Miracle-dz/UniFAR-FTUs huggingface dataset:
Tunica intima compensation for reduced stiffness of the tunica media in aging renal arteries as measured with scanning acoustic microscopy

Objectives Aging causes stiffness and decreased function of the renal artery (RA). Histological study with light microscopy can reveal microscopic structural remodeling but no functional changes. The present study aimed to clarify the association between structural and functional aging of the RA through the use of scanning acoustic microscopy. Methods Formalin-fixed, paraffin-embedded cross-sections of renal arteries from 64 autopsy cases were examined. Speed-of-sound (SOS) values of three layers, which correspond to the stiffness, were compared among different age groups. SOS of the tunica media was examined in terms of blood pressure (BP) and SOS of the ascending aorta. Vulnerability to proteases was assessed by SOS reduction after collagenase treatment. Results The tunica intima presented inward hypertrophy with luminal narrowing, and the tunica media showed outward hypertrophic remodeling with aging. SOS of the tunica media and internal and external elastic laminae showed a reverse correlation with age. SOS of the tunica media was negatively correlated with BP and strongly associated with that of the aorta. The tunica media of young RAs were more sensitive to collagenase compared with the old ones. Conclusions Scanning acoustic microscopy is useful for observing the aging process of the RA. This technique simultaneously shows structural and mechanical information from each portion of the RA. In the process of aging, the RA loses contractile function and elasticity as a result of protease digestion. The tunica media and the internal and external elastic laminae exhibit reduced stiffness, but the tunica intima stiffens with atherosclerosis. As a consequence, the RA’s outer shape changes from round to oval with inward and outward hypertrophy. This indicates that the inner resistant intima supports the mechanical weakness of the tunica media to compensate for an increase in BP with aging.
The use of negative control outcomes in Mendelian Randomisation to detect potential population stratification or selection bias

A key assumption of Mendelian randomisation (MR) analysis is that there is no association between the genetic variants used as instruments and the outcome other than through the exposure of interest. Two ways in which this assumption can be violated are through population stratification and selection bias which can introduce confounding of the relationship between the genetic variants and the outcome and so induce an association between them. Negative control outcomes are increasingly used to detect unobserved confounding in observational epidemiological studies. Here we consider the use of negative control outcomes in MR studies. As a negative control outcome in an MR study we propose the use of phenotypes which are determined before the exposure and outcome but which are likely to be subject to the same confounding as the exposure or outcome of interest. We illustrate our method with a two-sample MR analysis of a preselected set of exposures on self-reported tanning ability and hair colour. Our results show that, of the 33 exposures considered, GWAS studies of adiposity and education related traits are likely to be subject to population stratification and/or selection bias that is not controlled for through adjustment and so any MR study including these traits may be subject to bias that cannot be identified through standard pleiotropy robust methods.
The therapeutic effects of intratumoral injection of IL12IL2GMCSF fusion protein on canine tumors

Regulating the immune system through tumor immunotherapy to defeat tumors is currently one of the most popular methods of tumor treatment. We previously found that the combinations of IL12, IL2 and GMCSF has superior antitumor activities. In this study, IL12IL2GMCSF fusion protein was produced from 293 cells transduced by expression lentiviral vector. IL12IL2GMCSF fusion protein was injected into canine tumors, and the efficacy was monitored to evaluate the potential of tumor immunotherapy. In 14 canines injected with IL12IL2GMCSF protein, 6 had a complete response (CR), 7 had a partial response (PR), and 1 had stable disease (SD). IL12IL2GMCSF fusion protein has great anti-tumor potential. Intratumoral injection of IL12IL2GMCSF can effectively treat tumors without severe adverse effects. It provides a promising immune therapeutics in canine cancers.
Optical TrkB activation in Parvalbumin interneurons regulates intrinsic states to orchestrate cortical plasticity

Activation state of Parvalbumin (PV) interneurons regulates neuronal plasticity, driving the closure of developmental critical periods and alternating between high and low plasticity states in response to experience in adulthood. We now show that PV plasticity states are regulated through the activation of TrkB neurotrophin receptors. Activation of an optically activatable TrkB (optoTrkB) specifically in PV interneurons switches adult cortical networks into a state of elevated plasticity within minutes by decreasing excitability of PV neurons. OptoTrkB activation induces changes in gene expression related to neuronal plasticity and excitability, and increases the phosphorylation of Kv3.1 channels. OptoTrkB activation shifted cortical networks towards a low PV configuration, promoting oscillatory synchrony and ocular dominance plasticity. Visual plasticity induced by fluoxetine was lost in mice lacking TrkB in PV neurons. Our data suggest a novel mechanism that dynamically regulates PV interneurons configuration state and orchestrates cortical networks during adulthood.
Experiences of cervical cancer survivors in Chitwan, Nepal: A qualitative study

Introduction Cervical cancer is a global leading cause of morbidity and mortality. The majority of cervical cancer deaths occur in developing countries including Nepal. Though knowledge of cervical cancer is an important determinant of women’s participation in prevention and screening for cervical cancer, little is known about this topic in Nepal. This study explores the experiences of cervical cancer survivors and assesses the attitude of family and community towards it and stigma related to this disease in Bharatpur, Nepal. Methods The study design is qualitative methods involving two focus-group discussions. A total of 17 cervical cancer survivors were selected purposively from Chitwan. All qualitative data were transcribed and translated into English and were thematically analyzed. Results Majority of the participants had scant knowledge about cervical cancer, its causative agent, showed less cervical cancer screening, delayed healthcare-seeking behavior despite having persistent symptoms before the diagnosis. The main reasons identified for not uptaking the cervical screening methods are an embarrassment and having no symptoms at all. Most of them endured social stigma related to cervical cancer in the form of physical isolation and verbal abuse. Conclusions There is an urgent need for interventions to make women and the public aware of cervical cancer and launch effective health education campaigns, policies for cervical cancer prevention programs. This implementation can save the lives of hundreds of women and help them avoid going through all the negative experiences related to cervical cancer. More studies are required to gain the perspectives, knowledge, experiences, and attitudes of cervical cancer survivors to add to the research.
Multifactorial and closed head impact traumatic brain injuries cause distinct tactile hypersensitivity profiles

Chronic complications of traumatic brain injury (TBI) represent one of the greatest financial burdens and sources of suffering in society today. A substantial number of these patients suffer from post-traumatic headache (PTH), which is typically associated with tactile allodynia. Unfortunately, this phenomenon has been under-studied, in large part due to the lack of well-characterized laboratory animal models. We have addressed this gap in the field by characterizing the tactile sensory profile of two non-penetrating models of PTH. We show that multifactorial TBI, consisting of aspects of impact, acceleration/deceleration, and blast wave exposure, produces long term tactile hypersensitivity and central sensitization, phenotypes reminiscent of PTH in patients, in both cephalic and extracephalic regions. By contrast, closed head injury induces only transient cephalic tactile hypersensitivity, with no extracephalic consequences. Both models show more severe phenotype with repetitive daily injury for three days, compared to either one or three successive injuries in a single day, providing new insight into patterns of injury that may place patients at greater risk of developing PTH. Importantly, even after recovery from transient cephalic tactile hypersensitivity, mice subjected to closed head injury had persistent hypersensitivity to established migraine triggers, including calcitonin gene-related peptide (CGRP) and sodium nitroprusside, a nitric oxide donor. Our results offer new tools for studying PTH, as well as preclinical support for a pathophysiologic role of CGRP in this condition. Summary Two models of post-traumatic headache after traumatic brain injury provide novel laboratory tools and insights in relative risks of injury and therapeutic opportunities.
The Neural Representation of Force across Grasp Types in Motor Cortex of Humans with Tetraplegia

Abstract Intracortical brain-computer interfaces (iBCIs) have the potential to restore hand grasping and object interaction to individuals with tetraplegia. Optimal grasping and object interaction require simultaneous production of both force and grasp outputs. However, since overlapping neural populations are modulated by both parameters, grasp type could affect how well forces are decoded from motor cortex in a closed-loop force iBCI. Therefore, this work quantified the neural representation and offline decoding performance of discrete hand grasps and force levels in two human participants with tetraplegia. Participants attempted to produce three discrete forces (light, medium, hard) using up to five hand grasp configurations. A two-way Welch ANOVA was implemented on multiunit neural features to assess their modulation to force and grasp. Demixed principal component analysis (dPCA) was used to assess for population-level tuning to force and grasp and to predict these parameters from neural activity. Three major findings emerged from this work: (1) force information was neurally represented and could be decoded across multiple hand grasps (and, in one participant, across attempted elbow extension as well); (2) grasp type affected force representation within multiunit neural features and offline force classification accuracy; and (3) grasp was classified more accurately and had greater population-level representation than force. These findings suggest that force and grasp have both independent and interacting representations within cortex, and that incorporating force control into real-time iBCI systems is feasible across multiple hand grasps if the decoder also accounts for grasp type.
Comparative Effects of Protracted Exposures to 60Co γ-radiation and 239Pu α-radiation on Breeding Performance in Female Mice

SummaryBreeding performances are compared of hybrid female mice given 239Pu (5 or 10 μCikg−1 body mass in 1 per cent trisodium citrate via the tail-vein), or kept in a 10 rad/day or 20 rad/day 60Co γ-irradiation field (but mated in the control area), or unirradiated. Ovarian dose-rates from the injected plutonium were initially 0·8 and 1·7 rad/day, changing little thereafter; actual γ-ray dose-rates to breeding females averaged around 8 and 16 rad/day respectively. Both γ-ray treatments affected reproductive performance more than the plutonium injections, with respect to duration of fertility and to offspring per litter in successive 4-weekly periods, though overall mean litter-sizes were not significantly less than controls. The r.b. e. for these effects on reproduction, attributed to germ-cell killing, is about 2·5 for the α-particles vs. γ-rays, lower than for testis mass reduction in males. This low r.b. e. may be connected with inhomogeneity of α-particle dose within the ovary, but it is known that fis.
Patient Similarity Network of Multiple Myeloma Identifies Patient Sub-groups with Distinct Genetic and Clinical Features

The remarkable genetic heterogeneity of Multiple Myeloma (MM) poses a significant challenge for proper prognostication and clinical management of patients. Accurate dissection of the genetic and molecular landscape of the disease and the robust identification of homogeneous classes of patients are essential steps to reliable risk stratification and the development of novel precision medicine strategies. Here we introduce MM-PSN, the first multi-omics Patient Similarity Network of newly diagnosed MM. MM-PSN has enabled the identification of three broad patient groups and twelve distinct sub-groups defined by five data types generated from genomic and transcriptomic patient profiling of 655 patients. The MM-PSN classification uncovered novel associations between distinct MM hallmarks with significant prognostic implications and allowed further refinement of risk stratification. Our analysis revealed that gain of 1q is the most important single lesion conferring high risk of relapse, and its association with an MMSET translocation is the most significant determinant of poor outcome. We developed a classifier and validated these results in an independent dataset of 559 pts. Our findings suggest that gain of 1q should be incorporated in routine staging systems and risk assessment tools. The MM-PSN classifier is available as a free resource to allow for an easy implementation in most clinical settings.
Abuse liability, antinociceptive, and discriminative stimulus properties of IBNtxA

Rationale IBNtxA (3-iodobenzoyl naltrexamine) is a novel μ opioid receptor (MOR) agonist structurally related to the classical MOR antagonist naltrexone. Recent studies suggest IBNtxA preferentially signals through truncated MOR splice variants, producing a unique pharmacological profile resulting in antinociception with reduced side effects, including no conditioned place preference (CPP) when tested at a single dose. IBNtxA represents an intriguing lead compound for preclinical drug development targeting truncated MOR splice variants but further evaluation of its in vivo pharmacological profile is necessary to evaluate its potential. Objective The purpose of this study was to independently verify the antinociceptive properties of IBNtxA and to more completely examine the rewarding properties and discriminative stimulus effects of IBNtxA. These results will allow broader assessment of IBNtxA as a translational candidate or lead compound for further development. Results IBNtxA was synthesized and compared to morphine in a variety of mouse behavioral assays. 3 mg/kg IBNtxA was equipotent to 10 mg/kg morphine in a hot plate analgesia assay. In drug discrimination testing using mice trained to discriminate between 3 mg/kg IBNtxA and DMSO/saline vehicle, the κ agonist U-50488 fully substituted for IBNtxA. Classical μ agonist morphine, δ agonist SNC162, NOP agonist SCH 221510, and μ/NOP partial agonist buprenorphine each partially substituted for IBNtxA. IBNtxA up to 3 mg/kg did not produce a place preference in CPP. Pretreatment with 3 mg/kg IBNtxA but not 1 mg/kg IBNtxA attenuated acquisition of place preference for 10 mg/kg morphine. 3 mg/kg IBNtxA attenuated morphine-induced hyperlocomotion but did not alter naloxone-precipitated morphine withdrawal. Conclusions Overall IBNtxA has a complicated opioid receptor pharmacology in vivo. These results indicate that IBNtxA produces potent antinociception and has low abuse liability, likely driven by substantial κ agonist signaling effects.
Targeting methionine synthase in a fungal pathogen causes a metabolic imbalance that impacts cell energetics, growth and virulence

There is an urgent need to develop novel antifungals to tackle the threat fungal pathogens pose to human health. In this work, we have performed a comprehensive characterisation and validation of the promising target methionine synthase (MetH). We uncover that in Aspergillus fumigatus the absence of this enzymatic activity triggers a metabolic imbalance that causes a reduction in intracellular ATP, which prevents fungal growth even in the presence of methionine. Interestingly, growth can be recovered in the presence of certain metabolites, which evidences that metH is a conditionally essential gene. As this implies that for a correct validation MetH should be targeted in established infections, we have validated the use of the tetOFF genetic model for fungal research and optimised its performance to mimic treatment of established infections. We show that repression of metH in growing hyphae halts growth in vitro, which translates into a beneficial effect when targeting established infections using this model in vivo. Finally, a structural-based virtual screening of methionine synthases reveals key differences between the human and fungal structures and unravels features in the fungal enzyme that can guide the design of novel specific inhibitors. Therefore, methionine synthase is a valuable target for the development of new antifungals. IMPORTANCE Fungal pathogens are responsible for millions of life-threatening infections on an annual basis worldwide. The current repertoire of antifungal drugs is very limited and, worryingly, resistance has emerged and already become a serious threat to our capacity to treat fungal diseases. The first step to develop new drugs often is to identify molecular targets which inhibition during infection can prevent pathogen growth. However, the current models are not suitable to validate targets in established infections. Here we have characterised the promising antifungal target methionine synthase in great detail, using the prominent fungal pathogen Aspergillus fumigatus as a model. We have uncovered the underlying reason for its essentiality and confirmed its druggability. Furthermore, we have optimised the use of a genetic system to show a beneficial effect of targeting methionine synthase in established infections. Therefore, we believe that antifungal drugs to target methionine synthase should be pursued and additionally, we propose that antifungal targets should be validated in a model of established infection.
Xrn1 influences RNA pol II-dependent transcription elongation rates across the yeast genome and this control is particularly relevant for late elongation of regulatory genes

mRNA homeostasis is favored by crosstalks between transcription and degradation machineries. This involves co-transcriptional modulation of mRNA decay by molecular imprinting, and feedback regulation of transcription by degradation factors. Both the Ccr4-NOT and the Xrn1-decaysome complexes have been described to influence transcription. While Ccr4-NOT has been shown to directly stimulate transcription elongation, the information available on how Xrn1 influences transcription is scarce and, in some cases, contradictory. In this study we have addressed this issue by mapping RNA polymerase II (RNApol II) at high resolution, using CRAC and BioGRO-seq techniques in Saccharomyces cerevisiae. We found significant effects of Xrn1 perturbation on RNA pol II profiles across the genome, in both the 5’ and 3’ ends of gene bodies. Downstream of the transcription start site, RNA pol II profiles exhibited significant reductions in slope that were compatible with decreased elongation rates. This phenomenon was also observed soon after the nuclear pool of Xrn1 was depleted. Nucleosome mapping confirmed drastically altered chromatin dynamics during early elongation. We also found an accumulation of arrested RNApol II at the 3’ end, immediately upstream of polyadenylation sites of most genes, with particular incidence in those genes functionally related to regulatory processes. Lack of Xrn1 provoked alterations in RNApol II CTD phosphorylation and increased recruitment of 3’ pre-mRNA processing factors. However, accumulation of RNApol II at 3’ ends was rather related to the nucleosomal configuration of those regions. We conclude that Xrn1 influences RNA pol II-dependent transcription elongation and this control is particularly relevant for genes with a certain type of chromatin structure at 3’.
Secreted inhibitors drive the loss of regeneration competence in Xenopus limbs

Absence of a specialised wound epidermis is hypothesised to block limb regeneration in higher vertebrates. To elucidate the cellular and molecular determinants of this tissue, we performed single-cell transcriptomics in regeneration-competent, -restricted, and -incompetent Xenopus tadpoles. We identified apical-ectodermal-ridge (AER) cells as the specialised wound epidermis, and found that their abundance on the amputation plane correlates with regeneration potential and injury-induced mesenchymal plasticity. By using ex vivo regenerating limb cultures, we demonstrate that extrinsic cues produced during limb development block AER cell formation. We identify Noggin, a morphogen expressed in cartilage/bone progenitor cells, as one of the key inhibitors of AER cell formation in regeneration-incompetent tadpoles. Extrinsic inhibitory cues can be overridden by Fgf10, which operates upstream of Noggin and blocks chondrogenesis. Together, these results indicate that manipulation of the extracellular environment and/or chondrogenesis may provide a strategy to restore regeneration potential in higher vertebrates. One Sentence Summary Extrinsic cues associated with chondrogenic progression inhibit AER cell formation and restrict limb regeneration potential.
Carbon fluxes from a tropical peat swamp forest floor

A tropical ombrotrophic peatland ecosystem is one of the largest terrestrial carbon stores. Flux rates of carbon dioxide (CO2) and methane (CH4) were studied at various peat water table depths in a mixed‐type peat swamp forest floor in Central Kalimantan, Indonesia. Temporary gas fluxes on microtopographically differing hummock and hollow peat surfaces were combined with peat water table data to produce annual cumulative flux estimates. Hummocks formed mainly from living and dead tree roots and decaying debris maintained a relatively steady CO2 emission rate regardless of the water table position in peat. In nearly vegetation‐free hollows, CO2 emission rates were progressively smaller as the water table rose towards the peat surface. Methane emissions from the peat surface remained small and were detected only in water‐saturated peat. By applying long‐term peat water table data, annual gas emissions from the peat swamp forest floor were estimated to be 3493±316 g CO2 m−2 and less than 1.36±0.57 g CH4 m−2. On the basis of the carbon emitted, CO2 is clearly a more important greenhouse gas than CH4. CO2 emissions from peat are the highest during the dry season, when the oxic peat layer is at its thickest because of water table lowering.