bluuebunny/crossref_metadata_2025_split huggingface dataset:
Brookhart's Acid‐Catalyzed Switchable RegioselectiveN‐Alkylation of Arylamines/Heterocyclic Amines with Cyclopropylcarbinols by Temperature Regulation
Authors: Yadav Naveen , Tyagi Aparna , Khan Jabir , Kumar Hazra Chinmoy 
Published: August 2022

AbstractAn unprecedented, Brookhart's acid‐catalyzed temperature‐switchable regioselective divergent approach forN‐alkylation of arylamines and heterocyclic amines by utilising cyclopropylcarbinols is presented herein. The reaction offersN‐alkylated cyclopropyl derivatives and homoallyl amines by employing 2.5 mol% catalyst loading at different temperatures in excellent regioselectivity and yields. This method has shown to be relevant with a wide range of cyclopropylcarbinols, including aliphatic ones. Several control experiments and spectroscopic studies have been performed to gain insight into the reaction mechanism. Further, the synthetic utility of the protocol has also been described.
Intracellular Assembly of Interacting Enzymes Yields Highly‐Active Nanoparticles for Flow Biocatalysis
Authors: Bitterwolf Patrick , Zoheir Ahmed E. , Hertel Julian , Kröll Sandra , Rabe Kersten S. , Niemeyer Christof M. 
Published: August 2022

AbstractAll‐enzyme hydrogel (AEH) particles with a hydrodynamic diameter of up to 120 nm were produced intracellularly with an Escherichia coli‐based in vivo system. The inCell‐AEH nanoparticles were generated from polycistronic vectors enabling simultaneous expression of two interacting enzymes, the Lactobacillus brevis alcohol dehydrogenase (ADH) and the Bacillus subtilis glucose‐1‐dehydrogenase (GDH), fused with a SpyCatcher or SpyTag, respectively. Formation of inCell‐AEH was analyzed by dynamic light scattering and atomic force microscopy. Using the stereoselective two‐step reduction of a prochiral diketone substrate, we show that the inCell‐AEH approach can be advantageously used in whole‐cell flow biocatalysis, by which flow reactors could be operated for >4 days under constant substrate perfusion. More importantly, the inCell‐AEH concept enables the recovery of efficient catalyst materials for stable flow bioreactors in a simple and economical one‐step procedure from crude bacterial lysates. We believe that our method will contribute to further optimization of sustainable biocatalytic processes.
Analysis of digitalized ECG signals based on artificial intelligence and spectral analysis methods specialized in ARVC
Authors: Papageorgiou Vasileios E. , Zegkos Thomas , Efthimiadis Georgios , Tsaklidis George 
Published: August 2022

AbstractArrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease that appears between the second and forth decade of a patient's life, being responsible for 20% of sudden cardiac deaths before the age of 35. The effective and punctual diagnosis of this disease based on electrocardiograms (ECGs) could have a vital role in reducing premature cardiovascular mortality. In our analysis, we first outline the digitalization process of paper‐based ECG signals enhanced by a spatial filter aiming to eliminate dark regions in the dataset's images that do not correspond to ECG waveform, producing undesirable noise. Next, we propose the utilization of a low‐complexity convolutional neural network for the detection of an arrhythmogenic heart disease, that has not been studied through the usage of deep learning methodology to date, achieving high classification accuracy, namely 99.98% training and 98.6% testing accuracy, on a disease the major identification criterion of which are infinitesimal millivolt variations in the ECG's morphology, in contrast with other arrhythmogenic abnormalities. Finally, by performing spectral analysis we investigate significant differentiations in the field of frequencies between normal ECGs and ECGs corresponding to patients suffering from ARVC. In 16 out of the 18 frequencies where we encounter statistically significant differentiations, the normal ECGs are characterized by greater normalized amplitudes compared to the abnormal ones. The overall research carried out in this article highlights the importance of integrating mathematical methods into the examination and effective diagnosis of various diseases, aiming to a substantial contribution to their successful treatment.
An Open‐Label, Randomized Pharmacokinetic Study of 2 Formulations of Eldecalcitol Capsules Following Single Oral Administration in Healthy Chinese Volunteers Under Fasting and Fed Conditions
Authors: Wu Juan , Fan Yuru , Zheng Liang , Wang Zhiqiang , Liu Yueyue , Shen Chenlin , Hu Wei 
Published: August 2022

AbstractEldecalcitol is an active vitamin D3 derivative that is used for the prevention and treatment of osteoporosis. The objectives of this study were to evaluate the bioequivalence and safety of 2 formulations of eldecalcitol capsule (0.75 μg) in healthy Chinese male and female volunteers, as well as to investigate the food effect on the pharmacokinetics of this drug. An open label, randomized, 3‐period, 3‐sequence, reference replicated crossover clinical study was performed in 27 healthy Chinese volunteers under fasting conditions, while a 2‐way crossover study was carried out in 28 healthy Chinese volunteers under fed conditions. Volunteers were administered a single oral dose of 0.75 μg eldecalcitol after fasting overnight. Blood samples were collected at scheduled time points from 0 to 168 hours after administration of eldecalcitol. The 90%CIs of the test/reference geometric mean ratio (area under the plasma concentration–time curve and maximum plasma concentration) of eldecalcitol after a single‐dose administration were within the acceptance criteria based on the average bioequivalence method. The time to maximum concentration of the test and reference formulations were elevated by ≈2.3‐fold and 1.7‐fold, respectively, after a high‐fat meal. Only mild and transient adverse events were reported in this study, and no severe adverse events occurred. These results indicated that the 2 formulations of eldecalcitol were bioequivalent under both fasting and fed conditions. Food intake prolonged the oral absorption of eldecalcitol but did not significantly influence systemic exposure.
Phase 1 Study to Investigate the Safety, Tolerability, and Pharmacokinetics of EPI‐589 in Healthy Participants
Authors: Noda Naoto , Hamatani Tatsuto , Shibue Yuta , Takagaki Takeshi , Kitamura Atsushi , Haranaka Miwa , Ogama Yoichiro , Kakuyama Hiroyoshi 
Published: August 2022

AbstractEPI‐589 attenuates oxidative stress due to the radical scavenging activity of the reduced form and affects mitochondrial energy metabolism as a substrate of quinone‐oxidoreductases. Given the effects of EPI‐589 on oxidative stress and mitochondrial dysfunction, EPI‐589 shows promise as a potential therapy for patients with amyotrophic lateral sclerosis. This phase 1 study evaluated the safety, tolerability, and pharmacokinetic profiles of EPI‐589. Sixty‐eight healthy participants were randomly assigned to EPI‐589 or placebo. All adverse events were mild or moderate in severity, and no severe adverse events were reported. After single‐dose administration under fasting conditions, time to maximum plasma concentration (tmax) occurred 0.25 to 1.00 hour after administration. Both peak plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) were approximately linear with increases in single doses over a dose range of 250–1000 mg. Under fed conditions, the Cmax decreased to 62.6% of the Cmax under fasting conditions, the AUC was slightly increased, and the tmax was delayed by 1 hour. When EPI‐589 was administered daily on days 1 and 7 with twice‐daily dosing on days 2 through 6, the plasma trough concentration appeared to reach steady state by day 3. At both doses studied (500 mg twice daily and 750 mg twice daily), Cmax, tmax, and AUC were generally comparable between day 1 and day 7 and between the Japanese and White participants. EPI‐589 was well tolerated as a single daily dose up to 1000 mg and as twice‐daily doses up to 750 mg, with a linear pharmacokinetic profile.
Photodetachment of Deprotonated R‐Mandelic Acid: The Role of Proton Delocalization on the Radical Stability
Authors: Molina Franco L. , Jara‐Toro Rafael A. , Noble Jennifer A. , Dedonder‐Lardeux Claude , Jouvet Christophe , Pino Gustavo A. 
Published: August 2022

AbstractThe photodetachment and stability of R‐Mandelate, the deprotonated form of the R‐Mandelic acid, was investigated by observing the neutral species issued from either simple photodetachment or dissociative photodetachment in a cold anions set‐up. R‐Mandalate has the possibility to form an intramolecular ionic hydrogen‐bond between adjacent hydroxyl and carboxylate groups. The potential energy surface along the proton transfer (PT) coordinate between both groups (O−…H+…−OCO) features a single local minima, with the proton localized on the O− group (OH…−OCO). However, the structure with the proton localized on the −OCO group (O−…HOCO) is also observed because it falls within the extremity of the vibrational wavefunction of the OH…−OCO isomer along the PT coordinate. The stability of the corresponding radicals, produced upon photodetachment, is strongly dependent on the position of the proton in the anion: the radicals produced from the OH…−OCO isomer decarboxylate without barrier, while the radicals produced from the O−…HOCO isomer are stable.
Promising use of immune cell‐derived exosomes in the treatment of SARS‐CoV‐2 infections
Authors: Alahdal Murad , Elkord Eyad 
Published: August 2022

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection is persistently threatening the lives of thousands of individuals globally. It triggers pulmonary oedema, driving to dyspnoea and lung failure. Viral infectivity of coronavirus disease 2019 (COVID‐19) is a genuine challenge due to the mutagenic genome and mysterious immune‐pathophysiology. Early reports highlighted that extracellular vesicles (exosomes, Exos) work to enhance COVID‐19 progression by mediating viral transmission, replication and mutations. Furthermore, recent studies revealed that Exos derived from immune cells play an essential role in the promotion of immune cell exhaustion by transferring regulatory lncRNAs and miRNAs from exhausted cells to the active cells. Fortunately, there are great chances to modulate the immune functions of Exos towards a sustained repression of COVID‐19. Engineered Exos hold promising immunotherapeutic opportunities for remodelling cytotoxic T cells’ function. Immune cell‐derived Exos may trigger a stable epigenetic repression of viral infectivity, restore functional cytokine‐producing T cells and rebalance immune response in severe infections by inducing functional T regulatory cells (Tregs). This review introduces a view on the current outcomes of immunopathology, and immunotherapeutic applications of immune cell‐derived Exos in COVID‐19, besides new perspectives to develop novel patterns of engineered Exos triggering novel anti‐SARS‐CoV‐2 immune responses.
Integration of aerial surveys and resource selection analysis indicates human land use supports boreal deer expansion
Authors: Fuller Hugh W. , Frey Sandra , Fisher Jason T. 
Published: August 2022

AbstractLandscape change is a driver of global biodiversity loss. In the western Nearctic, petroleum exploration and extraction is a major contributor to landscape change, with concomitant effects on large mammal populations. One of those effects is the continued expansion of invasive white‐tailed deer populations into the boreal forest, with ramifications for the whole ecosystem. We explored deer resource selection within the oil sands region of the boreal forest using a novel application of aerial ungulate survey (AUS) data. Deer locations from AUS were “used” points and together with randomly allocated “available” points informed deer resource selection in relation to landscape variables in the boreal forest. We created a candidate set of generalized linear models representing competing hypotheses about the role of natural landscape features, forest harvesting, cultivation, roads, and petroleum features. We ranked these in an information‐theoretic framework. A combination of natural and anthropogenic landscape features best explained deer resource selection. Deer strongly selected seismic lines and other linear features associated with petroleum exploration and extraction, likely as movement corridors and resource subsidies. Forest harvesting and cultivation, important contributors to expansion in other parts of the white‐tailed deer range, were not as important here. Stemming deer expansion to conserve native ungulates and maintain key predator–prey processes will likely require landscape management to restore the widespread linear features crossing the vast oil sands region.
Retracted: Distributions of trace elements with long‐term grazing exclusion in a semi‐arid grassland of inner Mongolia
Authors: Hu Juan , Li Qiang , Huang Yingxin , Zhang Qilin , Zhou Daowei 
Published: August 2022

AbstractWe still know little about the distributions of trace elements in grassland with long‐term grazing exclusion. The contents, stocks, and proportions of iron (Fe), aluminum (Al), manganese (Mn), and boron (B) in green plant–litter–root–soil were evaluated by enclosing for 18‐, and 39 years inside the fence (F18 and F39) and grazing outside the fence (F0) in Mongolia grassland. Results showed that F18 and F39 decreased the stocks of Fe, Al, and Mn in green plant and root compared with F0 (p < .05), while increased the stocks of them in litter (p < .05). The F18 obviously increased the stocks of Fe and Mn in soil, especially B (p < .05). The stock of Fe, Al, and Mn in green plant at F39 was 28.6%, 13.9%, and 39.2% higher than that at F18. The stocks of trace elements in undecomposed litter at F39 were increased by 12.7%–52.2% compared with F18, while the stocks of them in complete decomposed litter were decreased by 32.2%–42.5%. The stocks of trace elements in soil at F39 were 9.1%–28.0% lower than that at F18, especially B (p < .05). In conclusion, the trace elements were mainly shifted from green plant and root to soil and complete decomposed litter with 18‐year grazing exclusion. The trace elements were shifted from complete decomposed litter and soil to root with 39‐year grazing exclusion compared with 18‐year grazing exclusion.
Mammal responses to predator scents across multiple study areas
Authors: Sunde Peter , Böcker Felix , Rauset Geir Rune , Kjellander Petter , Chrenkova Monika , Skovdal Trine Munck , van Beeck Calkoen Suzanne , Mayer Martin , Heurich Marco 
Published: August 2022

AbstractAntipredator behaviors allow prey to mitigate the impacts of their predators. We investigated antipredator responses of two herbivore species, roe deer and European hare, and one mesopredator, red fox, toward predation risk imposed by lynx and wolf. We collected data (using camera traps) on visitation frequency and vigilance behavior to olfactory predator stimuli during 158 standardized scent trials in five areas across Europe, where lynx and wolves either occurred or had been absent for centuries. After a period without scent, trial sites were either marked with lynx or wolf urine, or butyric acid (unspecific scent used to contrast species‐specific scent responses). We expected the two herbivores to respond aversively (reduced visitation frequency, and increased vigilance) to predator urine, while red foxes (scavengers) might adopt a risk‐sensitive exploration strategy by increasing vigilance near predator urine without reducing visitation frequency. For all species, we expected stronger responses toward the ambush predator lynx than to the pursue predator wolf (cryptic predator hypothesis). If prey responds more strongly to predator stimuli when coexisting with the predator, we expected stronger reactions to predator urine in areas where predators occurred (naïve prey hypothesis). Roe deer significantly avoided lynx urine and butyric acid, but not wolf urine. However, roe deer visitation frequency did not differ between scent treatment with large carnivore urine and butyric acid (suggesting that roe deer generally avoid areas with unfamiliar scent), or between areas where large carnivores were present and absent. Hares did not significantly avoid predator urine. Red foxes were attracted to lynx urine in sympatry, but not in allopatry with large carnivores. They increased vigilance rates in the presence of lynx urine independent of sympatry/allopatry with large carnivores. These findings generally confirm our expectations of predator avoidance by herbivores, and attraction combined with increased vigilance of mesopredators. In all species, lynx urine elicited stronger responses than wolf urine (although not significantly different), which to some extent conforms to the cryptic predator hypothesis. We found no support for the naïve prey hypothesis. However, higher attraction of red foxes to lynx urine in sympatric situations might indicate that positive responses by scavengers are learning based.
Right ventricular dysfunction predicts outcome after transcatheter mitral valve repair for primary mitral valve regurgitation
Authors: Doldi Philipp M. , Stolz Lukas , Kalbacher Daniel , Köll Benedikt , Geyer Martin , Ludwig Sebastian , Orban Mathias , Braun Daniel , Weckbach Ludwig T. , Stocker Thomas J. , Näbauer Michael , Higuchi Satoshi , Ruf Tobias , Da Rocha e Silva Jaqueline , Wild Mirjam , Tence Noemie , Unterhuber Matthias , Schofer Niklas , Petrescu Aniela , Thiele Holger , Lurz Philipp , Lubos Edith , von Bardeleben Stephan , Karam Nicole , Samim Daryoush , Paradis Jean‐Michel , Iliadis Christos , Xhepa Erion , Hagl Christian , Massberg Steffen , Hausleiter Jörg ,   EuroSMR and PRIME‐MR Investigators
Published: August 2022

AbstractAimsRight ventricular dysfunction (RVD), as expressed by right ventricular to pulmonary artery coupling, has recently been identified as a strong outcome predictor in patients undergoing mitral valve edge‐to‐edge repair (M‐TEER) for secondary mitral regurgitation (MR). The aim of this study was to define RVD in patients undergoing M‐TEER for primary MR (PMR) and to evaluate its impact on procedural MR reduction, symptomatic development and 2‐year all‐cause mortality.Methods and resultsThis multicentre study included patients undergoing M‐TEER for symptomatic PMR at nine international centres. The study cohort was divided into a derivation (DC) and validation cohort (VC) for calculation and validation of the best discriminatory value for RVD. A total of 648 PMR patients were included in the study. DC and VC were comparable regarding procedural success and outcomes at follow‐up. Sensitivity analysis identified RVD as an independent predictor for 2‐year mortality in the DC (hazard ratio [HR] 2.37, 95% confidence interval [CI] 1.47–3.81, p < 0.001), which was confirmed in the VC (HR 2.06, 95% CI 1.36–3.13, p < 0.001). Procedural success (MR ≤2+) and symptomatic improvement at follow‐up (New York Heart Association [NYHA] class ≤II) were lower in PMR patients with RVD (MR ≤2+: 82% vs. 93%, p = 0.002; NYHA class ≤II: 57.3% vs. 66.5%, p = 0.09 for with vs. without RVD). In all PMR patients, the presence of RVD significantly impaired 2‐year survival after M‐TEER (HR 2.23, 95% CI 1.63–3.05, p < 0.001).ConclusionsMitral valve edge‐to‐edge repair is an effective treatment option for PMR patients. The presence of RVD is associated with less MR reduction, less symptomatic improvement and increased 2‐year mortality. Accordingly, RVD might be included into pre‐procedural prognostic considerations.
Novel homozygous CD46 variant with C‐isoform expression affects C3b inactivation in atypical hemolytic uremic syndrome
Authors: Schack Vivien R. , Herlin Morten K. , Pedersen Henrik , Jensen J. Magnus Bernth , Færch Mia , Bundgaard Bettina , Jensen Rasmus K. , Jensen Uffe B. , Christensen Rikke , Andersen Gregers R. , Thiel Steffen , Höllsberg Per 
Published: August 2022

AbstractAtypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy that may lead to organ failure. Dysregulation of the complement system can cause aHUS, and various disease‐related variants in the complement regulatory protein CD46 are described. We here report a pediatric patient with aHUS carrying a hitherto unreported homozygous variant in CD46 (NM_172359.3:c.602C>T p.(Ser201Leu)). In our functional analyses, this variant caused complement dysregulation through three separate mechanisms. First, CD46 surface expression on the patient's blood cells was significantly reduced. Second, stably expressing CD46(Ser201Leu) cells bound markedly less to patterns of C3b than CD46 WT cells. Third, the patient predominantly expressed the rare isoforms of CD46 (C dominated) instead of the more common isoforms (BC dominated). Using BC1 and C1 expressing cell lines, we found that the C1 isoform bound markedly less C3b than the BC1 isoform. These results highlight the coexistence of multiple mechanisms that may act synergistically to disrupt CD46 function during aHUS development.
Temperature and non‐communicable diseases: Evidence from Indonesia's primary health care system
Authors: Fritz Manuela 
Published: August 2022

AbstractClimate change induced rising temperatures will pose a detrimental threat to decent health in the coming decades. Especially at risk are individuals with chronic diseases, since heat can exacerbate a variety of health conditions. In this article, I examine the heat‐morbidity relationship in the context of Indonesia, focusing on chronic, non‐communicable diseases, namely diabetes, cardiovascular and respiratory diseases. Using a novel dataset from the Indonesian national health insurance scheme Jaminan Kesehatan Nasional/Badan Penyelenggara Jaminan Sosial (BPJS) and linking it with meteorological data on the daily‐district level, I estimate the causal effect of high temperatures on the daily number of primary health care visits. The results show that on a hot day all‐cause visits and visits with a diagnosis of diabetes and cardiovascular diseases increase by 8%, 25% and 14%, respectively. These increases are permanent and not offset by visit displacement or ‘harvesting’. Visits related to respiratory diseases seem not to be affected by high temperatures. I use several climate change scenarios to predict the increase in visits and costs by the end of the century, which all forecast a substantial financial burden for the health care system. These results might have relevance for other middle‐income countries with similar climatic conditions.
Challenges in the implementation of an electronic referral system: A qualitative study in the Iranian context
Authors: Kabir Mohammad Javad , Heidari Alireza , Honarvar Mohammad Reza , Khatirnamani Zahra , Rafiei Narges 
Published: August 2022

AbstractReferral chain reduces patient costs and results in more efficient use of workforce and equipment. Despite the implementation of the Family Physician Programme in Iran, the referral system does not function as intended. Therefore, this study was conducted to explain the challenges in the implementation of an electronic referral system in Iran. This qualitative study was performed in Golestan province in northern Iran. The participants were 46 family physicians, specialist physicians, healthcare managers, experts, and patients who were selected through purposive sampling. Data were collected using in‐depth individual interviews and were analysed using content analysis. Implementation of the electronic referral system faces management challenges (planning, organisation, motivation, control), administrative challenges (scheduling, patient load and waiting time, visit and diagnosis, feedback), and educational, policy, sociocultural, technological, and economic challenges. Policymakers can adopt appropriate strategies to improve the quantity and quality of their electronic referral system according to the challenges identified herein.