Structural determinants of TRPV4 inhibition and identification of new antagonists with antiviral activity.

Background And Purpose: The transient receptor potential vanilloid 4 (TRPV4) cation channel participates in multiple physiological processes and is also at the core of different diseases, making this channel an interesting pharmacological target with therapeutic potential. However, little is known about the structural elements governing its inhibition.

Experimental Approach: We have now combined in silico drug discovery and molecular dynamics simulation based on Xenopus tropicalis xTRPV4 structure with functional studies measuring cell Ca influx mediated by human TRPV4 channel to characterize the binding site of known TRPV4 inhibitors and to identify novel small molecule channel modulators.

Belowground impacts of alpine woody encroachment are determined by plant traits, local climate, and soil conditions.

Global climate and land use change are causing woody plant encroachment in arctic, alpine, and arid/semi-arid ecosystems around the world, yet our understanding of the belowground impacts of this phenomenon is limited. We conducted a globally distributed field study of 13 alpine sites across four continents undergoing woody plant encroachment and sampled soils from both woody encroached and nearby herbaceous plant community types. We found that woody plant encroachment influenced soil microbial richness and community composition across sites based on multiple factors including woody plant traits, site level climate, and abiotic soil conditions.

Cross-neutralization activity against SARS-CoV-2 is present in currently available intravenous immunoglobulins.

Cross-reactivity against human coronaviruses with Flebogamma DIF and Gamunex-C, two available intravenous immunoglobulins (IVIG), has been reported. In this study, these IVIG were tested for neutralization activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), SARS-CoV and Middle East respiratory syndrome CoV (MERS-CoV). Neutralization capacity of lots of IVIG manufactured prior to COVID-19 pandemic was assessed against these viruses in cell culture.

Cardiac magnetic resonance-derived fibrosis, strain and molecular biomarkers of fibrosis in hypertensive heart disease.

Aims: Myocardial fibrosis is a relevant component of hypertensive heart disease (HHD). Novel cardiovascular magnetic resonance (CMR) imaging techniques have shown potential in quantification of diffuse cardiac fibrosis, with T1 mapping, and estimating preclinical cardiac dysfunction, with strain analysis. Molecular biomarkers of fibrosis have been related with clinical outcomes and histologically proven myocardial fibrosis.

Host-derived circular RNAs display proviral activities in Hepatitis C virus-infected cells.

Viruses subvert macromolecular pathways in infected host cells to aid in viral gene amplification or to counteract innate immune responses. Roles for host-encoded, noncoding RNAs, including microRNAs, have been found to provide pro- and anti-viral functions. Recently, circular RNAs (circRNAs), that are generated by a nuclear back-splicing mechanism of pre-mRNAs, have been implicated to have roles in DNA virus-infected cells.

Role of Cardiac Lymphatics in Myocardial Edema and Fibrosis: JACC Review Topic of the Week.

The cardiac lymphatic network plays a key role in regulation of myocardial extracellular volume and immune cell homeostasis. In different pathological conditions cardiac lymphatics undergo significant remodeling, with insufficient lymphatic function and/or lymphangiogenesis leading to fluid accumulation and development of edema. Additionally, by modulating the reuptake of tissue-infiltrating immune cells, lymphatics regulate immune responses.

Characteristics and Outcomes in Patients Presenting With COVID-19 and ST-Segment Elevation Myocardial Infarction.

There is limited information regarding clinical characteristics and outcomes of patients with SARS-CoV-2 (COVID-19) disease presenting with ST-segment elevation myocardial infarction (STEMI). In this multicenter retrospective study, we reviewed charts of patients admitted with symptomatic COVID-19 infection and STEMI to a total of 4 hospitals spanning Italy, Lithuania, Spain and Iraq from February 1, 2020 to April 15, 2020. A total of 78 patients were included in this study, 49 (63%) of whom were men, with a median age of 65 [58, 71] years, and high comorbidity burden.

Beyond resource limitation: an expanded test of the niche dimension hypothesis for multiple types of niche axes.

The niche dimension hypothesis predicts that more species can coexist given a greater number of niche axes along which they partition the environment. Although this hypothesis has been broadly supported by nutrient enrichment experiments, its applicability to other ecological factors, such as natural enemies and abiotic stresses, has not been vigorously tested. Here, we examined the generality of the niche dimension hypothesis by experimentally manipulating both resource and non-resource niche dimensions-nitrogen limitation, pathogens and low-temperature stress-in a Tibetan alpine meadow.

Social inequities in cardiovascular risk factors in women and men by autonomous regions in Spain.

Objective: To describe social inequities in cardiovascular risk factors in women and men by autonomous regions in Spain.

Method: We used data from 20,406 individuals aged 18 or older from the 2017 Spanish National Health Survey. We measured socioeconomic position using occupational social class and used data on self-reported cardiovascular risk factors: high cholesterol, diabetes, hypertension, obesity, and smoking.

Pheochromocytoma: A three-decade clinical experience in a multicenter study.

Objective: To analyze the clinical and analytical features, diagnostic tests, therapies, and outcomes of pheochromocytoma (PCC).

Design And Methods: A multicenter retrospective study in surgically treated patients with PCC followed in 3 Spanish tertiary referral hospitals.

Results: A total of 106 patients (61 [57.

Adenohypophyseal hyperfunction syndromes and posterior pituitary tumors: prevalence, clinical characteristics, and pathophysiological mechanisms.

Posterior pituitary tumors are rare nonneuroendocrine neoplasms originating in the neurohypophysis that lack hormonal secretory capacity. Surprisingly, these tumors are relatively frequently associated with adenohypophyseal syndromes of hormonal hypersecretion such as Cushing's disease and acromegaly. Fifteen cases of posterior pituitary tumor associated with hypercortisolism have been reported to date, 13 of them were pituicytomas (Pi) and 2 were granular cell tumors (GCT).

Prognostic factors in patients with vulvar cancer: the VULCAN study.

Objective: This study aimed to analyze the prognostic factors for overall and progression-free survival in patients with vulvar cancer.

Methods: This international, multicenter, retrospective study included 2453 patients diagnosed with vulvar cancer at 100 different institutions. Inclusion criteria were institutional review board approval from each collaborating center, pathologic diagnosis of invasive carcinoma of the vulva, and primary treatment performed at the participating center.

Transcatheter Mitral Repair for Functional Mitral Regurgitation According to Left Ventricular Function: A Real-Life Propensity-Score Matched Study.

Background: Transcatheter mitral valve repair (TMVR) could improve survival in functional mitral regurgitation (FMR), but it is necessary to consider the influence of left ventricular ejection fraction (LVEF). Therefore, we compare the outcomes after TMVR with Mitraclip between two groups according to LVEF.

Methods: In an observational registry study, we compared the outcomes in patients with FMR who underwent TMVR with and without LVEF <30%.

Currently available intravenous immunoglobulin contains antibodies reacting against severe acute respiratory syndrome coronavirus 2 antigens.

There is a critical need for effective therapies that are immediately available to control the spread of COVID-19 disease. Gamunex-C and Flebogamma DIF (Grifols) intravenous immunoglobulin (IVIG) products were tested using ELISA techniques for antibodies against several antigens of human common betacoronaviruses that may crossreact with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. Both IVIGs showed consistent reactivity to components of the tested viruses.

Myocardial Interstitial Fibrosis in Nonischemic Heart Disease, Part 3/4: JACC Focus Seminar.

Myocardial interstitial fibrosis (MIF) is a histological hallmark of several cardiac diseases that alter myocardial architecture and function and are associated with progression to heart failure. MIF is a diffuse and patchy process, appearing as a combination of interstitial microscars, perivascular collagen fiber deposition, and increased thickness of mysial collagen strands. Although MIF arises mainly because of alterations in fibrillar collagen turnover leading to collagen fiber accumulation, there are also alterations in other nonfibrillar extracellular matrix components, such as fibronectin and matricellular proteins.

Hypertrophic cardiomyopathy in myosin-binding protein C () Icelandic founder mutation carriers.

Objective: The myosin-binding protein C () c.927-2A>G founder mutation accounts for >90% of sarcomeric hypertrophic cardiomyopathy (HCM) in Iceland. This cross-sectional observational study explored the penetrance and phenotypic burden among carriers of this single, prevalent founder mutation.

Real-time loop-mediated isothermal amplification assay for rapid detection of .

is the causal agent of pitch canker, a lethal disease of pine and other conifers. Since is a quarantine organism, its timely detection could efficiently prevent its introduction into new areas or facilitate spread management in already infected sites. In this study, we developed a sequence-specific probe loop-mediated isothermal amplification (LAMP) assay for using a field-deployable portable instrument.

Author Correction: MicroRNA-19b is a potential biomarker of increased myocardial collagen cross-linking in patients with aortic stenosis and heart failure.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Debenzylative Cycloetherification as a Synthetic Tool in the Diastereoselective Synthesis of 3,6-Disubstituted Hexahydro-2-furo[3,2-]pyrroles, PDE1 Enzyme Inhibitors with an Antiproliferative Effect on Melanoma Cells.

Two series of novel chiral hexahydro-2-furo[3,2-]pyrroles, 4-(7,8-dimethoxyquinazolin-4-yl) series A and 4-(6,7- dimethoxyquinazolin-4-yl) series B, were synthesized in enantiomerically pure form and evaluated for their inhibitory effects on phosphodiesterase 1 (PDE1) and phosphodiesterase 4 (PDE4) as well as for their inhibitory activity on cell proliferation in A375 melanoma and 3T3 fibroblast cells in vitro. Key steps of synthesis were (i) diastereoselective nucleophilic addition of vinylmagnesium bromide to -allylimine derived from conveniently protected d-glyceraldehyde, (ii) ring-closing metathesis, (iii) debenzylative cycloetherification, and (iv) aromatic nucleophilic substitution. Some of the obtained compounds were proven to be active as inhibitors of PDE1 isoforms, with IC values in the high nanomolar/low micromolar concentration range, and showed antiproliferative activity on A375 melanoma cells.

Asymmetric Transfer Hydrogenation of Arylketones Catalyzed by Enantiopure Ruthenium(II)/Pybox Complexes Containing Achiral Phosphonite and Phosphinite Ligands.

A family of complexes of the formula -[RuCl(L)(R-pybox)] (R-pybox = (,)-Pr-pybox, (,)-Ph-pybox, L = monodentate phosphonite, PPh(OR), and phosphinite, L = PPh(OR), ligands) were screened in the catalytic asymmetric transfer hydrogenation of acetophenone, observing a strong influence of the nature of both the R-pybox substituents and the L ligand in the process. The best results were obtained with complex -[RuCl{PPh(OEt)}{(,)-Ph-pybox}] (), which provided high conversion and enantioselectivity (up to 96% enantiomeric excess, ) for the reduction of a variety of aromatic ketones, affording the ()-benzylalcohols.

Sleep misalignment and circadian rhythm impairment in long-haul bus drivers under a two-up operations system.

Objectives: The objective of the study was to describe working and sleep conditions and to assess how sleep opportunities are associated with obtained sleep and alertness, in a sample of long-haul bus drivers working with a two-up operations system.

Methods: Measures of subjective sleep and sleepiness, actigraphy, circadian temperature rhythm, and psychomotor vigilance tasks were obtained from a sample of 122 drivers from Argentina. Variables were compared between high and low fatigue risk groups, which were formed using a median split of a fatigue risk score.

The PALBONET Trial: A Phase II Study of Palbociclib in Metastatic Grade 1 and 2 Pancreatic Neuroendocrine Tumors (GETNE-1407).

Lessons Learned: Palbociclib demonstrated no detectable activity in molecularly unselected and heavily pretreated patients with advanced grade 1/2 pancreatic neuroendocrine tumors. Predictive biomarkers that improve patient selection should be investigated in future studies of palbociclib.

Background: Palbociclib, a CDK4/6 inhibitor, has shown in vitro activity in pancreatic neuroendocrine tumor (pNET) cell lines.

Mixotrophy in marine picocyanobacteria: use of organic compounds by Prochlorococcus and Synechococcus.

Marine picocyanobacteria of the Prochlorococcus and Synechococcus genera have been longtime considered as autotrophic organisms. However, compelling evidence published over the last 15 years shows that these organisms can use different organic compounds containing key elements to survive in oligotrophic oceans, such as N (amino acids, amino sugars), S (dimethylsulfoniopropionate, DMSP), or P (ATP). Furthermore, marine picocyanobacteria can also take up glucose and use it as a source of carbon and energy, despite the fact that this compound is devoid of limiting elements and can also be synthesized by using standard metabolic pathways.

Does Chronic Kidney Disease Facilitate Malignant Myocardial Fibrosis in Heart Failure with Preserved Ejection Fraction of Hypertensive Origin?

In hypertensive patients with heart failure (HF) a serum biomarker combination of high carboxy-terminal propeptide of procollagen type-I (PICP) and low carboxy-terminal telopeptide of collagen type-I to matrix metalloproteinase-1 (CITP:MMP-1) ratio identifies a histomolecular phenotype of malignant myocardial fibrosis (mMF) associated with severe diastolic dysfunction (DD) and poor outcomes. As chronic kidney disease (CKD) facilitates MF and DD, we investigated the influence of CKD on the mMF biomarker combination in HF patients with preserved ejection fraction (HFpEF). Hypertensives ( = 365), 232 non-HF and 133 HFpEF, were studied, and 35% non-HF and 46% HFpEF patients had CKD (estimated glomerular filtration rate < 60 mL/min/1.

Spores Onboard a Stratospheric NASA Balloon and Its Complete Life Cycle.

The aim of this study was to demonstrate for the first time spore viability in the stratosphere through spore germination and its complete life cycle. These protozoan spores were flown by the National Aeronautics and Space Administration (NASA) Columbia Scientific Balloon Facility (CSBF) flight 667NT, launched from its base in Fort Sumner, New Mexico. spores were exposed to stratospheric conditions on board the NASA/CSBF 667 balloon flight for 9 h.