Noncanonical Roles of tRNAs: tRNA Fragments and Beyond.

As one of the most abundant and conserved RNA species, transfer RNAs (tRNAs) are well known for their role in reading the codons on messenger RNAs and translating them into proteins. In this review, we discuss the noncanonical functions of tRNAs. These include tRNAs as precursors to novel small RNA molecules derived from tRNAs, also called tRNA-derived fragments, that are abundant across species and have diverse functions in different biological processes, including regulating protein translation, Argonaute-dependent gene silencing, and more. Furthermore, the role of tRNAs in biosynthesis and other regulatory pathways, including nutrient sensing, splicing, transcription, retroelement regulation, immune response, and apoptosis, is reviewed. Genome organization and sequence variation of tRNA genes are also discussed in light of their noncanonical functions. Lastly, we discuss the recent applications of tRNAs in genome editing and microbiome sequencing.

XRN2 suppresses aberrant entry of tRNA trailers into argonaute in humans and Arabidopsis.

MicroRNAs (miRNAs) are a well-characterized class of small RNAs (sRNAs) that regulate gene expression post-transcriptionally. miRNAs function within a complex milieu of other sRNAs of similar size and abundance, with the best characterized being tRNA fragments or tRFs. The mechanism by which the RNA-induced silencing complex (RISC) selects for specific sRNAs over others is not entirely understood in human cells. Several highly expressed tRNA trailers (tRF-1s) are strikingly similar to microRNAs in length but are generally excluded from the microRNA effector pathway. This exclusion provides a paradigm for identifying mechanisms of RISC selectivity. Here, we show that 5' to 3' exoribonuclease XRN2 contributes to human RISC selectivity. Although highly abundant, tRF-1s are highly unstable and degraded by XRN2 which blocks tRF-1 accumulation in RISC. We also find that XRN mediated degradation of tRF-1s and subsequent exclusion from RISC is conserved in plants. Our findings reveal a conserved mechanism that prevents aberrant entry of a class of highly produced sRNAs into Ago2.

Unraveling the enigma of root-knot nematodes: from origins to advanced management strategies in agriculture.

MAIN CONCLUSION: Integrated management strategies, including novel nematicides and resilient cultivars, offer sustainable solutions to combat root-knot nematodes, crucial for safeguarding global agriculture against persistent threats. Root-knot nematodes (RKN) pose a significant threat to a diverse range of host plants, with their obligatory endoparasitic nature leading to substantial agricultural losses. RKN spend much of their lives inside or in contact by secreting plant cell wall-modifying enzymes resulting in the giant cell development for establishing host-parasite relationships. Additionally, inflicting physical harm to host plants, RKN also contributes to disease complexes creation with fungi and bacteria. This review comprehensively explores the origin, history, distribution, and physiological races of RKN, emphasizing their economic impact on plants through gall formation. Management strategies, ranging from cultural and physical to biological and chemical controls, along with resistance mechanisms and marker-assisted selection, are explored. While recognizing the limitations of traditional nematicides, recent breakthroughs in non-fumigant alternatives like fluensulfone, spirotetramat, and fluopyram offer promising avenues for sustainable RKN management. Despite the success of resistance mechanisms like the Mi gene, challenges persist, prompting the need for integrative approaches to tackle Mi-virulent isolates. In conclusion, the review stresses the importance of innovative and resilient control measures for sustainable agriculture, emphasizing ongoing research to address evolving challenges posed by RKN. The integration of botanicals, resistant cultivars, and biological controls, alongside advancements in non-fumigant nematicides, contributes novel insights to the field, laying the ground work for future research directions to ensure the long-term sustainability of agriculture in the face of persistent RKN threats.

Nitric oxide mediated kisspeptin regulation of steroidogenesis and gametogenesis in the catfish, Clarias batrachus.

Nitric oxide (NO) is a gaseous molecule that regulates various reproductive functions. It is a well-recognized regulator of GnRH-FSH/LH-sex steroid secretion in vertebrates including fish. Kisspeptin is a recently discovered neuropeptide which also regulates GnRH secretion. Nitrergic and kisspeptin neurons are reported in close physical contact in the mammalian brain suggesting their interactive role in the release of GnRH. The existence of kisspeptin and NOS is also demonstrated in vertebrate gonads, but information on their reciprocal relation in gonads, if any, is obscure. Therefore, attempts were made to evaluate the functional reciprocal relation between nitric oxide and kisspeptin in the catfish gonads, if any, by administering the nitric oxide synthase (NOS) inhibitor, L-NAME {N(G)-nitro-L-arginine methyl ester}, which reduces NO production, and kisspeptin agonist (KP-10) and assessing their impacts on the expressions of kisspeptin1, different NOS isoforms, NO and steroid production in the gonadal tissue. The results revealed that L-NAME suppressed the expression of kiss1 in gonads of the catfish establishing the role of NO in kisspeptin expression. However, KP-10 increased the expression of all the isoforms of NOSs (iNOS, eNOS, nNOS) and concurrently NO and steroids in the ovary and testis. In vitro studies also indicate that kisspeptin stimulates the production of NO and estradiol and testosterone levels in the gonadal explants and medium. Thus, in vivo results clearly suggest a reciprocal interaction between kisspeptin and NO to regulate the gonadal activity of the catfish. The in vitro findings further substantiate our contention regarding the interactive role of kisspeptin and NO in gonadal steroidogenesis.

Zeb1 and Tle3 are trans-factors that differentially regulate the expression of myosin heavy chain-embryonic and skeletal muscle differentiation.

Myosin heavy chain-embryonic encoded by the Myh3 gene is a skeletal muscle-specific contractile protein expressed during mammalian development and regeneration, essential for proper myogenic differentiation and function. It is likely that multiple trans-factors are involved in this precise temporal regulation of Myh3 expression. We identify a 4230 bp promoter-enhancer region that drives Myh3 transcription in vitro during C2C12 myogenic differentiation and in vivo during muscle regeneration, including sequences both upstream and downstream of the Myh3 TATA-box that are necessary for complete Myh3 promoter activity. Using C2C12 mouse myogenic cells, we find that Zinc-finger E-box binding homeobox 1 (Zeb1) and Transducin-like Enhancer of Split 3 (Tle3) proteins are crucial trans-factors that interact and differentially regulate Myh3 expression. Loss of Zeb1 function results in earlier expression of myogenic differentiation genes and accelerated differentiation, whereas Tle3 depletion leads to reduced expression of myogenic differentiation genes and impaired differentiation. Tle3 knockdown resulted in downregulation of Zeb1, which could be mediated by increased expression of miR-200c, a microRNA that binds to Zeb1 transcript and degrades it. Tle3 functions upstream of Zeb1 in regulating myogenic differentiation since double knockdown of Zeb1 and Tle3 resulted in effects seen upon Tle3 depletion. We identify a novel E-box in the Myh3 distal promoter-enhancer region, where Zeb1 binds to repress Myh3 expression. In addition to regulation of myogenic differentiation at the transcriptional level, we uncover post-transcriptional regulation by Tle3 to regulate MyoG expression, mediated by the mRNA stabilizing Human antigen R (HuR) protein. Thus, Tle3 and Zeb1 are essential trans-factors that differentially regulate Myh3 expression and C2C12 cell myogenic differentiation in vitro.

Protein coupled thionine acetate probed silica nanoparticles: An integrated laser-assisted therapeutic approach for treating cancer.

Herein, we report a multifaceted nanoformulation, developed by binding thionine acetate (TA) in silica matrix to form TA loaded silica nanoparticles (STA Nps), which were characterized using various physicochemical techniques. STA NPs were spherical shaped having size 40-50 nm and exhibited good heating efficiency, improved photostability and singlet oxygen production rate than TA alone. In PDT experiment, the rate of degradation for ABDMA was enhanced from 0.1367 min-1 for TA alone to 0.1774 min-1 for STA Nps, depicting an increase in the reactive oxygen species (ROS) generation ability of STA Nps. Further, the cytotoxicity of STA Nps was investigated by carrying out the biophysical studies with Calf thymus DNA (Ct-DNA) and Human Serum Albumin (HSA). The results indicated that the binding of STA Nps to Ct-DNA causes alterations in the double helix structure of DNA and as a result, STA Nps can impart chemotherapeutic effects via targeting DNA. STA Nps showed good binding affinity with HSA without compromising the structure of HSA, which is important for STA Nps sustainable biodistribution and pharmacokinetics. Based on this study, it is suggested that because of the synergistic effect of chemo and phototherapy, STA Nps can be extensively utilized as potential candidates for treating cancer.

Dual site reactivity of indole-3-Schiff bases with S/Se/Cl substituted ketenes for stereoselective C-4 substituted indole-ß-lactams, biological evaluations, magic chloro effect and molecular docking studies.

A convenient methodology for C-4 indole-ß-lactam hybrids with chloro, sulphur and seleno substitutions through dual site reactivity of indole-3-Schiff bases towards ketenes has been developed. The reaction proceeded in a stereospecific manner with the exclusive formation of trans-ß-lactams assigned with respect to C3-H and C4-H. The synthesized novel ß-lactams have been characterized with the help of elemental analysis (CHNS) and spectroscopic techniques viz.1H NMR, 13C NMR, DEPT 135, HSQC and IR. The trans configuration was further estabilished based on X-ray crystallographic data. Examination of antibacterial properties unveiled that only derivatives 5a and 5b, featuring chloro substitution, exhibited potent activities, underscoring the emergence of the recently coined term "magic chloro effect". Molecular docking analysis provided additional support for the observed in vitro antibacterial activities of compounds 5a-b.

A comprehensive in silico analysis of putative outer membrane and secretory hydrolases from the pathogenic Leptospira: Possible implications in pathogenesis.

Outer surface/membrane and virulent secretory proteins are primarily crucial for pathogenesis. Secreted and outer membrane hydrolases of many pathogens play an important role in attenuating the host immune system. Leptospira expresses many such proteins, and few have been characterized to display various roles, including host immune evasion. However, identification, classification, characterization, and elucidation of the possible role of Leptospira's outer membrane and secretory hydrolases have yet to be explored. In the present study, we used bioinformatics tools to predict exported proteins from the pathogenic Leptospira proteome. Moreover, we focused on secretory and outer membrane putative hydrolases from the exported proteins to generate a deeper understanding. Our analysis yielded four putative outer/secretory hydrolases, LIC_10995, LIC_11183, LIC_11463, and LIC_12988, containing α/ß hydrolase fold and displayed similarity with lipase motif. Moreover, their conservation analysis of the predicted hydrolases across the spectrum of different Leptospira species showed high clustering with the pathogenic species. Outer membrane and secretory proteins with lipolytic activity may have a role in pathogenesis. This is the first bioinformatics analysis of secretory and outer membrane α/ß hydrolases from leptospiral species. However, experimental studies are indeed required to unravel this possibility.

Protein extracted from Moringa oleifera Lam. Leaves: Bio-evaluation and characterization as suitable plant-based meat-protein alternative.

This study aimed to isolate and characterize moringa leaf protein (MLP) via HPLC and evaluate its consumption's effects through rat model. Four groups of Albino Wistar rats (n = 25 each) along with a control group (n = 25) were acclimatized. The isolated MLP was added to the basal diet (casein; control) in various percentages (25, 50, 75, 100%) for a 21-day experimental period. On three intervals (1st, 11th, 21st days), blood samples were collected and subjected for hematological and biochemical examination (Renal Function Test (RFT), Liver Function Test (LFT)). MLP contained a variety of essential and non-essential amino acids in substantial amounts. The Protein Efficiency Ratio (PER) of 50% MLP-treated group was the highest (1.72) among MLP treatments. Increases in feed intake and weight were observed in treated rats compared to the control. The hematological profile of the rats revealed increases in Hemoglobin (Hb) (7.9-14.0%), White Blood Cell (WBC) (35.9-51.5%), Red Blood Cell (RBC) (17.1-22.2%), Hematocrit (HCT) (13.1-22.9%), and platelets levels (36.5-40.6%) from day 1. Protein isolates decreased liver parameters but resulted in non-significant changes in liver and kidney functions in rats. Further investigation is needed to determine the safe daily intake of MLP.

On and off controls within dynein-dynactin on native cargoes.

The dynein-dynactin nanomachine transports cargoes along microtubules in cells. Why dynactin interacts separately with the dynein motor and also with microtubules is hotly debated. Here we disrupted these interactions in a targeted manner on phagosomes extracted from cells, followed by optical trapping to interrogate native dynein-dynactin teams on single phagosomes. Perturbing the dynactin-dynein interaction reduced dynein's on rate to microtubules. In contrast, perturbing the dynactin-microtubule interaction increased dynein's off rate markedly when dynein was generating force against the optical trap. The dynactin-microtubule link is therefore required for persistence against load, a finding of importance because disease-relevant mutations in dynein-dynactin are known to interfere with "high-load" functions of dynein in cells. Our findings call attention to a less studied property of dynein-dynactin, namely, its detachment against load, in understanding dynein dysfunction.

Longitudinal Pilot Evaluation of the Gut Microbiota Comparing Patients With and Without Chronic Kidney Disease.

OBJECTIVE: The gut microbiota contributes to metabolic diseases, such as diabetes and hypertension, but is poorly characterized in chronic kidney disease (CKD). DESIGN AND METHODS: We enrolled 24 adults within household pairs, in which at least one member had self-reported kidney disease, diabetes, or hypertension. CKD was classified based on estimated glomerular filtration rate < 60 mL/min/1.73 m2 or urine-albumin-to-creatinine ratio of ≥ 30 mg/g. Participants collected stool and dietary recalls seasonally over a year. Gut microbiota was characterized using 16s rRNA and metagenomic sequencing. RESULTS: Ten participants had CKD (42%) with a median (interquartile range) estimated glomerular filtration rate of 49 (44, 54) mL/min/1.73 m2. By 16s rRNA sequencing, there was moderate to high intraclass correlation (ICC = 0.63) for seasonal alpha diversity (Shannon index) within individuals and modest differences by season (P < .01). ICC was lower with metagenomics, which has resolution at the species level (ICC = 0.26). There were no differences in alpha or beta diversity by CKD with either method. Among 79 genera, Frisingicoccus, Tuzzerella, Faecalitalea, and Lachnoclostridium had lower abundance in CKD, while Collinsella, Lachnospiraceae_ND3007, Veillonella, and Erysipelotrichaceae_UCG_003 were more abundant in CKD (each nominal P < .05) using 16s rRNA sequencing. Higher Collinsella and Veillonella and lower Lachnoclostridium in CKD were also identified by metagenomics. By metagenomics, Coprococcus catus and Bacteroides stercoris were more and less abundant in CKD, respectively, at false discovery rate corrected P = .02. CONCLUSIONS: We identified candidate taxa in the gut microbiota associated with CKD. High ICC in individuals with modest seasonal impacts implies that follow-up studies may use less frequent sampling.

Distinct orchid mycorrhizal fungal communities among co-occurring Vanilla species in Costa Rica: root substrate and population-based segregation.

Despite being the second largest family of flowering plants, orchids represent community structure variation in plant-microbial associations, contributes to niche partitioning in metacommunity assemblages. Yet, mycorrhizal communities and interactions remain unknown for orchids that are highly specialized or even obligated in their associations with their mycorrhizal partners. In this study, we sought to compare orchid mycorrhizal fungal (OMF) communities of three co-occurring hemiepiphytic Vanilla species (V. hartii, V. pompona, and V. trigonocarpa) in tropical forests of Costa Rica by addressing the identity of their OMF communities across species, root types, and populations, using high-throughput sequencing. Sequencing the nuclear ribosomal internal transcribed spacer (nrITS) yielded 299 fungal Operational Taxonomic Units (OTUs) from 193 root samples. We showed distinct segregation in the putative OMF (pOMF) communities of the three coexisting Vanilla hosts. We also found that mycorrhizal communities associated with the rare V. hartii varied among populations. Furthermore, we identified Tulasnellaceae and Ceratobasidiaceae as dominant pOMF families in terrestrial roots of the three Vanilla species. In contrast, the epiphytic roots were mainly dominated by OTUs belonging to the Atractiellales and Serendipitaceae. Furthermore, the pOMF communities differed significantly across populations of the widespread V. trigonocarpa and showed patterns of distance decay in similarity. This is the first report of different pOMF communities detected in roots of wild co-occurring Vanilla species using high-throughput sequencing, which provides evidence that three coexisting Vanilla species and their root types exhibited pOMF niche partitioning, and that the rare and widespread Vanilla hosts displayed diverse mycorrhizal preferences.

Point-of-care impedimetric aptasensor to detect the luteinizing hormone.

Luteinizing hormone (LH) is a useful biomarker for identifying ovulation events in the cows to predict the time of ovulation to achieve a high success rate of conception following artificial insemination. Although antibody-based radioimmunoassay and enzyme-linked immunosorbent assay are being used for LH measurement, these techniques are expensive, time-consuming, and require expertise and sophisticated laboratory facilities. So, there is a need for a field-applicable, affordable, easy-to-use method for LH detection. For developing such a specific, quantitative, and inexpensive system, an aptamer-based smartphone-enabled aptasensor has been investigated. The aptamer was used instead of the antibody as a biorecognition element due to its comparative stability at ambient temperature, ease of synthesis, and cost-effectiveness. Electrochemical impedance spectroscopy has been used to obtain label-free detection of LH within 20 min in ~ 20 µL sample volume. The screen-printed gold electrode is compatible with a smartphone-enabled miniaturized device (Sensit Smart; Palmsens BV, The Netherlands) and was fabricated with the aptamer to detect LH in biological fluids (limit of detection 0.80 and 0.61 ng/mL in buffer and undiluted/unprocessed serum, respectively, with the dynamic range of detection of 0.01 to 50 ng/mL). All the data were obtained in the 10 kHz to 0.10 Hz frequency range at a bias potential of 0.30 V with an alternating potential of 10 mV. The clinical relevance of the sensor was evaluated in 10 serum samples collected from dairy animals which established a high correlation with standard LH-ELISA (κ > 0.87). The aptasensor can be stored at room temperature for 30 days without any significant loss in electrochemical sensing ability.

Uttarakhand State Earthquake Early Warning System: A Case Study of the Himalayan Environment.

The increased seismic activity observed in the Himalayas, coupled with the expanding urbanization of the surrounding areas in northern India, poses significant risks to both human lives and property. Developing an earthquake early warning system in the region could help in alleviating these risks, especially benefiting cities and towns in mountainous and foothill regions close to potential earthquake epicenters. To address this concern, the government and the science and engineering community collaborated to establish the Uttarakhand State Earthquake Early Warning System (UEEWS). The government of Uttarakhand successfully launched this full-fledged operational system to the public on 4 August 2021. The UEEWS includes an array of 170 accelerometers installed in the seismogenic areas of the Uttarakhand. Ground motion data from these sensors are transmitted to the central server through the dedicated private telecommunication network 24 hours a day, seven days a week. This system is designed to issue warnings for moderate to high-magnitude earthquakes via a mobile app freely available for smartphone users and by blowing sirens units installed in the buildings earmarked by the government. The UEEWS has successfully issued alerts for light earthquakes that have occurred in the instrumented region and warnings for moderate earthquakes that have triggered in the vicinity of the instrumented area. This paper provides an overview of the design of the UEEWS, details of instrumentation, adaptation of attributes and their relation to earthquake parameters, operational flow of the system, and information about dissemination of warnings to the public.

Radiological complexity of nuclear facilities: an information complexity approach to workplace monitoring.

Nuclear energy is crucial for achieving net-zero carbon emissions. A big challenge in the nuclear sector is ensuring the safety of radiation workers and the environment, while being cost-effective. Workplace monitoring is key to protecting workers from risks of ionising radiation. Traditional monitoring involves radiological surveillance via installed radiation monitors, continuously recording measurements like radiation fields and airborne particulate radioactivity concentrations, especially where sudden radiation changes could significantly impact workers. However, this approach struggles to detect incremental changes over a long period of time in the radiological measurements of the facility. To address this limitation, we propose abstracting a nuclear facility as a complex system. We then quantify the information complexity of the facility's radiological measurements using an entropic metric. Our findings indicate that the inferences and interpretations from our abstraction have a firm basis for interpretation and can enhance current workplace monitoring systems. We suggest the implementation of a radiological complexity-based alarm system to complement existing radiation level-based systems. The abstraction synthesized here is independent of the type of nuclear facility, and hence is a general approach to workplace monitoring at a nuclear facility.

Flood susceptibility assessment of the Agartala Urban Watershed, India, using Machine Learning Algorithm.

Frequent floods are a severe threat to the well-being of people the world over. This is particularly severe in developing countries like India where tropical monsoon climate prevails. Recently, flood hazard susceptibility mapping has become a popular tool to mitigate the effects of this threat. Therefore, the present study utilized four distinctive Machine Learning algorithms i.e., K-Nearest Neighbor, Decision Tree, Naive Bayes, and Random Forest to estimate flood susceptibility zones in the Agartala Urban Watershed of Tripura, India. The latter experiences debilitating floods during the monsoon season. A multicollinearity test was conducted to examine the collinearity of the chosen flood conditioning factors, and it was seen that none of the factors were compromised by multicollinearity. Results showed that around three-fourths of the AUW area was classified as moderate to very high flood-prone zones, while over 20 percent was between low and very low flood-prone zones. The models applied performed well with ROC-AUC scores greater than 70 percent and MAE, MSE, and RMSE scores less than 30 percent. DT and RF algorithms were suggested for places with similar physical characteristics based on their outstanding performance and the training datasets. The study provides valuable insights to policymakers, administrative authorities, and local stakeholders to cope with floods and enhance flood prevention measures as a climate change adaptation strategy in the AUW.

Statistical modeling, optimization and characterization of andrographolide loaded emulgel for its therapeutic application on skin cancer through enhancing its skin permeability.

Andrographolide is a natural diterpene lactone with multiple biological effects. In the present study, a total of 11 andrographolide-loaded emulgels (ANG 1- ANG 11) were prepared by emulsification and solvent evaporation method using flaxseed oil and xanthan gum in different ratios, as suggested by the Design-Expert software. A 2-factor-5-level design was employed with different responses including spreadability, extrudability, viscosity, and drug release after 1 h (h) and 24 h. Based on the Design-Expert software response, the optimized emulgel ANG 12 was formulated and evaluated. The 24 h In-vitro drug release was found to be 95.7 % following Higuchi kinetics. Ex-vivo skin retention of 784.78 ug/cm2 was observed during the study. MTT assay performed on Human epidermoid carcinoma (A-431) cells demonstrated cell growth arrest at G0/G1 and G2/M phase after 24 h of ANG 12 treatment (IC50: 11.5 µg/ml). The cellular permeability of ANG-12 was assessed by Fluorescein isothiocyanate (FITC) assay. Compared to untreated cells (0.54 % uptake) the ANG-12 treated cells had shown 87.17 % FITC permeation. The biocompatibility study performed on non-cancerous human dermal fibroblast cells (HDF cells) shows 91.54 % viability after 24 h of the treatment showing the non-toxic nature of ANG-12. Confocal imaging had shown a significant time-dependent increase in in-vivo cellular uptake with enhanced, progressive penetration of the emulgel into the skin. An in-vivo skin irritation study conducted on Swiss albino mice confirmed the safety aspects of the ANG 12. Hence, it can be concluded that nanoemulgel of andrographolide (ANG 12) could be a novel approach to treating skin cancer.

Physical activity in recurrent colon cancer: Cancer and Leukemia Group B/SWOG 80702 (Alliance).

BACKGROUND: One in three patients with stage III colon cancer will experience tumor recurrence. It is uncertain whether physical activity during and after postoperative chemotherapy for stage III colon cancer improves overall survival after tumor recurrence. METHODS: A prospective cohort study nested within a randomized multicenter trial of patients initially diagnosed with stage III colon cancer who experienced tumor recurrence (N = 399) was conducted. Postoperative physical activity before tumor recurrence was measured. Physical activity energy expenditure was quantified via metabolic equivalent task hours per week (MET-h/week). The primary end point was overall survival after tumor recurrence. Multivariable flexible parametric survival models estimated relative and absolute effects with two-sided hypothesis tests. RESULTS: Compared with patients expending <3.0 MET-h/week of physical activity (comparable to <1.0 h/week of brisk walking), patients with ≥18.0 MET-h/week of physical activity (comparable to 6 h/week of brisk walking) had a 33% relative improvement in overall survival time after tumor recurrence (hazard ratio, 0.67; 95% CI, 0.42-0.96). The overall survival rate at 3 years after tumor recurrence was 61.3% (95% CI, 51.8%-69.2%) with <3.0 MET-h/week of physical activity and 72.2% (95% CI, 63.1%-79.6%) with ≥18 MET-h/week of physical activity (risk difference, 10.9 percentage points; 95% CI, 1.2-20.8 percentage points). CONCLUSIONS: Higher postoperative physical activity is associated with improved overall survival after tumor recurrence in patients initially diagnosed with stage III colon cancer. These data may be relevant to patients who, despite optimal postoperative medical therapy, have a high risk of tumor recurrence.

Sleep and cancer recurrence and survival in patients with resected Stage III colon cancer: findings from CALGB/SWOG 80702 (Alliance).

BACKGROUND: We sought to assess the influences of sleep duration, sleep adequacy, and daytime sleepiness on survival outcomes among Stage III colon cancer patients. METHODS: We conducted a prospective observational study of 1175 Stage III colon cancer patients enrolled in the CALGB/SWOG 80702 randomised adjuvant chemotherapy trial who completed a self-reported questionnaire on dietary and lifestyle habits 14-16 months post-randomisation. The primary endpoint was disease-free survival (DFS), and secondary was overall survival (OS). Multivariate analyses were adjusted for baseline sociodemographic, clinical, dietary and lifestyle factors. RESULTS: Patients sleeping ≥9 h-relative to 7 h-experienced a worse hazard ratio (HR) of 1.62 (95% confidence interval (CI), 1.01-2.58) for DFS. In addition, those sleeping the least (≤5 h) or the most (≥ 9 h) experienced worse HRs for OS of 2.14 (95% CI, 1.14-4.03) and 2.34 (95% CI, 1.26-4.33), respectively. Self-reported sleep adequacy and daytime sleepiness showed no significant correlations with outcomes. CONCLUSIONS: Among resected Stage III colon cancer patients who received uniform treatment and follow-up within a nationwide randomised clinical trial, very long and very short sleep durations were significantly associated with increased mortality. Interventions targeting optimising sleep health among indicated colon cancer patients may be an important method by which more comprehensive care can be delivered. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01150045.

Interleukin-9 rescues class switching of Memory B cells derived from Common variable immunodeficiency patients.

Impaired class switch memory (CSM) B cell formation is the hallmark of common variable immunodeficiency (CVID). Various T cell abnormalities have been observed in CVID patients indicating inadequate T-cell help to B cells. A major setback in understanding its pathogenesis is due to diverse clinical presentation. Therefore, we performed extensive immunological investigation in a cohort of CVID patients with similar clinical findings in order to unravel the T cell dysfunction and its influence on the defective humoral immune response. All recruited CVID patients exhibited B cells in the normal range, but reduced CSM B cells. However, patients showed reduced T cell proliferation, reduced level of serum Interleukin-9 (IL-9) and frequency of IL-9 expressing CD4 (Th-9) cells. IL-9 supplementation along with CD40 engagement was effective in inducing in vitro CSM B cells formation in CVID patients. Thus, IL-9 supplementation has the potential to restore impaired CSM B cell formation in CVID.