Isospin Mixing and Model Dependence

We show that recent calculations of \Delta I=3/2 effects in nonleptonic hyperon decay induced by m_d-m_u\neq 0 are subject to significant model dependence.Comment: 8 page standard Latex fil

Predicting “pain genes”: multi-modal data integration using probabilistic classifiers and interaction networks

Accurate identification of pain-related genes remains challenging due to the complex nature of pain pathophysiology and the subjective nature of pain reporting in humans, or inferring pain states in animals on the basis of behaviour. Here, we use a machine learning approach to identify possible “pain genes”. Labelling was based on a gold-standard list of genes with validated involvement across pain conditions, and was trained on a selection of -omics (eg. transcriptomics, proteomics, etc.), protein-protein interaction (PPI) network features, and biological function readouts for each gene. Multiple classifiers were trained, and the top-performing model was selected to predict a “pain score” per gene. The top ranked genes were then validated against pain-related human SNPs to validate against human genetics studies. Functional analysis revealed JAK2/STAT3 signal, ErbB, and Rap1 signalling pathways as promising targets for further exploration, while network topological features contribute significantly to the identification of “pain” genes. As such, a PPI network based on top-ranked genes was constructed to reveal previously uncharacterised pain-related genes including CHRFAM7A and UNC79. These analyses can be further explored using the linked open-source database at https://livedataoxford.shinyapps.io/drg-directory/, which is accompanied by a freely accessible code template and user guide for wider adoption across disciplines. Together, the novel insights into pain pathogenesis can indicate promising directions for future experimental research

Predicting “pain genes”: multi-modal data integration using probabilistic classifiers and interaction networks

Accurate identification of pain-related genes remains challenging due to the complex nature of pain pathophysiology and the subjective nature of pain reporting in humans, or inferring pain states in animals on the basis of behaviour. Here, we use a machine learning approach to identify possible “pain genes”. Labelling was based on a gold-standard list of genes with validated involvement across pain conditions, and was trained on a selection of -omics, protein-protein interaction network features, and biological function readouts for each gene. Multiple classifiers were trained, and the top-performing model was selected to predict a “pain score” per gene. The top ranked genes were validated against pain-related human SNPs to validate against human genetics studies. Functional analysis revealed JAK2/STAT3 signal, ErbB, and Rap1 signalling pathways as promising targets for further exploration, while network topological features contribute significantly to the identification of “pain” genes. As such, a network based on top-ranked genes was constructed to reveal previously uncharacterised pain-related genes including CHRFAM7A and UNC79. These analyses can be further explored using the linked open-source database at https://livedataoxford.shinyapps.io/drg-directory/, which is accompanied by a freely accessible code template and user guide for wider adoption across disciplines. Together, the novel insights into pain pathogenesis can indicate promising directions for future experimental research

Deep RNA-seq of male and female murine sensory neuron subtypes after nerve injury

Dorsal root ganglia (DRG) neurons have been well described for their role in driving both acute and pain. Although nerve injury is known to cause transcriptional dysregulation, how this differs across neuronal subtypes and the impact of sex is unclear. Here, we study the deep transcriptional profiles of multiple murine DRG populations in early and late pain states while considering sex. We have exploited currently available transgenics to label numerous subpopulations for fluorescent activated cell sorting (FACS) and subsequent transcriptomic analysis. Using bulk tissue samples, we are able to circumvent the issues of low transcript coverage and drop-outs seen with single cell datasets. This increases our power to detect novel and even subtle changes in gene expression within neuronal subtypes and discuss sexual dimorphism at the neuronal subtype level. We have curated this resource into an accessible database for other researchers (https://livedataoxford.shinyapps.io/drg-directory/). We see both stereotyped and unique subtype signatures in injured states after nerve injury at both an early and late timepoint. While all populations contribute to a general injury signature, subtype enrichment changes can also be seen. Within populations, there is not a strong intersection of sex and injury, but previously unknown sex differences in naïve states-particularly in Aβ-RA + Aδ-LTMRs - still contribute to differences in injured neurons

Deep RNA-seq of male and female murine sensory neuron subtypes after nerve injury

Dorsal root ganglia (DRG) neurons have been well described for their role in driving both acute and chronic pain. Although nerve injury is known to cause transcriptional dysregulation, how this differs across neuronal subtypes and the impact of sex is unclear. Here, we study the deep transcriptional profiles of multiple murine DRG populations in early and late pain states while considering sex. We have exploited currently available transgenics to label numerous subpopulations for fluorescent-activated cell sorting and subsequent transcriptomic analysis. Using bulk tissue samples, we are able to circumvent the issues of low transcript coverage and drop-outs seen with single-cell data sets. This increases our power to detect novel and even subtle changes in gene expression within neuronal subtypes and discuss sexual dimorphism at the neuronal subtype level. We have curated this resource into an accessible database for other researchers (https://livedataoxford.shinyapps.io/drg-directory/). We see both stereotyped and unique subtype signatures in injured states after nerve injury at both an early and late timepoint. Although all populations contribute to a general injury signature, subtype enrichment changes can also be seen. Within populations, there is not a strong intersection of sex and injury, but previously unknown sex differences in naïve states—particularly in Aβ-RA + Aδ-low threshold mechanoreceptors—still contribute to differences in injured neurons

Differential GFP Expression Patterns Induced by Different Heavy Metals in Tg(hsp70:gfp) Transgenic Medaka (Oryzias latipes)

Heat shock protein 70 (Hsp70) is one of the most widely used biomarker for monitoring environment perturbations in biological systems. To facilitate the analysis of hsp70 expression as a biomarker, we generated a Tg(hsp70:gfp) transgenic medaka line in which green fluorescence protein (GFP) reporter gene was driven by the medaka hsp70 promoter. Here, we characterized Tg(hsp70:gfp) medaka for inducible GFP expression by seven environment-relevant heavy metals, including mercury, arsenic, lead, cadmium, copper, chromium, and zinc. We found that four of them (mercury, arsenic, lead, and cadmium) induced GFP expression in multiple and different organs. In general, the liver, kidney, gut, and skin are among the most frequent organs to show induced GFP expression. In contrast, no detectable GFP induction was observed to copper, chromium, or zinc, indicating that the transgenic line was not responsive to all heavy metals. RT-qPCR determination of hsp70 mRNA showed similar induction and non-induction by these metals, which also correlated with the levels of metal uptake in medaka exposed to these metals. Our observations suggested that these heavy metals have different mechanisms of toxicity and/or differential bioaccumulation in various organs; different patterns of GFP expression induced by different metals may be used to determine or exclude metals in water samples tested. Furthermore, we also tested several non-metal toxicants such as bisphenol A, 2,3,7,8-tetrachlorodibenzo-p-dioxin, 4-introphenol, and lindane; none of them induced significant GFP expression in Tg(hsp70:gfp) medaka, further suggesting that the inducibility of Tg(hsp70:gfp) for GFP expression is specific to a subset of heavy metals

An ectomycorrhizal fungus alters sensitivity to jasmonate, salicylate, gibberellin, and ethylene in host roots.

The phytohormones jasmonate, gibberellin, salicylate, and ethylene regulate an interconnected reprogramming network integrating root development with plant responses against microbes. The establishment of mutualistic ectomycorrhizal symbiosis requires the suppression of plant defense responses against fungi as well as the modification of root architecture and cortical cell wall properties. Here, we investigated the contribution of phytohormones and their crosstalk to the ontogenesis of ectomycorrhizae (ECM) between grey poplar (Populus tremula x alba) roots and the fungus Laccaria bicolor. To obtain the hormonal blueprint of developing ECM, we quantified the concentrations of jasmonates, gibberellins, and salicylate via liquid chromatography-tandem mass spectrometry. Subsequently, we assessed root architecture, mycorrhizal morphology, and gene expression levels (RNA sequencing) in phytohormone-treated poplar lateral roots in the presence or absence of L. bicolor. Salicylic acid accumulated in mid-stage ECM. Exogenous phytohormone treatment affected the fungal colonization rate and/or frequency of Hartig net formation. Colonized lateral roots displayed diminished responsiveness to jasmonate but regulated some genes, implicated in defense and cell wall remodelling, that were specifically differentially expressed after jasmonate treatment. Responses to salicylate, gibberellin, and ethylene were enhanced in ECM. The dynamics of phytohormone accumulation and response suggest that jasmonate, gibberellin, salicylate, and ethylene signalling play multifaceted roles in poplar L. bicolor ectomycorrhizal development

CD4+ T-lymphopenia in HIV negative tuberculous patients at King Khalid University Hospital in Riyadh, Saudi Arabia

Tuberculosis (Tb) is a chronic infectious disease in which the cellular immunity (specifically CD4+ and CD8 lymphocytes) provides the most important defense in controlling infection. CD4 lymphopenia is a well-defined risk factor for the development of active tuberculosis in patients infected with Human Immunodeficiency Virus. In HIV - negative patients, CD4 and CD8 cell count suppression has been associated with Tb infection. Our study was designed to deter mine the baseline and post-treatment values of CD4 and CD8 in HIV negative patients diagnosed with active Tb in Saudi Arabian patients. We recruited twentyeight, non-HIV patients with tuberculosis for the study group comprising 16 males and 12 females with either disseminated or localized active Tb infection. Two control groups were selected - one of twenty one matched healthy controls and the second of fortytwo subjects from pool of controls of an ongoing study in same population for normal CD4 and CD8 counts. The baseline pre-treatment CD4 and CD8 counts in the study group were significantly lower than either control group. Specifically the mean ± SD of CD4 counts were 556.79 ± 298.81 in the study group vs 1,132.38 ± 259.90 in control group 1 and 1,424.38 ± 870.98 in control group 2 (p 0.000). Likewise the CD8 counts in the study group were 1,136.00 ± 512.06 vs. 1,461.90 ± 367.02 in control group 1 and 1,495.90 ± 565.32 in control group 2 (p 0.000) respectively. After treatment of tuberculosis, the study patients experienced a significant increase in their mean ± SD CD4 and CD8 cell counts, from 556.79 ± 297.81 to 954.29 ± 210.90 for CD4 cells (p 0.005) and 1136.00 ± 512.06 to 1,316.54 ± 286.17 for CD8 cells (p 0.002). Analysis of study patients with disseminated disease found significantly lower CD4 cells (but not lower CD8 cells) compared to study patients with localized disease, both at baseline and after treatment. The mean ± SD baseline CD4 cells were 247.60 ± 187.80 with disseminated vs 728.56 ± 186.32 for localized disease (p = 0.000) which rose to 842.30 ± 93.55 vs 1016.50 ± 233.51 (p = 0.033) respectively. We conclude that tuberculosis may be associated with CD4 and CD8 lymphopenia even in patients without human immunodeficiency virus infection, there was the tendency of recovery towards normality especially of the CD4 and CD8 counts after treatment, and that disseminated disease is associated specifically with profound CD4 lymphopenia

Appetite, gut hormone and energy intake responses to low volume sprint interval and traditional endurance exercise.

Sprint interval exercise improves several health markers but the appetite and energy balance response is unknown. This study compared the effects of sprint interval and endurance exercise on appetite, energy intake and gut hormone responses. Twelve healthy males [mean (SD): age 23 (3) years, body mass index 24.2 (2.9) kg m(-2), maximum oxygen uptake 46.3 (10.2) mL kg(-1) min(-1)] completed three 8 h trials [control (CON), endurance exercise (END), sprint interval exercise (SIE)] separated by 1 week. Trials commenced upon completion of a standardised breakfast. Sixty minutes of cycling at 68.1 (4.3) % of maximum oxygen uptake was performed from 1.75-2.75 h in END. Six 30-s Wingate tests were performed from 2.25-2.75 h in SIE. Appetite ratings, acylated ghrelin and peptide YY (PYY) concentrations were measured throughout each trial. Food intake was monitored from buffet meals at 3.5 and 7 h and an overnight food bag. Appetite (P 0.05). Therefore, relative energy intake (energy intake minus the net energy expenditure of exercise) was lower in END than that in CON (15.7 %; P = 0.006) and SIE (11.5 %; P = 0.082). An acute bout of endurance exercise resulted in lower appetite perceptions in the hours after exercise than sprint interval exercise and induced a greater 24 h energy deficit due to higher energy expenditure during exercise

Differential susceptibility of human motor neurons to infection with Usutu and West Nile virus

West Nile virus (WNV) and Usutu virus (USUV) are closely related flaviviruses with differing capacities to cause neurological disease in humans. WNV is thought to use a transneural route of neuroinvasion along motor neurons and causes severe motor deficits. The potential for use of transneural routes of neuroinvasion by USUV has not been investigated experimentally, and evidence from the few clinical case reports of USUV-associated neuroinvasive disease is lacking. We hypothesised that, compared with WNV, USUV is less able to infect motor neurons, and therefore determined the susceptibility of human induced pluripotent stem cell (iPSC)-derived spinal cord motor neurons to infection. Both viruses could grow to high titres in iPSC-derived neural cultures. However, USUV could not productively infect motor neurons due to restriction by the antiviral response, which was not induced upon WNV infection. Inhibition of the antiviral response allowed for widespread infection and transportation of USUV along motor neurons within a compartmented culture system. These results show a stark difference in the ability of these two viruses to evade initiation of intrinsic antiviral immunity. Our data suggests that USUV cannot infect motor neurons in healthy individuals but in case of immunodeficiency may pose a risk for motor-related neurological disease and transneural invasion.</p