Miracle-dz/UniFAR-FTUs huggingface dataset:
The human motor neuron pools receive a dominant slow‐varying common synaptic input

Motor neurons in a pool receive both common and independent synaptic inputs, although the proportion and role of their common synaptic input is debated. Classic correlation techniques between motor unit spike trains do not measure the absolute proportion of common input and have limitations as a result of the non‐linearity of motor neurons. We propose a method that for the first time allows an accurate quantification of the absolute proportion of low frequency common synaptic input (<5 Hz) to motor neurons in humans. We applied the proposed method to three human muscles and determined experimentally that they receive a similar large amount (>60%) of common input, irrespective of their different functional and control properties. These results increase our knowledge about the role of common and independent input to motor neurons in force control.
Selective and sensitive quantification of the cytochrome P450 3A4 protein in human liver homogenates through multiple reaction monitoring mass spectrometry

This study aimed at establishing a sensitive multiple reaction monitoring‐mass spectrometry (MRM‐MS) method for the quantification of the drug metabolizing cytochrome P450 (CYP)3A4 enzyme in human liver homogenates. Liver samples were subjected to trypsin digestion. MRM‐MS analyses were performed using three transitions optimized on one purified synthetic peptide unique to CYP3A4 and the standardizing protein, calnexin. Coefficient of variations for the precision and reproducibility of the MRM‐MS measurement were also determined. The method was applied to liver samples from ten non‐cholestatic donors and 34 cholestatic patients with primary biliary cholangitis (n = 12; PBC), primary sclerosing cholangitis (n = 10; PSC) or alcoholic liver disease (n = 12; ALD). The established method presented high sensitivity with limit of detection lower than 5 fmol, and was successfully applied for the absolute and relative quantification of CYP3A4 in both whole liver homogenate and microsomal fractions. When all groups were analyzed together, a significant correlation was observed for the MRM‐based CYP3A4 protein quantification in homogenates and microsomes (r = 0.49, p < 0.001). No statistically significant difference was detected between CYP3A4 levels in PSC, PBC, ALD and control samples. Finally, the MRM‐MS quantification of CYP3A4 in homogenates also correlated (r = 0.44; p < 0.05) with the level of enzyme activity in the same samples, as determined by measuring the chenodeoxycholic to hyocholic acid conversion. The established method provides a sensitive tool to evaluate the CYP3A4 protein in human liver homogenates from patients with normal or chronic/severe hepatic injury.
Short‐term depression of gap junctional coupling in reticular thalamic neurons of absence epileptic rats

Gap junctional electrical coupling between neurons of the reticular thalamic nucleus (RTN) is critical for hypersynchrony in the thalamo‐cortical network. This study investigates the role of electrical coupling in pathological rhythmogenesis in RTN neurons in a rat model of absence epilepsy. Rhythmic activation resulted in a Ca2+‐dependent short‐term depression (STD) of electrical coupling between pairs of RTN neurons in epileptic rats, but not in RTN of a non‐epileptic control strain. Pharmacological blockade of gap junctions in RTN in vivo induced a depression of seizure activity. The STD of electrical coupling represents a mechanism of Ca2+ homeostasis in RTN aimed to counteract excessive synchronization.
ARTIFICIAL FEEDING IN EARLY INFANCY

Somatic Stability in the Newly Born A Ciba Foundation Symposium edited by G. E. W. WOLSTENHOLME, O.B. E. , M.A., M.B. , M.R. C.P., and MAEVA O'CONNOR, B.A. Pp. xii + 393, illustrated. London: J. & A. Churchill. I96I. 50s. This is an excellent symposium. The overall theme is that of homoeostasis in the perinatal period. Papers and discussions range over renal, cardiovascular, endocrine and nervous system aspects, whilst metabolism in relation to the intrauterine environment, carbohydrates and the role of the liver and body temperature regulation are considered. The human, the rat, the pig, the rabbit are among the new-born animals described and to the special problem of the Pulmonary Syndrome in New-born Foals is devoted a single paper. Almost every paper has something of value to give to the paediatrician, physiologist, biochemist, veterinarian and indeed to any experimental worker in the human or animal neonatal field. The clinician can receive help in his problems from Usher's views on the Respiratory Distress Syndrome, Villee on Establishment of Enzyme Systems, Richter on the Nervous System, Midgeon on Endocrine Function, Dawes on Oxygen Consumption and Hypoxia, Widdowson on Metabolic Effects of Fasting and Food, James on Asphyxia, Vesterdal on Kidney Function and Kerpel-Fronius on the Clinical Aspects of Stability. The research worker will surely read with interest Hill's treatment of the Physics and Physiology of the development of Homoeothermy, Holm et. al on Aspects of Homoeothermy in Rats, Mount on Metabolic rate and Body Temperature, and Zetterstrom on the Liver and Carbohydrate Metabolism (not excluding the papers enumerated for their clinical value). All the papers give evidence of the meticulous nature of the investigations and the high standard of the research carried out. The discussions recorded must stimulate many new thoughts and new ideas. How pleasant it is to see so excellent a publication in print in the same year as the symposium occurred.
Perfil socioeconômico e satisfação dos pacientes atendidos no mutirão de catarata do Instituto da Visão - UNIFESP

OBJECTIVE: To identify the socioeconomic profile as well as epidemiological data and evaluate the satisfaction of patients examined during a community project for the treatment of senile cataracts conducted by the Instituto da Visao/Ophthalmology Department - UNIFESP-EPM. METHOD: During the Cataract Project which occurred on 5th Sept, 2002 at the Ophthalmology Department - UNIFESP/EPM, subjects were surveyed by questionnaires developed to identify their socioeconomic characteristics and evaluate their satisfaction regarding attendance. They were randomly selected from the waiting line. RESULTS: The sample was composed of 133 subjects, which represents 50% of patients examined during this Cataract Project. Sixty-one (46%) were male and 72 (54%) female; 117 (87%) were older than 50 years; 111 (84%) finished high school; 74 (55%) were retired and/or pensioners; 99 (74%) had a family income of up to R$ 500,00; 91 (68%) needed someone to assist or accompany them during the visit; 95 (71%) presented cataract with surgical indication. Regarding their satisfaction with the service, 122 (91%) considered the general quality of attendance good; 10 (8%) considered it regular and 1 (1%) bad. CONCLUSION: As a whole the population examined during this Cataract Project was satisfied with the services, but, some aspects have to be improved to better meet their expectations. It is a needy population, with low visual acuity, depends on public health services, has low level education and, most, need someone to accompany them during the visit to the hospital.
Optogenetic and pharmacological evidence that somatostatin‐GABA neurons are important regulators of parasympathetic outflow to the stomach

The dorsal motor nucleus of the vagus (DMV) in the brainstem consists primarily of vagal preganglionic neurons that innervate postganglionic neurons of the upper gastrointestinal tract. The activity of the vagal preganglionic neurons is predominantly regulated by GABAergic transmission in the DMV. The present findings indicate that the overwhelming GABAergic drive present at the DMV is primarily from somatostatin positive GABA (Sst‐GABA) DMV neurons. Activation of both melanocortin and μ‐opioid receptors at the DMV inhibits Sst‐GABA DMV neurons. Sst‐GABA DMV neurons may serve as integrative targets for modulating vagal output activity to the stomach.
A rapid differential display analysis of nasal swab fingerprints to distinguish allergic from non‐allergic rhinitis subjects by mesoporous silica particles and MALDI‐TOF mass spectrometry

Discriminating different rhinitis cases can sometimes be difficult as the diagnostic criteria used to identify the various subgroups are not always unambiguous. The nasal fluid (NF) highly reflects the pathophysiology of these inflammatory diseases. However, its collection, as nasal lavage fluid, may cause discomfort. Due to the non‐invasiveness and rapidity of collection, nasal swab might represent an alternative to overcome these problems and also an ideal source of biomarkers. In this study, we demonstrate that the combined use of mesoporous silica (MPS) with MALDI‐TOF MS allows the rapid detection of differential nasal peptide profiles from nasal swabs of healthy (H), allergic rhinitis (AR) and non‐allergic rhinitis (NAR) subjects. NF peptides from nasal swabs were captured by the mean of MPS then profiled by MALDI‐TOF MS. As a proof‐of‐principle, we also explored the ability of our platform to discriminate between nasal swabs of patients with AR and NAR, and between these groups and H controls. Four peaks resulted differentially expressed between NAR and AR, two peaks discriminated AR from H while one peak segregated NAR from H group. Therefore, peptides selected and enriched by our platform could form a part of a diagnostic ‘‘rhinomic’’ profile of the allergic and non‐allergic patients.
A targeted proteomic assay for the measurement of plasma proteoforms related to human aging phenotypes

Circulating polypeptides and proteins have been implicated in reversing or accelerating aging phenotypes, including growth/differentiation factor 8 (GDF8), GDF11, eotaxin, and oxytocin. These proteoforms, which are defined as the protein products arising from a single gene due to alternative splicing and PTMs, have been challenging to study. Both GDF8 and GDF11 have known antagonists such as follistatin (FST), and WAP, Kazal, immunoglobulin, Kunitz, and NTR domain‐containing proteins 1 and 2 (WFIKKN1, WFIKKN2). We developed a novel multiplexed SRM assay using LC‐MS/MS to measure five proteins related to GDF8 and GDF11 signaling, and in addition, eotaxin, and oxytocin. Eighteen peptides consisting of 54 transitions were monitored and validated in pooled human plasma. In 24 adults, the mean (SD) concentrations (ng/mL) were as follows: GDF8 propeptide, 11.0 (2.4); GDF8 mature protein, 25.7 (8.0); GDF11 propeptide, 21.3 (10.9); GDF11 mature protein, 16.5 (12.4); FST, 29.8 (7.1); FST cleavage form FST303, 96.4 (69.2); WFIKKN1, 38.3 (8.3); WFIKKN2, 32.2 (10.5); oxytocin, 1.9 (0.9); and eotaxin, 2.3 (0.5). This novel multiplexed SRM assay should facilitate the study of the relationships of these proteoforms with major aging phenotypes.
Influence of brain‐derived neurotrophic factor‐tyrosine receptor kinase B signalling in the nucleus tractus solitarius on baroreflex sensitivity in rats with chronic heart failure

Impairment of baroreflex function is associated with the progression of chronic heart failure (CHF) and a poor prognosis. The baroreflex desensitization in CHF is at least partly the result of central neuronal network dysfunction. The dorsal medial nucleus tractus solitarius (dmNTS) has long been appreciated as a primary site of baroreceptor afferent termination in the central nervous system. However, the influence of neurotransmitters and neuromodulators in the dmNTS on baroreflex function both in normal and CHF states is not fully understood. The present study provides the first evidence showing a tonic sympatho‐inhibitory role for brain‐derived neurotrophic factor (BDNF) neurotransmission in the dmNTS. Most importantly, BDNF‐ tyrosine receptor kinase B (TrkB) signalling in the dmNTS is integral for normal baroreflex function as indicated by the blunting of baroreflex sensitivity (BRS) following the antagonization of TrkB, which inhibited baroreflex gain and range. Furthermore, we found that the tonic sympatho‐inhibition of BDNF was withdrawn in the CHF state, thus contributing to the increased sympathetic tone associated with CHF. Consistent with this finding, BDNF/TrkB antagonism had little effect on reducing BRS in CHF animals, which is corroborated by the observation of decreased TrkB expression in the dmNTS during CHF. Taken together, these results implicate a reduction in BDNF‐TrkB signalling in the dmNTS during CHF that contributes to sympatho‐excitation and baroreflex desensitization. The observation that the BDNF/TrkB pathway is impaired in the dmNTS during CHF provides a novel mechanism for understanding the central alterations that contribute to baroreflex desensitization during CHF.
Over 4100 protein identifications from a Xenopus laevis fertilized egg digest using reversed‐phase chromatographic prefractionation followed by capillary zone electrophoresis–electrospray ionization–tandem mass spectrometry analysis

A tryptic digest generated from Xenopus laevis fertilized embryos was fractionated by RPLC. One set of 30 fractions was analyzed by 100‐min CZE‐ESI‐MS/MS separations (50 h total instrument time), and a second set of 15 fractions was analyzed by 3‐h UPLC‐ESI‐MS/MS separations (45 h total instrument time). CZE‐MS/MS produced 70% as many protein IDs (4134 versus 5787) and 60% as many peptide IDs (22 535 versus 36 848) as UPLC‐MS/MS with similar instrument time (50 h versus 45 h) but with 50 times smaller total consumed sample amount (1.5 μg versus 75 μg). Surprisingly, CZE generated peaks that were 25% more intense than UPLC for peptides that were identified by both techniques, despite the 50‐fold lower loading amount; this high sensitivity reflects the efficient ionization produced by the electrokinetically pumped nanospray interface used in CZE. This report is the first comparison of CZE‐MS/MS and UPLC‐MS/MS for large‐scale eukaryotic proteomic analysis. The numbers of protein and peptide identifications produced by CZE‐ESI‐MS/MS approach those produced by UPLC‐MS/MS, but with nearly two orders of magnitude lower sample amounts.
Declining performance of master athletes: silhouettes of the trajectory of healthy human ageing?

Analysis of world record performances by master athletes suggests an essentially linear decline with age until around the eighth decade after which performance decline accelerates. Because these records are obtained from highly trained individuals they can be viewed as being reflective of the diminution of integrative physiological prowess that occurs solely as a result of ageing, unaffected by the confounding effects of inactivity. It can also be argued that these performance profiles mirror and provide an insight into the trajectory of the physiology of the human ageing process. Here we propose a set point theory that hypothesises that a given threshold of physical activity is needed to age optimally and to maximise the ‘healthspan’. Exercising at levels below the set point will result in ageing being contaminated by the unpredictable and pathological effects of inactivity. Exercise above this threshold stimulates adaptations towards maximising athletic performance, but is unlikely to have further beneficial effects on health. Thus the decades‐long, controlled diminution in athletic performance, should not be seen as a disease process. The ageing process is separate from, and independent of, exercise‐mediated processes that maintain or adapt physiological function. Whether an understanding of these mechanisms will also help uncover mechanisms underpinning the ageing process itself is open to question. However, any model which does not take into account the effects of activity will not adequately describe the inherent ageing process.
Discovery of putative breast cancer antigens using an integrative platform of genomics‐driven immunoproteomics

Recent advances in cancer immuno‐therapeutics such as checkpoint inhibitors, chimeric antigen‐receptor T cells, and tumor infiltrating T cells (TIL) are now significantly impacting cancer patients in a positive manner. Although very promising, reports indicate no more than 25% of cases result in complete remission. One of the limitations of these treatments is the identity of putative cancer antigens in each patient, as it is technically challenging to identify cancer antigens in a rapid fashion. Thus, identification of cancer antigens followed by targeted treatment will increase the efficacy of cancer immunotherapies. To achieve this goal, a combined technologies platform of deep genomic sequencing and personalized immune assessment was devised, termed Genomics Driven Immunoproteomics (GDI). Using this technological platform, we report the discovery of 149 tumor antigens from human breast cancer patients. Significant number of these putative cancer antigens arise from single nucleotide variants (SNVs), as well as insertions and deletions that results into frame‐shift mutations. We propose a general model of anti‐cancer immunity and suggest that the GDI platform may help identify patient‐specific tumor antigens in a timely fashion for precision immunotherapies.
Views of alcohol control policies in the 2000 National Alcohol Survey: What news for alcohol policy development in the US and its States?

This article examines public opinion in US alcohol policies during the 1990s and their correlates in 2000, using five national telephone surveys. Trend analyses of public opinion on 11 common alcohol policies is presented and factor‐based policy scales, based on 14 items in 2000, are used to examine demographic correlates of support for various policy areas, using bivariate, linear (OLS) and logistic regression analyses. With the exception of the alcohol warning label policy, national support for alcohol policies declined (eight policies) or was unchanged in the 1990s for 11 measured policies. In 2000, four meaningful policy opinion factors were found with adequate reliabilities (αs 0.65–0.75) for three of four derived scales. In 2000, support for specific policies varies. Warnings on labels and advertisements have highest support (>90%), then interventions like prevention, treatment, and responsible beverage service at 70% (with similar levels seen for improving access to treatment). Alcohol controls show varied, but lower support from 25% (raising minimum drinking age further), to above 60% for banning sales in corner stores; only about a third favor higher alcohol taxes (35%) and more restrictive hours of sale (32%). In general, women and those with lower socio‐economic status show higher alcohol policy support. Multivariate results show heavier drinkers are least supportive of alcohol policy, while ethnic minorities, especially Hispanics are more favorable to alcohol controls and raising alcohol taxes. Since evidence‐based alcohol control policies show mixed, but lower public support than treatment, prevention and consumer warnings, there is a need for community‐based strategies to increase awareness of environmentally orientated alcohol policies and their public health benefits.
Mechanical activation of angiotensin II type 1 receptors causes actin remodelling and myogenic responsiveness in skeletal muscle arterioles

Candesartan, an inverse agonist of the type 1 angiotensin II receptor (AT1R), causes a concentration‐dependent inhibition of pressure‐dependent myogenic tone consistent with previous reports of mechanosensitivity of this G protein‐coupled receptor. Mechanoactivation of the AT1R occurs independently of local angiotensin II production and the type 2 angiotensin receptor. Mechanoactivation of the AT1R stimulates actin polymerization by a protein kinase C‐dependent mechanism, but independently of a change in intracellular Ca2+. Using atomic force microscopy, changes in single vascular smooth muscle cell cortical actin are observed to remodel following mechanoactivation of the AT1R.
Visceral and somatic pain modalities reveal NaV1.7‐independent visceral nociceptive pathways

Voltage‐gated sodium channels play a fundamental role in determining neuronal excitability. Specifically, voltage‐gated sodium channel subtype NaV1.7 is required for sensing acute and inflammatory somatic pain in mice and humans but its significance in pain originating from the viscera is unknown. Using comparative behavioural models evoking somatic and visceral pain pathways, we identify the requirement for NaV1.7 in regulating somatic (noxious heat pain threshold) but not in visceral pain signalling. These results enable us to better understand the mechanisms underlying the transduction of noxious stimuli from the viscera, suggest that the investigation of pain pathways should be undertaken in a modality‐specific manner and help to direct drug discovery efforts towards novel visceral analgesics.
Development of a high‐throughput method for real‐time assessment of cellular metabolism in intact long skeletal muscle fibre bundles

We developed a method that allows for real‐time assessment of cellular metabolism in isolated, intact long skeletal muscle fibre bundles from adult mice. This method can be used to study changes in mitochondrial function and fuel utilisation in live skeletal muscle fibre bundles. Our method enables flexibility in experimental design and high‐throughput assessment of mitochondrial parameters in isolated skeletal muscle fibre bundles. Extensor digitorum longus (EDL) fibre bundles obtained from chronic high‐fat diet fed mice had lower basal oxygen consumption under FCCP‐induced maximal respiration, when compared to control chow‐fed mice. EDL fibre bundles obtained from chronic high‐fat diet fed mice had enhanced mitochondrial oxidation capacity under FCCP‐induced maximal respiration, when compared to control chow‐fed mice.
Mechanical Ventilation and the Adult Respiratory Distress Syndrome

In 1967, Ashbaugh and colleagues introduced the term "adult respiratory distress syndrome" (ARDS) to describe 12 patients with the acute onset of tachypnea, hypoxemia, and a decline in pulmonary compliance. The incidence of ARDS, although controversal, is estimated to be approximately 150,000 cases per year in the United States. Even with the recent advances in medical technology, the mortality remains unacceptably high at 40 to 60%. Although only 15% of patients die of primary respiratory failure, the role of mechanical ventilation in ARDS is often considered the most important aspect of the patient's supportive care. ' In this article we shall review the available conventional and nonconventional strategies for mechanically ventilating patients with ARDS and explore the rationale for the development of these techniques.
Adenosine receptors regulate gap junction coupling of the human cerebral microvascular endothelial cells hCMEC/D3 by Ca2+ influx through cyclic nucleotide‐gated channels

Gap junction channels are essential for the formation and regulation of physiological units in tissues by allowing the lateral cell‐to‐cell diffusion of ions, metabolites and second messengers. Stimulation of the adenosine receptor subtype A2B increases the gap junction coupling in the human blood–brain barrier endothelial cell line hCMEC/D3. Although the increased gap junction coupling is cAMP‐dependent, neither the protein kinase A nor the exchange protein directly activated by cAMP were involved in this increase. We found that cAMP activates cyclic nucleotide‐gated (CNG) channels and thereby induces a Ca2+ influx, which leads to the increase in gap junction coupling. The report identifies CNG channels as a possible physiological link between adenosine receptors and the regulation of gap junction channels in endothelial cells of the blood–brain barrier.