms with an average peak milk yield of 18 litters/head/day. Salt-range dairy cows prefer S-adenosyl-L-methionine (SAMe) to S-adenosyl-L-homocysteine (SAH) conversion reactions and are responsible for low milk protein content. It is linked to Bacteroides fragilles which account for 10% of the total Bacteroides, compared to 3% in the Patoki region. The solid Non-Fat in the salt range was 8.29%, whereas that in patoki was 6.34%. Moreover, Lactobacillus plantarum high abundance in Salt Range provided propionate as alternate sink to [H], and overcoming a Methanobrevibacter ruminantium high methane emissions in the Salt Range. Furthermore, our results identified ruminant fecal microbiomes that can be used as fecal microbiota transplants (FMT) to high-methane emitters and low-performing herds to increase farm output and reduce the environmental damage caused by anthropogenic gases emitted by dairy cows.

Inhaled volatile anesthetic gas for severe bronchospasm in the emergency department.

Bronchospasm is caused by reversible constriction of the smooth muscles of the bronchial tree. This causes obstruction of the lower airways, which is commonly seen at the emergency department (ED) in patients with acute exacerbation of asthma or chronic obstructive pulmonary disease. Ventilation may be difficult in mechanically intubated patients with severe bronchospasm due to airflow limitation, air trapping, and high airway resistance. The beneficial effects of volatile inhaled anesthetic gas had been reported due to its bronchodilation properties. In this case series, we would like to share our experience delivering inhaled volatile anesthetic gas via a conserving device for three patients with refractory bronchospasm at the ED. Inhaled anesthetic gas is safe, feasible and should be considered as an alternative rescue therapy for ventilated patients with severe lower airway obstruction.

Automated rapid response system activation-Impact on nurses' attitudes and perceptions towards recognising and responding to clinical deterioration: Mixed-methods study.

AIM: To explore general ward nurses' attitudes and perceptions towards recognising and responding to clinical deterioration in a hospital with automated rapid response system activation. BACKGROUND: There is growing interest in deploying automated clinical deterioration notification systems to reduce delayed or failed recognition and response to clinical deterioration of ward patients. However, little is known about its impact on ward nurses' perspectives and work patterns. DESIGN: A mixed-methods study. METHODS: Online survey of 168 registered nurses and individual interviews with 10 registered nurses in one acute hospital in Singapore. The study adhered to the STROBE checklist for cross-sectional studies and the COREQ guidelines for qualitative studies. RESULTS: Many nurses (38.1%) rarely performed patient assessments or observations other than vital signs assessment to assess for early signs of clinical deterioration. About 30% were worried about being criticised for calling the primary team doctors. Four themes emerged from the qualitative analysis: automated rapid response system activation as a safety net, being more cautious with vital signs monitoring, the NEWS2 alone is inadequate, and ward nurses as the 'middleman' between the intensive care unit outreach nurse and primary team doctors. CONCLUSIONS: Although nurses value the automated rapid response system activation as a safety net to minimise delays in accessing urgent critical care resources, it does not address the sociocultural barriers inherent in escalation of care. Although the automated system led nurses to be more cautious with vital signs monitoring, it does not encourage them to perform comprehensive patient assessments to detect early signs of deterioration. RELEVANCE TO CLINICAL PRACTICE: Nurse education on assessing for clinical deterioration should focus on the use of broader patient assessment skills other than vital signs. Sociocultural barriers to escalation of care remain a key issue that needs to be addressed by hospital management. NO PATIENT OR PUBLIC CONTRIBUTION: No patients, service users, care-givers or members of the public were involved in the study.

Alternative splicing and MicroRNA: epigenetic mystique in male reproduction.

Infertility is rarely life threatening, however, it poses a serious global health issue posing far-reaching socio-economic impacts affecting 12-15% of couples worldwide where male factor accounts for 70%. Functional spermatogenesis which is the result of several concerted coordinated events to produce sperms is at the core of male fertility, Alternative splicing and microRNA (miRNA) mediated RNA silencing (RNAi) constitute two conserved post-transcriptional gene (re)programming machinery across species. The former by diversifying transcriptome signature and the latter by repressing target mRNA activity orchestrate a spectrum of testicular events, and their dysfunctions has several implications in male infertility. This review recapitulates the knowledge of these mechanistic events in regulation of spermatogenesis and testicular homoeostasis. In addition, miRNA payload in sperm, vulnerable to paternal inputs, including unhealthy diet, infection and trauma, creates epigenetic memory to initiate intergenerational phenotype. Naive zygote injection of sperm miRNAs from stressed father recapitulates phenotypes of offspring of stressed father. The epigenetic inheritance of paternal pathologies through miRNA could be a tantalizing avenue to better appreciate 'Paternal Origins of Health and Disease' and the power of tiny sperm.