tbuckley/cabot-search huggingface dataset:
How Pairwise Coevolutionary Models Capture the Collective Residue Variability in Proteins?
Authors: Matteo Figliuzzi, Pierre Barrat-Charlaix, Martin Weigt
Journal: Molecular Biology and Evolution (2018)

Global coevolutionary models of homologous protein families, as constructed by direct coupling analysis (DCA), have recently gained popularity in particular due to their capacity to accurately predict residue–residue contacts from sequence information alone, and thereby to facilitate tertiary and quaternary protein structure prediction. More recently, they have also been used to predict fitness effects of amino-acid substitutions in proteins, and to predict evolutionary conserved protein–protein interactions. These models are based on two currently unjustified hypotheses: 1) correlations in the amino-acid usage of different positions are resulting collectively from networks of direct couplings; and 2) pairwise couplings are sufficient to capture the amino-acid variability. Here, we propose a highly precise inference scheme based on Boltzmann-machine learning, which allows us to systematically address these hypotheses. We show how correlations are built up in a highly collective way by a large number of coupling paths, which are based on the proteins three-dimensional structure. We further find that pairwise coevolutionary models capture the collective residue variability across homologous proteins even for quantities which are not imposed by the inference procedure, like three-residue correlations, the clustered structure of protein families in sequence space or the sequence distances between homologs. These findings strongly suggest that pairwise coevolutionary models are actually sufficient to accurately capture the residue variability in homologous protein families.
Nephronectin Regulates Mesangial Cell Adhesion and Behavior in Glomeruli
Authors: Susan E. Zimmerman, Chitkale Hiremath, Jun Tsunezumi, Zhufeng Yang, Bronwyn Finney, Denise K. Marciano
Journal: Journal of the American Society of Nephrology (2018)

A critical aspect of kidney function occurs at the glomerulus, the capillary network that filters the blood. The glomerular basement membrane (GBM) is a key component of filtration, yet our understanding of GBM interactions with mesangial cells, specialized pericytes that provide structural stability to glomeruli, is limited. We investigated the role of nephronectin ( Npnt ), a GBM component and known ligand of α 8 β 1 integrin. Immunolocalization and in situ hybridization studies in kidneys of adult mice revealed that nephronectin is produced by podocytes and deposited into the GBM. Conditional deletion of Npnt from nephron progenitors caused a pronounced increase in mesangial cell number and mesangial sclerosis. Nephronectin colocalized with α 8 β 1 integrin to novel, specialized adhesion structures that occurred at sites of mesangial cell protrusion at the base of the capillary loops. Absence of nephronectin disrupted these adhesion structures, leading to mislocalization of α 8 β 1. Podocyte-specific deletion of Npnt also led to mesangial sclerosis in mice. These results demonstrate a novel role for nephronectin and α 8 β 1 integrin in a newly described adhesion complex and begin to uncover the molecular interactions between the GBM and mesangial cells, which govern mesangial cell behavior and may have a role in pathologic states.
When the CHIPs Are Down — Health Coverage and Care at Risk for U.S. Children
Authors: Lisa C. Dubay, Genevieve M. Kenney
Journal: New England Journal of Medicine (2018)

Congress failed to reauthorize the Children's Health Insurance Program (CHIP) last fall, causing uncertainty and worry for families and state CHIP directors alike. After a period of stopgap funding, CHIP was reauthorized for 6 years in late January.
Abstract 19685: Noxa1-Dependent Regulation of Nox1 NADPH Oxidase Activity in the Development of Angiotensin II-Induced Hypertension and an Early Phase of Renal Na+ Retention
Authors: Aleksandr E Vendrov, Nicholas G Moss, Mark D Stevenson, Takayuki Hayami, Xi Yang, Nageswara R Madamanchi, Marschall S Runge, William J Arendshorst
Journal: Circulation (2016)

Abnormal renal function, a major contributor to hypertension (HTN), in conjunction with oxidative stress, enhances the risk for renal failure and the development of cardiovascular disease. Increased reactive oxygen species (ROS) levels, resulting from the activation of NADPH oxidases, in the renal vascular and tubular cells have been implicated in pathophysiology of angiotensin II (Ang II)- and high salt (HS)- induced HTN. We previously reported that the deletion of NoxA1 subunit of Nox1 NADPH oxidase decreased ROS levels in the aortic smooth muscle cells and vasculature under pathophysiologic conditions. In this study, we investigated the importance of NoxA1-dependent Nox1 activity in the regulation of renal Na +  excretion and blood pressure (BP). Chronic Ang II infusion (500ng/kg/min) for 2 weeks increased systolic BP (DSI telemetry) by 33 mmHg in the wild-type (WT) (p -/-  mice. BP was unchanged in mice infused with saline. After 4 weeks of L-NAME-induced hypertension and recovery for 1 week, HTN induction by HS for 2 weeks increased BP by 17 mmHg in WT (p -/-  mice. Na +  excretion was measured in metabolic cages for 8 hr in response to an acute salt load (10% body weight of isotonic saline injected ip) before and during HTN. The rate of Na +  excretion was similar in WT and systemic NoxA1 -/-  mice before and 14 days after Ang II infusion. However, WT excreted Na +  at a slower rate than NoxA1 -/-  mice, with a smaller fraction (P +  excretion was noted in WT vs. systemic NoxA1 -/-  mice during the development of HTN 2-4 days after initiation of HS diet. This is consistent with the notion that relative positive renal Na +  balance related to ROS generation is a causative factor of HTN. Supporting this, Ang II infusion increased NoxA1 protein levels in the cortex and medulla and ENaC protein levels in the medulla. These findings indicate that Ang II activation of NoxA1/Nox1 signaling in the kidney increases ROS levels, causing reduced Na +  excretion, presumably due to renal vasoconstriction and/or enhanced tubular Na +  reabsorption, which leads to increased BP.
Image Gallery: Gin, tonic water and the sun
Authors: S.A. Chan, T.N. Shim
Journal: British Journal of Dermatology (2017)

Funding sources: none. Conflicts of interest: none declared. Dear Editor, Tonic water is a common carbonated drink used in mixed drinks. It is particularly well known for making the alcoholic beverage ‘gin and tonic’. Quinine adds a bitter flavour to drinks and is found in many ‘bitters’, as well as other soft drinks such as bitter lemon and Irn‐Bru. Excessive intake of gin and tonic has been associated with a photodistributed dermatitis, as quinine is a well‐known photosensitizer. This dermatitis is similar to quinine sulfate‐induced photodermatitis. This photograph demonstrates the fluorescence of quinine in tonic water under ultraviolet/Wood's lamp.
Prevalence, severity, and risk factors for acute exacerbations of nasal and sinus symptoms by chronic rhinosinusitis status
Authors: J. R. Kuiper, A. G. Hirsch, K. Bandeen‐Roche, A. S. Sundaresan, B. K. Tan, R. P. Schleimer, R. C. Kern, W. F. Stewart, B. S. Schwartz
Journal: Allergy (2018)

Nasal and sinus symptoms (NSS) are common to many health conditions, including chronic rhinosinusitis (CRS). Few studies have investigated the occurrence and severity of, and risk factors for, acute exacerbations of NSS (AENSS) by CRS status (current, past, or never met European Position Paper on Rhinosinusitis [EPOS] criteria for CRS).
<i>HER2</i> amplification, HER2 overexpression,and <i>TOP2A </i>abnormalities in gastroesophageal cancers: Do they predict responsiveness to epirubicin-based chemotherapy?
Authors: Nicola Personeni, Silvia Bozzarelli, Paola Spaggiari, Luca Rubino, Laura Giordano, Massimo Roncalli, Armando Santoro
Journal: Journal of Clinical Oncology (2012)

e14672 Background: Abnormalities of TOP2A, a major target of anthracyclines, have been reported as positive predictive markers of response to anthracycline-based therapy in breast cancer. We determined abnormalities of TOP2A and HER2, and HER2 protein expression, in a cohort of patients with gastric or gastro-oesophageal junction adenocarcinomas treated with epirubicin-based chemotherapy. Methods: We studied 50 patients that received either adjuvant (74%) or perioperative (26%) epirubicin, cisplatin and 5-fluorouracil. All patients were screened for TOP2A amplification/deletion by fluorescent in situ hybridization (FISH), and for HER2 protein expression by immunohistochemistry (IHC). For each patient at least two paired surgical samples were examined. Tumors exhibiting a HER2 score of 2+ were further screened for gene amplification by FISH. We studied the association of TOP2A abnormalities and HER2 amplification/expression with recurrence free survival (RFS) and overall survival (OS). Results: By IHC, HER2 overexpression (score 3+) was detected in 9 patients. Intra-tumor heterogeneity of HER2 staining, resulting in discrepant HER2 scores, was detected in 4 of 50 (8%) paired samples analyzed. HER2 amplification was detected in 1 of 8 tumors with a HER2 score 2+. TOP2A amplification was observed in 1 of 50 tumors; none exhibited TOP2A deletions. In patients whose tumors showed HER2 overexpression or gene amplification (HER2-positive) and in patients with HER2-negative tumors, median RFS was 11.0 and 13.9 months, respectively (p= 0.35); median OS was 28.8 and 29.9 months, respectively (p= 0.56). A pathological complete response was observed in 1 of 4 HER2-positive patients that underwent perioperative chemotherapy. Conclusions: In this cohort of patients with early-stage gastroesophageal cancers who were treated with epirubicin-based chemotherapy, neither HER2 amplification nor HER2 overexpression were associated with outcome. TOP2A abnormalities are rare and their putative role as a determinant of responsiveness to anthracycline-based chemotherapy in gastroesophageal cancers is not supported by our findings.
Hypertension and Atrial Fibrillation
Authors: Paolo Verdecchia, Fabio Angeli, Gianpaolo Reboldi
Journal: Circulation Research (2018)

Hypertension and atrial fibrillation (AF) are 2 important public health priorities. Their prevalence is increasing worldwide, and the 2 conditions often coexist in the same patient. Hypertension and AF are strikingly related to an excess risk of cardiovascular disease and death. Hypertension ultimately increases the risk of AF, and because of its high prevalence in the population, it accounts for more cases of AF than other risk factors. Among patients with established AF, hypertension is present in about 60% to 80% of individuals. Despite the well-known association between hypertension and AF, several pathogenetic mechanisms underlying the higher risk of AF in hypertensive patients are still incompletely known. From an epidemiological standpoint, it is unclear whether the increasing risk of AF with blood pressure (BP) is linear or threshold. It is uncertain whether an intensive control of BP or the use of specific antihypertensive drugs, such as those inhibiting the renin-angiotensin-aldosterone system, reduces the risk of subsequent AF in hypertensive patients in sinus rhythm. Finally, in spite of the observational evidence suggesting a progressive relation between BP levels and the risk of thromboembolism and bleeding in patients with hypertension and AF, the extent to which BP should be lowered in these patients, including those who undergo catheter ablation, remains uncertain. This article summarizes the main basic mechanisms through which hypertension is believed to promote AF. It also explores epidemiological data supporting an evolutionary pathway from hypertension to AF, including the emerging evidence favoring an intensive BP control or the use of drugs, which inhibit the renin-angiotensin-aldosterone system to reduce the risk of AF. Finally, it examines the impact of non-vitamin K antagonist oral anticoagulants compared with warfarin in relation to hypertension.
Spend more on NHS or see services deteriorate further, hospital leaders warn
Authors: Abi Rimmer
Journal: BMJ (2018)

A lack of funding and staffing shortages have made managing winter pressures “unsustainable,” NHS Providers has warned.

The organisation, which represents NHS hospitals and mental health, community, and ambulance services in England, said that the NHS had reached a “watershed moment,” and it called on the government to accept that the service could no longer deliver what was required of it within current levels of funding.

In a letter to England’s secretary of state for health and social care, Jeremy Hunt, the chief executive of NHS Providers, Chris Hopson, called for the government to “create a sustainable long term funding settlement for health and care.”1

Decisions on …
National roll-out of latent tuberculosis testing and treatment for new migrants in England: a retrospective evaluation in a high-incidence area
Authors: Miranda G. Loutet, Matthew Burman, Nivenka Jayasekera, Duncan Trathen, Susan Dart, Heinke Kunst, Dominik Zenner
Journal: European Respiratory Journal (2018)

Latent tuberculosis infection (LTBI) screening is an important intervention for tuberculosis (TB) elimination in low-incidence countries and is, therefore, a key component of England's TB control strategy. This study describes outcomes from a LTBI screening programme in a high-incidence area to inform national LTBI screening in England and other low-incidence countries. We conducted a retrospective cohort study of LTBI screening among eligible migrants (from high-incidence countries and entered the UK within the last 5 years), who were identified at primary-care clinics in Newham, London between August 2014 and August 2015. Multivariable logistic regression was used to identify factors associated with LTBI testing uptake, interferon-γ release assay (IGRA) positivity and treatment uptake. 40% of individuals offered LTBI screening received an IGRA test. The majority of individuals tested were 16–35 years old, male and born in India, Bangladesh or Pakistan. Country of birth, smoking status and co-morbidities were associated with LTBI testing uptake. IGRA positivity was 32% among those tested and was significantly associated with country of birth, age, sex and co-morbidities. This study identifies factors associated with screening uptake, IGRA positivity and treatment uptake, and improves understanding of groups that should be supported to increase acceptability of LTBI testing and treatment in the community.
Patient Autonomy Is a Right, But Exercising That Right May Not Be an Obligation for Patients and Kin
Authors: Thor Willy Ruud Hansen
Journal: The American Journal of Bioethics (2018)

"Patient Autonomy Is a Right, But Exercising That Right May Not Be an Obligation for Patients and Kin." The American Journal of Bioethics, 18(1), pp. 32–33
Engineering Approaches to Study Cellular Decision Making
Authors: Pamela K. Kreeger, Laura E. Strong, Kristyn S. Masters
Journal: Annual Review of Biomedical Engineering (2018)

In their native environment, cells are immersed in a complex milieu of biochemical and biophysical cues. These cues may include growth factors, the extracellular matrix, cell–cell contacts, stiffness, and topography, and they are responsible for regulating cellular behaviors such as adhesion, proliferation, migration, apoptosis, and differentiation. The decision-making process used to convert these extracellular inputs into actions is highly complex and sensitive to changes both in the type of individual cue (e.g., growth factor dose/level, timing) and in how these individual cues are combined (e.g., homotypic/heterotypic combinations). In this review, we highlight recent advances in the development of engineering-based approaches to study the cellular decision-making process. Specifically, we discuss the use of biomaterial platforms that enable controlled and tailored delivery of individual and combined cues, as well as the application of computational modeling to analyses of the complex cellular decision-making networks.
Особливості клінічної симптоматики у хворих на гастроезофагеальну рефлюксну хворобу при поєднанні з дисфункцією сфінктера Одді
Authors: L.M. Mosiychuk, I.V. Kushnirenko, L.V. Demeshkina, I.O. Vasilieva, V.M. Yarosh, G.I. Bocharov
Journal: GASTROENTEROLOGY (2020)

Стаття присвячена вивченню особливостей клінічної симптоматики в пацієнтів із поєднаними захворюваннями — гастроезофагеальною рефлюксною хворобою та дисфункцією сфінктера Одді (СфО). Дослідження проведено на 78 пацієнтах, які були розподілені на три групи залежно від характеру дисфункції сфінктера Одді. Такий підхід дозволив зробити низку важливих висновків, які свідчать про обтяжливий вплив дисфунції жовчовивідних шляхів на перебіг гастроезофагеальної рефлюксної хвороби незалежно від форми дисфункції, що підтверджується зростанням частоти та інтенсивності основних симптомів дис-пептичного та больового синдромів.
Hepatic PPARα function is controlled by polyubiquitination and proteasome‐mediated degradation through the coordinated actions of PAQR3 and HUWE1
Authors: Zilong Zhao, Daqian Xu, Zheng Wang, Lin Wang, Ruomei Han, Zhenzhen Wang, Lujian Liao, Yan Chen
Journal: Hepatology (2018)

Peroxisome proliferator-activated receptor α (PPARα) is a key transcriptional factor that regulates hepatic lipid catabolism by stimulating fatty acid oxidation and ketogenesis in an adaptive response to nutrient starvation. However, how PPARα is regulated by posttranslational modification is poorly understood. In this study, we identified that progestin and adipoQ receptor 3 (PAQR3) promotes PPARα ubiquitination through the E3 ubiquitin ligase HUWE1, thereby negatively modulating PPARα functions both in vitro and in vivo. Adenovirus-mediated Paqr3 knockdown and liver-specific deletion of the Paqr3 gene reduced hepatic triglyceride levels while increasing fatty acid oxidation and ketogenesis upon fasting. PAQR3 deficiency enhanced the fasting-induced expression of PPARα target genes, including those involved in fatty acid oxidation and fibroblast growth factor 21, a key molecule that mediates the metabolism-modulating effects of PPARα. PAQR3 directly interacted with PPARα and increased the polyubiquitination and proteasome-mediated degradation of PPARα. Furthermore, the E3 ubiquitin ligase HUWE1 was identified to mediate PPARα polyubiquitination. Additionally, PAQR3 enhanced the interaction between HUWE1 and PPARα.Ubiquitination modification through the coordinated action of PAQR3 with HUWE1 plays a crucial role in regulating the activity of PPARα in response to starvation. (Hepatology 2018;68:289-303).
Mutant Isocitrate Dehydrogenase (mIDH) Inhibitors, Enasidenib or Ivosidenib, in Combination with Azacitidine (AZA): Preliminary Results of a Phase 1b/2 Study in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML)
Authors: Courtney D. DiNardo, Anthony S. Stein, Amir T. Fathi, Pau Montesinos, Olatoyosi Odenike, Hagop M. Kantarjian, Richard M. Stone, Daniel O. Koralek, Jason Van Oostendorp, Jing Gong, Ira Gupta, Paresh Vyas
Journal: Blood (2017)
Skin inflammation exacerbates food allergy symptoms in epicutaneously sensitized mice
Authors: A. Kawasaki, N. Ito, H. Murai, M. Yasutomi, H. Naiki, Y. Ohshima
Journal: Allergy (2018)

Abstract Background Cutaneous exposure to food antigen through impaired skin barrier has been shown to induce epicutaneous sensitization, thereby causing IgE‐mediated food allergies. Objective We examined whether skin barrier impairment following epicutaneous sensitization exacerbates food allergies. Methods BALB /c mice were epicutaneously sensitized by repeated application of ovalbumin ( OVA ) to MC 903‐pretreated ear skin for 48 hours weekly and then intragastrically challenged with OVA . After the first oral challenge, the skin barrier was disrupted with topical application of MC 903 or by tape‐stripping. Mice were monitored for changes in body temperature and the occurrence of diarrhea after undergoing the second oral challenge. Serum levels of mouse mast cell protease‐1 (mmcp1) and OVA ‐specific IgE, IgG1, IgG2a antibodies and OVA ‐specific IgA levels in intestinal lavage fluid were measured by ELISA . Tissue accumulation of eosinophils was determined histologically. Results Epicutaneously sensitized mice developed anaphylaxis after intragastric challenge, as evidenced by diarrhea, decreased body temperature, and increased serum mmcp1 levels. Skin barrier disruption by MC 903 treatment or tape‐stripping exacerbated allergic reactions induced by oral challenge. MC 903 treatment increased serum baseline and postchallenge mmcp1 levels. Topical pretreatment with dexamethasone alleviated allergic reactions that were exacerbated by MC 903 treatment. Conclusion Even after eliminating exposure to the antigen, inflammation from skin barrier disruption can exacerbate the severity of food allergy symptoms. Serum baseline mmcp1 levels might be an effective marker for predicting the severity of antigen‐induced allergic symptoms.
The Fragile State of the National Institutes of Health Pediatric Research Portfolio, 1992-2015
Authors: Daniel P. Gitterman, W. Scott Langford, William W. Hay
Journal: JAMA Pediatrics (2018)

In this article, we examine the status of the National Institutes of Health (NIH) pediatric research portfolio between start of federal fiscal year (FY) 1992 and end of FY 2015. The NIH experienced the greatest mean annual growth rate during the "doubling era" (FY 1998-2003): both the NIH budget (13.5%) and pediatric research portfolios (11.5%) increased annually by double digits. However, in the "postdoubling" era (FY 2004-2009), both the NIH (2.0%) and pediatric (−0.2%) mean annual growth rates decreased dramatically. In the most recent era (FY 2010-2015), the NIH mean annual growth rate has been flat (−0.1%) and pediatric research funding has posted very modest gains (3.5%) without accounting for 1-time increases under the 2009 American Recovery and Reinvestment Act. We offer recommendations to protect against further erosion of the pediatric research portfolio because continuation of these trends will have a negative effect on the health of children during their childhood and as adults. As capacity to conduct basic and applied research is further constrained, it will be a challenge for pediatric researchers to do more with less and less.
Pharmacokinetic Profile of Subcutaneous C1-Esterase Inhibitor (C1-INH [SC]) in Adolescent and Adult Patients with Hereditary Angioedema (HAE)
Authors: Dipti K. Pawaskar, Iris Jacobs, Ingo Pragst, Henrike Feuersenger
Journal: Journal of Allergy and Clinical Immunology (2018)
Ongoing nationwide outbreak of Salmonella Agona associated with internationally distributed infant milk products, France, December 2017
Authors: Nathalie Jourdan-da Silva, Laetitia Fabre, Eve Robinson, Nelly Fournet, Athinna Nisavanh, Mathias Bruyand, Alexandra Mailles, Estelle Serre, Magali Ravel, Véronique Guibert, Sylvie Issenhuth-Jeanjean, Charlotte Renaudat, Mathieu Tourdjman, Alexandra Septfons, Henriette de Valk, Simon Le Hello
Journal: Eurosurveillance (2018)

On 1 December 2017, an outbreak of Salmonella Agona infections among infants was identified in France. To date, 37 cases (median age: 4 months) and two further international cases have been confirmed. Five different infant milk products manufactured at one facility were implicated. On 2 and 10 December, the company recalled the implicated products; on 22 December, all products processed at the facility since February 2017. Trace-forward investigations indicated product distribution to 66 countries.