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Heart failure remains one of the largest clinical burdens globally, with little to no improvement in the development of disease-eradicating therapeutics. Integrin targeting has been used in the treatment of ocular disease and cancer, but little is known about its utility in the treatment of heart failure. Here we sought to determine whether the second generation orally available, αvβ3-specific RGD-mimetic, 29P, was cardioprotective. Male mice were subjected to transverse aortic constriction (TAC) and treated with 50 μg/kg 29P or volume-matched saline as Vehicle control. At 3 weeks post-TAC, echocardiography showed that 29P treatment significantly restored cardiac function and structure indicating the protective effect of 29P treatment in this model of heart failure. Importantly, 29P treatment improved cardiac function giving improved fractional shortening, ejection fraction, heart weight and lung weight to tibia length fractions, together with partial restoration of Ace and Mme levels, as markers of the TAC insult. At a tissue level, 29P reduced cardiomyocyte hypertrophy and interstitial fibrosis, both of which are major clinical features of heart failure. RNA sequencing identified that, mechanistically, this occurred with concomitant alterations to genes involved molecular pathways associated with these processes such as metabolism, hypertrophy and basement membrane formation. Overall, targeting αvβ3 with 29P provides a novel strategy to attenuate pressure-overload induced cardiac hypertrophy and fibrosis, providing a possible new approach to heart failure treatment.

Abstract Atrial fibrillation (AF) is the most common sustained heart arrhythmia in adults. Holter monitoring, a long-term 2-lead electrocardiogram (ECG), is a key tool available to cardiologists for AF diagnosis. Machine learning (ML) and deep learning (DL) models have shown great capacity to automatically detect AF in ECG and their use as medical decision support tool is growing. Training these models rely on a few open and annotated databases. We present a new Holter monitoring database from patients with paroxysmal AF with 167 records from 152 patients, acquired from an outpatient cardiology clinic from 2006 to 2017 in Belgium. AF episodes were manually annotated and reviewed by an expert cardiologist and a specialist cardiac nurse. Records last from 19 hours up to 95 hours, divided into 24-hour files. In total, it represents 24 million seconds of annotated Holter monitoring, sampled at 200 Hz. This dataset aims at expanding the available options for researchers and offers a valuable resource for advancing ML and DL use in the field of cardiac arrhythmia diagnosis.

We describe the design, synthesis, and activity of a potent thiourea-bridged backbone cyclic peptidomimetic known as Clarstatin, comprising a 5-amino acid sequence (Q/D)1-(R/K)2-X3-X4-A5-(Gln/Asp)1-(Arg/Lys)2-AA3-AA4-Ala5-based on a motif called “shared epitope (SE)”, specifically present in specific alleles of the HLA-DRB1 gene. This SE binds to a particular site within the proline reach domain (P-domain) of the cell surface-calreticulin (CS-CRT). CS-CRT is a multifunctional endoplasmic reticulum (ER) calcium-binding protein that is located on the cell surface of T cells and triggers innate immune signaling, leading to the development of inflammatory autoimmune diseases. The development of Clarstatin was based on the parent peptide W-G-D1-K2-S3-G4-A5- derived from the active region of the SE. Following the design based on the cycloscan method, the synthesis of Clarstatin was performed by the Fmoc solid phase peptide synthesis (SPPS) method, purified by HPLC to 96% homogeneity, and its structure was confirmed by LC-MS. Clarstatin reduced calcium levels in Jurkat lymphocyte cultures, ameliorated uveitis in vivo in the experimental autoimmune uveitis (EAU) mice model, and was safe upon acute toxicity evaluation. These findings identify Clarstatin as a promising lead compound for future drug development as a novel class of therapeutic agents in the therapy of uveitis.

To develop peptide drugs targeting integrin receptors, synthetic peptide ligands endowed with well-defined selective binding motifs are necessary. The snake venom KTS-containing disintegrins, which selectively block collagen α1β1 integrin, were used as lead compounds for the synthesis and structure–activity relationship of a series of linear peptides containing the KTS-pharmacophore and alternating natural amino acids and 3-aminobenzoic acid (MABA). To ensure a better stiffness and metabolic stability, one, two and three MABA residues, were introduced around the KTS pharmacophore motif. Molecular dynamics simulations determined that the solution conformation of MABA peptide 4 is more compact, underwent larger conformational changes until convergence, and spent most of the time in a single cluster. The peptides’ binding affinity has been characterized by an enzyme linked immunosorbent assay in which the most potent peptide 4 inhibited with IC50 of 324 ± 8 µM and 550 ± 45 µM the binding of GST-α1-A domain to collagen IV fragment CB3, and the cell adhesion to collagen IV using α1-overexpressor cells, respectively. Docking studies and MM-GBSA calculations confirmed that peptide 4 binds a smaller region of the integrin near the collagen-binding site and penetrated deeper into the binding site near Trp1. Peptide 4 inhibited tube formation by endothelial cell migration in the Matrigel angiogenesis in vitro assay. Peptide 4 was acutely tolerated by mice, showed stability in human serum, decreased tumor volume and angiogenesis, and significantly increased the survival of mice injected with B16 melanoma cells. These findings propose that MABA-peptide 4 can further serve as an α1β1-integrin antagonist lead compound for further drug optimization in angiogenesis and cancer therapy.

Summary: Glucagon-like peptide 1 (GLP-1R) and glucose-dependent insulinotropic polypeptide (GIPR) receptors are G-protein-coupled receptors involved in glucose homeostasis. Diabetogenic conditions decrease β-arrestin 2 (ARRB2) levels in human islets. In mouse β cells, ARRB2 dampens insulin secretion by partially uncoupling cyclic AMP (cAMP)/protein kinase A (PKA) signaling at physiological doses of GLP-1, whereas at pharmacological doses, the activation of extracellular signal-related kinase (ERK)/cAMP-responsive element-binding protein (CREB) requires ARRB2. In contrast, GIP-potentiated insulin secretion needs ARRB2 in mouse and human islets. The GIPR-ARRB2 axis is not involved in cAMP/PKA or ERK signaling but does mediate GIP-induced F-actin depolymerization. Finally, the dual GLP-1/GIP agonist tirzepatide does not require ARRB2 for the potentiation of insulin secretion. Thus, ARRB2 plays distinct roles in regulating GLP-1R and GIPR signaling, and we highlight (1) its role in the physiological context and the possible functional consequences of its decreased expression in pathological situations such as diabetes and (2) the importance of assessing the signaling pathways engaged by the agonists (biased/dual) for therapeutic purposes.

Abstract High-quality datasets are essential to support hydrological science and modeling. Several CAMELS (Catchment Attributes and Meteorology for Large-sample Studies) datasets exist for specific countries or regions, however these datasets lack standardization, which makes global studies difficult. This paper introduces a dataset called Caravan (a series of CAMELS) that standardizes and aggregates seven existing large-sample hydrology datasets. Caravan includes meteorological forcing data, streamflow data, and static catchment attributes (e.g., geophysical, sociological, climatological) for 6830 catchments. Most importantly, Caravan is both a dataset and open-source software that allows members of the hydrology community to extend the dataset to new locations by extracting forcing data and catchment attributes in the cloud. Our vision is for Caravan to democratize the creation and use of globally-standardized large-sample hydrology datasets. Caravan is a truly global open-source community resource.

Ingesting near-real-time observation data is a critical component of many operational hydrological forecasting systems. In this paper, we compare two strategies for ingesting near-real-time streamflow observations into long short-term memory (LSTM) rainfall–runoff models: autoregression (a forward method) and variational data assimilation. Autoregression is both more accurate and more computationally efficient than data assimilation. Autoregression is sensitive to missing data, however an appropriate (and simple) training strategy mitigates this problem. We introduce a data assimilation procedure for recurrent deep learning models that uses backpropagation to make the state updates.

Google's operational flood forecasting system was developed to provide accurate real-time flood warnings to agencies and the public with a focus on riverine floods in large, gauged rivers. It became operational in 2018 and has since expanded geographically. This forecasting system consists of four subsystems: data validation, stage forecasting, inundation modeling, and alert distribution. Machine learning is used for two of the subsystems. Stage forecasting is modeled with the long short-term memory (LSTM) networks and the linear models. Flood inundation is computed with the thresholding and the manifold models, where the former computes inundation extent and the latter computes both inundation extent and depth. The manifold model, presented here for the first time, provides a machine-learning alternative to hydraulic modeling of flood inundation. When evaluated on historical data, all models achieve sufficiently high-performance metrics for operational use. The LSTM showed higher skills than the linear model, while the thresholding and manifold models achieved similar performance metrics for modeling inundation extent. During the 2021 monsoon season, the flood warning system was operational in India and Bangladesh, covering flood-prone regions around rivers with a total area close to 470 000 km2, home to more than 350 000 000 people. More than 100 000 000 flood alerts were sent to affected populations, to relevant authorities, and to emergency organizations. Current and future work on the system includes extending coverage to additional flood-prone locations and improving modeling capabilities and accuracy.

The most accurate rainfall–runoff predictions are currently based on deep learning. There is a concern among hydrologists that the predictive accuracy of data-driven models based on deep learning may not be reliable in extrapolation or for predicting extreme events. This study tests that hypothesis using long short-term memory (LSTM) networks and an LSTM variant that is architecturally constrained to conserve mass. The LSTM network (and the mass-conserving LSTM variant) remained relatively accurate in predicting extreme (high-return-period) events compared with both a conceptual model (the Sacramento Model) and a process-based model (the US National Water Model), even when extreme events were not included in the training period. Adding mass balance constraints to the data-driven model (LSTM) reduced model skill during extreme events.

BACKGROUND: Over the past 25 years, diagnosis and therapy for acute aortic dissection (AAD) have evolved. We aimed to study the effects of these iterative changes in care. METHODS: Patients with nontraumatic AAD enrolled in the International Registry of Acute Aortic Dissection (61 centers; 15 countries) were divided into time-based tertiles (groups) from 1996 to 2022. The impact of changes in diagnostics, therapeutic care, and in-hospital and 3-year mortality was assessed. Cochran-Armitage trend and Jonckheere-Terpstra tests were conducted to test for any temporal trend. RESULTS: Each group consisted of 3785 patients (mean age, ≈62 years old; ≈65.5% males); nearly two-thirds had type A AAD. Over time, the rates of hypertension increased from 77.8% to 80.4% (P=0.002), while smoking (34.1% to 30.6%, P=0.033) and atherosclerosis decreased (25.6%-16.6%; P<0.001). Across groups, the percentage of surgical repair of type A AAD increased from 89.1% to 92.5% (P<0.001) and was associated with decreased hospital mortality (from 24.1% in group 1 to 16.7% in group 3; P<0.001). There was no difference in 3-year survival (P=0.296). For type B AAD, stent graft therapy (thoracic endovascular aortic repair) was used more frequently (22.3%-35.9%; P<0.001), with a corresponding decrease in open surgery. Endovascular in-hospital mortality decreased from 9.9% to 6.2% (P=0.003). As seen with the type A AAD cohort, overall 3-year mortality for patients with type B AAD was consistent over time (P=0.084). CONCLUSIONS: Over 25 years, substantial improvements in-hospital survival were associated with a more aggressive surgical approach for patients with type A AAD. Open surgery has been partially supplanted by thoracic endovascular aortic repair for complicated type B AAD, and in-hospital mortality has decreased over the time period studied. Postdischarge survival for up to 3 years was similar over time. [ABSTRACT FROM AUTHOR]

Arginine, due to the guanidine moiety, increases peptides’ hydrophilicity and enables interactions with charged molecules, but at the same time, its presence in a peptide chain might reduce its permeability through biological membranes. This might be resolved by temporary coverage of the peptide charge by lipophilic, enzyme-sensitive alkoxycarbonyl groups. Unfortunately, such a modification of a guanidine moiety has not been reported to date and turned out to be challenging. Here, we present a new, optimized strategy to obtain arginine building blocks with increased lipophilicity that were successfully utilized in the solid-phase peptide synthesis of novel arginine vasopressin prodrugs.

Abstract Background/Objective: A growing number of biomedical doctoral graduates are entering the biotechnology and industry workforce, though most lack training in business practice. Entrepreneurs can benefit from venture creation and commercialization training that is largely absent from standard biomedical educational curricula. The NYU Biomedical Entrepreneurship Educational Program (BEEP) seeks to fill this training gap to prepare and motivate biomedical entrepreneurs to develop an entrepreneurial skill set, thus accelerating the pace of innovation in technology and business ventures. Methods: The NYU BEEP Model was developed and implemented with funding from NIDDK and NCATS. The program consists of a core introductory course, topic-based interdisciplinary workshops, venture challenges, on-line modules, and mentorship from experts. Here, we evaluate the efficacy of the core, introductory course, “Foundations of Biomedical Startups,” through the use of pre/post-course surveys and free-response answers. Results: After 2 years, 153 participants (26% doctoral students, 23% post-doctoral PhDs, 20% faculty, 16% research staff, 15% other) have completed the course. Evaluation data show self-assessed knowledge gain in all domains. The percentage of students rating themselves as either “competent” or “on the way to being an expert” in all areas was significantly higher post-course (P < 0.05). In each content area, the percentages of participants rating themselves as “very interested” increased post-course. 95% of those surveyed reported the course met its objectives, and 95% reported a higher likelihood of pursuing commercialization of discoveries post-course. Conclusion: NYU BEEP can serve as a model to develop similar curricula/programs to enhance entrepreneurial activity of early-stage researchers.

Abstract Background Elevated blood pressure among adolescents has been shown to be associated with future adverse cardiovascular outcomes and early onset diabetes. Most data regarding systolic and diastolic blood pressure trends are based on surveys of selected populations within 10–20-year periods. The goal of this study was to characterize the secular trend of blood pressure given the rising prevalence of adolescent obesity. Methods This nationwide population-based study included 2,785,515 Israeli adolescents (41.6% females, mean age 17.4 years) who were medically evaluated and whose weight, height and blood pressure were measured, prior to mandatory military service between 1977 and 2020. The study period was divided into 5-year intervals. Linear regression models were used to describe the P for trend along the time intervals. Analysis of covariance was used to calculate means of blood pressure adjusted for body mass index. Results During the study period, the mean body mass index increased by 2.1 and 1.6 kg/m2 in males and females, respectively (P for trend

Background: People over the age of 85 are the world's most rapidly growing age group. Ejection fraction (EF) may be limited prognostically in this population and myocardial contraction fraction (MCF) may be more accurate. The objective of this longitudinal study was to assess the prognosis of MCF in an age-homogenous, community-dwelling population of subjects. Methods: Subjects were recruited from the Jerusalem Longitudinal Cohort Study. Echocardiography was performed with a portable echocardiograph at the subjects place of residence. Standard echocardiographic assessment of cardiac structure and function including MCF was performed. Values of EF and MCF above and below the median for males and females were defined as normal and abnormal in categorical analysis. 5-year mortality was assessed via a centralized government database. Results: 418 subjects (199 males, 219 females) were enrolled in the study of whom 113 (27 %) died at the time of 5-year follow-up. Subjects who died had significantly lower MCF (32 ± 14 % vs 36 ± 12 %; p

Several multistep strategies were developed to ensure single methylation of amines on solid support. These strategies rely on the introduction of the o-NBS protecting/activating group as a key step. We found that the state-of-the-art strategies fail for the methylation of several primary amine motifs, largely due to inefficient sulfonylation. Here we show that using the superior nucleophilic base DMAP instead of the commonly used base collidine as a sulfonylation additive is essential for the introduction of the o-NBS group to these amine motifs. DFT calculations provide an explanation by showing that the energy barrier of the DMAP intermediate is significantly lower than the one of the collidine. We demonstrate that using DMAP as a sole additive in the sulfonylation step results in an overall effective and regioselective N-methylation. The method presented herein proved highly efficient in solid-phase synthesis of a somatostatin analogue bearing three Nα-methylation sites that could not be synthesized using the previously described state-of-the-art methods.

In vitro differentiation of human induced pluripotent stem cells (iPSCs) into beta cells represents an important cell source for diabetes research. Here, we fully characterized iPSC-derived beta cell function in vitro and in vivo in humanized mice. Using a 7-stage protocol, human iPSCs were differentiated into islet-like aggregates with a yield of insulin-positive beta cells comparable to that of human islets. The last three stages of differentiation were conducted with two different 3D culture systems, rotating suspension or static microwells. In the latter, homogeneously small-sized islet-like aggregates were obtained, while in rotating suspension size was heterogeneous and aggregates often clumped. In vitro function was assessed by glucose-stimulated insulin secretion, NAD(P)H and calcium fluctuations. Stage 7 aggregates slightly increased insulin release in response to glucose in vitro. Aggregates were transplanted under the kidney capsule of NOD-SCID mice to allow for further in vivo beta cell maturation. In transplanted mice, grafts showed glucose-responsiveness and maintained normoglycemia after streptozotocin injection. In situ kidney perfusion assays showed modulation of human insulin secretion in response to different secretagogues. In conclusion, iPSCs differentiated with equal efficiency into beta cells in microwells compared to rotating suspension, but the former had a higher experimental success rate. In vitro differentiation generated aggregates lacking fully mature beta cell function. In vivo, beta cells acquired the functional characteristics typical of human islets. With this technology an unlimited supply of islet-like organoids can be generated from human iPSCs that will be instrumental to study beta cell biology and dysfunction in diabetes.

Objective: The mechanisms by which glucose stimulates insulin secretion from β-cells are well established and involve inhibition of ATP-sensitive K+ (KATP) channels, followed by a rise in [Ca2+]c that triggers exocytosis. However, the mechanisms by which glucose controls glucagon release from α-cells are much less known. In particular, it is debated whether the sugar controls glucagon secretion by changing α-cell [Ca2+]c, and whether KATP channels or paracrine factors are involved. The present study addresses these issues. Methods: We tested the effect of a decrease or an increase of glucose concentration (Gx, with x = concentration in mM) on α-cell [Ca2+]c and glucagon secretion. α-cell [Ca2+]c was monitored using GluCreGCaMP6f mice expressing the Ca2+-sensitive fluorescent protein, GCaMP6f, specifically in α-cells. [Ca2+]c was compared between dispersed α-cells and α-cells within islets to evaluate the potential contribution of an indirect effect of glucose. The same protocols were used for experiments of glucagon secretion from whole islets and [Ca2+]c measurements to test if changes in glucagon release mirror those in α-cell [Ca2+]c. Results: Blockade of KATP channels by sulfonylureas (tolbutamide 100 μM or gliclazide 25 μM) strongly increased [Ca2+]c in both dispersed α-cells and α-cells within islets. By contrast, glucose had no effect on [Ca2+]c in dispersed α-cells, whereas it affected it in α-cells within islets. The effect of glucose was however different in islets expressing (Sst+/+) or not somatostatin (SST) (Sst−/−). Decreasing glucose concentration from G7 to G1 modestly increased α-cell [Ca2+]c, but to a slightly larger extent in Sst+/+ islets than in Sst−/− islets. This G1-induced [Ca2+]c rise was also observed in the continuous presence of sulfonylureas in both Sst+/+ and Sst−/− islets. Increasing glucose concentration from G7 to G20 did not affect α-cell [Ca2+]c in Sst+/+ islets which remained low, whereas it strongly increased it in Sst−/− islets. The observations that this increase was seen only in α-cells within islets but never in dispersed α-cells and that it was abrogated by the gap junction inhibitor, carbenoxolone, point to an indirect effect of G20 and suggest that, in Sst−/− islets, G20-stimulated β-cells entrain α-cells whereas, in Sst+/+ islets, the concomitant release of SST keeps α-cell [Ca2+]c at low levels. The [Ca2+]c lowering effect of endogenous SST is also supported by the observation that SST receptor antagonists (SSTR2/3) increased [Ca2+]c in α-cells from Sst+/+ islets. All these [Ca2+]c changes induced parallel changes in glucagon release. To test if glucose also controls glucagon release independently of [Ca2+]c changes, additional experiments were performed in the continuous presence of 30 mM K+ and the KATP channel opener diazoxide (250 μM). In these conditions, α-cell [Ca2+]c within islets was elevated and its steady-state level was unaffected by glucose. However, decreasing the glucose concentration from G7 to G1 stimulated glucagon release whereas increasing it from G1 to G15 inhibited it. These effects were also evident in Sst−/− islets, and opposite to those on insulin secretion. Conclusions: We propose a model according to which glucose controls α-cell [Ca2+]c and glucagon secretion through multiple mechanisms. Increasing the glucose concentration modestly decreases [Ca2+]c in α-cells independently of their KATP channels and partly via SST. The involvement of SST increases with the glucose concentration, and one major effect of SST is to keep α-cell [Ca2+]c at low levels by counteracting the effect of an entrainment of α-cells by β-cells when β-cells become stimulated by glucose. All these [Ca2+]c changes induce parallel changes in glucagon release. Glucose also decreases the efficacy of Ca2+ on exocytosis by an attenuating pathway that is opposite to the well-established amplifying pathway controlling insulin release in β-cells.

Cardiac myxoma is the most common benign tumor of the heart. In most cases, it is in the left atrium, which can generate neurological embolization; that can manifest as an ischemic event, aneurysm formation and less frequently as brain metastases. This is a case report of a 56-year-old male patient with cerebral embolisms secondary to a left cardiac myxoma. In these patients, the role of neurologic imaging is to detect the firsts complications and avoid secondary complications.

Abstract Background Automated machine-learning systems are able to de-identify electronic medical records, including free-text clinical notes. Use of such systems would greatly boost the amount of data available to researchers, yet their deployment has been limited due to uncertainty about their performance when applied to new datasets. Objective We present practical options for clinical note de-identification, assessing performance of machine learning systems ranging from off-the-shelf to fully customized. Methods We implement a state-of-the-art machine learning de-identification system, training and testing on pairs of datasets that match the deployment scenarios. We use clinical notes from two i2b2 competition corpora, the Physionet Gold Standard corpus, and parts of the MIMIC-III dataset. Results Fully customized systems remove 97–99% of personally identifying information. Performance of off-the-shelf systems varies by dataset, with performance mostly above 90%. Providing a small labeled dataset or large unlabeled dataset allows for fine-tuning that improves performance over off-the-shelf systems. Conclusion Health organizations should be aware of the levels of customization available when selecting a de-identification deployment solution, in order to choose the one that best matches their resources and target performance level.

Genuine leather is produced from animal skin by chemical tanning using chemical or vegetable agents, while synthetic leather is a combination of fabric and polymer. The replacement of natural leather by synthetic leather is becoming more difficult to identify. In this work, Laser Induced Breakdown Spectroscopy (LIBS) is evaluated to separate between very similar materials: leather, synthetic leather, and polymers. LIBS is now widely employed to provide a specific fingerprint from the different materials. Animal leathers processed with vegetable, chromium, or titanium tanning were analyzed together with polymers and synthetic leather from different origins. The spectra exhibited typical signatures from the tanning agents (Cr, Ti, Al) and the dyes and pigments, but also from polymer characteristic bands. The principal factor analysis allowed to discriminate between four main groups of samples representing the tanning processes and the polymer or synthetic leather character.

Background: Pregestational excessive body mass index (BMI) is linked to an increased risk for gestational diabetes mellitus (GDM), but less is known on the effect of adolescent BMI on GDM occurrence. The study aimed to investigate possible associations of adolescent BMI and changes in BMI experienced before first pregnancy, with gestational diabetes risk. Methods: This retrospective study was based on linkage of a military screening database of adolescent health status (Israel Defence Forces) including measured height and weight, with medical records (Maccabi Healthcare Services, MHS) of a state-mandated health provider. The latter covers about 25% of the Israeli population; about 90% of pregnant women undergo screening by the two-step Carpenter-Coustan method. Adolescent BMI was categorized according to Center of Disease Control and Prevention percentiles. Only first documented pregnanies were analyzed and GDM was the outcome. Findings: Of 190,905 nulliparous women, 10,265 (5.4%) developed GDM. Incidence proportions of GDM were 5.1%, 6.1%, 7.3%, and 8.9% among women with adolescent normal BMI, underweight, overweight, and obesity (p