bluuebunny/crossref_metadata_2025_split huggingface dataset:
De novo design and bioactivity prediction of SARS-CoV-2 main protease inhibitors using recurrent neural network-based transfer learning
Authors: Santana Marcos V. S. , Silva-Jr Floriano P. 
Published: February 2021

AbstractThe global pandemic of coronavirus disease (COVID-19) caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) created a rush to discover drug candidates. Despite the efforts, so far no vaccine or drug has been approved for treatment. Artificial intelligence offers solutions that could accelerate the discovery and optimization of new antivirals, especially in the current scenario dominated by the scarcity of compounds active against SARS-CoV-2. The main protease (Mpro) of SARS-CoV-2 is an attractive target for drug discovery due to the absence in humans and the essential role in viral replication. In this work, we developed a deep learning platform for de novo design of putative inhibitors of SARS-CoV-2 main protease (Mpro). Our methodology consists of 3 main steps: (1) training and validation of general chemistry-based generative model; (2) fine-tuning of the generative model for the chemical space of SARS-CoV- Mpro inhibitors and (3) training of a classifier for bioactivity prediction using transfer learning. The fine-tuned chemical model generated > 90% valid, diverse and novel (not present on the training set) structures. The generated molecules showed a good overlap with Mpro chemical space, displaying similar physicochemical properties and chemical structures. In addition, novel scaffolds were also generated, showing the potential to explore new chemical series. The classification model outperformed the baseline area under the precision-recall curve, showing it can be used for prediction. In addition, the model also outperformed the freely available model Chemprop on an external test set of fragments screened against SARS-CoV-2 Mpro, showing its potential to identify putative antivirals to tackle the COVID-19 pandemic. Finally, among the top-20 predicted hits, we identified nine hits via molecular docking displaying binding poses and interactions similar to experimentally validated inhibitors.
A feasibility study of combined epigenetic and vaccine therapy in advanced colorectal cancer with pharmacodynamic endpoint
Authors: Bever Katherine M. , Thomas Dwayne L. , Zhang Jiajia , Diaz Rivera Ernie A. , Rosner Gary L. , Zhu Qingfeng , Nauroth Julie M. , Christmas Brian , Thompson Elizabeth D. , Anders Robert A. , Judkins Carol , Liu Meizheng , Jaffee Elizabeth M. , Ahuja Nita , Zheng Lei , Azad Nilofer S. 
Published: February 2021

AbstractEpigenetic therapies may modulate the tumor microenvironment. We evaluated the safety and optimal sequence of combination DNA methyltransferase inhibitor guadecitabine with a granulocyte macrophage-colony-stimulating-factor (GM-CSF) secreting colon cancer (CRC) vaccine (GVAX) using a primary endpoint of change in CD45RO + T cells. 18 patients with advanced CRC enrolled, 11 underwent paired biopsies and were evaluable for the primary endpoint. No significant increase in CD45RO + cells was noted. Grade 3–4 toxicities were expected and manageable. Guadecitabine + GVAX was tolerable but demonstrated no significant immunologic activity in CRC. We report a novel trial design to efficiently evaluate investigational therapies with a primary pharmacodynamic endpoint.Trial registry Clinicaltrials.gov: NCT01966289. Registered 21 October, 2013.
Characteristic pancreatic and splenic immune cell infiltration patterns in mouse acute pancreatitis
Authors: Yang Baibing , Davis Joy M. , Gomez Thomas H. , Younes Mamoun , Zhao Xiurong , Shen Qiang , Wang Run , Ko Tien C. , Cao Yanna 
Published: February 2021

Abstract
Background
A systemic evaluation of immune cell infiltration patterns in experimental acute pancreatitis (AP) is lacking. Using multi-dimensional flow cytometry, this study profiled infiltrating immune cell types in multiple AP mouse models.

Methods
Three AP models were generated in C57BL/6 mice via cerulein (CAE) injection, alcohol and palmitoleic acid (EtOH + POA) injection, and alcohol diet feeding and cerulein (EtOH + CAE) injection. Primary pancreatic cells and splenocytes were prepared, and multi-dimensional flow cytometry was performed and analyzed by manual gating and computerized PhenoGraph, followed by visualization with t-distributed stochastic neighbor embedding (t-SNE).

Results
CAE treatment induced a time-dependent increase of major innate immune cells and a decrease of follicular B cells, and TCD4+ cells and the subtypes in the pancreas, whereas elicited a reversed pattern in the spleen. EtOH + POA treatment resulted in weaker effects than CAE treatment. EtOH feeding enhanced CAE-induced amylase secretion, but unexpectedly attenuated CAE-induced immune cell regulation. In comparison with manual gating analysis, computerized analysis demonstrated a remarkable time efficiency and reproducibility on the innate immune cells and B cells.

Conclusions
The reverse pattern of increased innate and decreased adaptive immune cells was consistent in the pancreas in CAE and EtOH + POA treatments. Alcohol feeding opposed the CAE effect on immune cell regulation. Together, the immune profiling approach utilized in this study provides a better understanding of overall immune responses in AP, which may facilitate the identification of intervention windows and new therapeutic strategies. Computerized analysis is superior to manual gating by dramatically reducing analysis time.
Global concerns of dental and oral health workers during COVID-19 outbreak: a scope study on the concerns and the coping strategies
Authors: Bastani Peivand , Mohammadpour Mohammadtaghi , Ghanbarzadegan Arash , Kapellas Kostas , Do Loc Giang 
Published: February 2021

AbstractBackgroundDental and oral health workers have direct contact with respiratory aerosols of patients during procedures. This study aimed to determine the main concerns of dental and oral health workers globally during COVID-19 outbreaks and the coping strategies that help the resilience of dental and oral healthcare system.MethodsThis scoping study was conducted in August 2020. After adjusting the search strategy, a systematic search of five databases (PubMed, ISI Web of Science, Scopus, ProQuest and EMBASE) was conducted. Data was extracted using Microsoft Excel and the contents of retrieved articles were analysed through a qualitative thematic analysis applying MAX QDA10.ResultsMost articles were either editorial/letters to the editor/commentary formats (34%), or literature reviews (26%). About half of the articles belonged to three countries of Italy, China and the USA (each 16% and totally 48%). Thematic analysis of included papers led to the identification of four main global concerns and 19 sub-concerns. Economic, ethical, social and professional concerns are among dental and oral health concerns. Other results indicate on three main themes and 13 sub-themes as the coping strategies including patient management, infection control and virtual strategies.ConclusionDental and oral health care workers have many concerns relating to COVID-19 including economic, ethical, social and professional factors. Resolution of concerns may involve enhancing coping strategies relating to patient management and infection control strategies as well as using new technologies for virtual contact with the patient without any risk of infection.
Monochromatic green light stimulation during incubation shortened the hatching time via pineal function in White Leghorn eggs
Authors: Wang Panlin , Sun Yanyan , Li Yunlei , Fan Jing , Zong Yunhe , Isa Adamu Mani , Shi Lei , Wang Yuanmei , Ni Aixin , Ge Pingzhuang , Jiang Linlin , Bian Shixiong , Ma Hui , Yuan Zhengdong , Liu Xiaolin , Chen Jilan 
Published: February 2021

AbstractBackgroundEffect of monochromatic green light illumination on embryo development has been reported in chickens. The avian pineal gland is an important photo-endocrine organ formed by a mediodorsal protrusion during embryonic development. However, the involvement of pineal gland in the light transduction process remains to be elucidated. In the present study, we investigated the influence of monochromatic green light on hatching time and explored the possible mechanism via pineal function.ResultsA total of 600 eggs of White Leghorn (Shaver strain) were incubated under photoperiods of either 12 h of light and 12 h of darkness using monochromatic green light (12L:12D group) or 24 h of darkness (0L:24D group) for 18 d. Compared to 0L:24D group, the green light stimulation shortened the hatching time without extending the hatch window or impairing hatchability. The liver of embryos incubated in the 12L:12D light condition was heavier than those of the 0L:24D group on d 21 post incubation which may be linked to the observed increase in the serum concentration of insulin-like growth factor 1 (IGF-1); primary secretion of the liver. Histological structure analysis of pineal gland demonstrated that the light stimulation increased follicle area, wall thickness and lumen area on d 10 and d 12 post incubation. Rhythmic function analysis demonstrated that three clock related genes (brain and muscle ARNT-like-1,BMAL1; circadian locomotor output cycles kaput,CLOCK; and cryptochrome-1,CRY1) and a melatonin rate-limiting enzyme related gene (arylalkylamine N-acetyltransferase,AANAT) were rhythmically expressed in the pineal gland of the 12L:12D group, but not in the 0L:24D group. Simultaneously, the light stimulation also increased the concentration of melatonin (MT), which was linked to hepatocyte proliferation and IGF-1 secretion in previous studies.ConclusionsThe 12L:12D monochromatic green light stimulation during incubation shortened hatching time without impairing hatching performance. Pineal gland’s early histological development and maturation of its rhythmic function were accelerated by the light stimulation. It may be the key organ in the photo-endocrine axis that regulates embryo development, and the potential mechanism could be through enhanced secretion of MT in the 12L:12D group which promotes the secretion of IGF-1.
Vocational training choice from a regional perspective
Authors: Schuster Katja , Margarian Anne 
Published: February 2021

AbstractMotivated by discussions of skill mismatches on local German vocational educational and training (VET) markets, this paper analyses how occupational segments of VET entry of individuals with lower and intermediate secondary school degree relate to local labor market characteristics. The econometric analysis applies data from a survey conducted with 9th graders within the German National Educational Panel Study (NEPS). Considering opportunity structures and the local competition for training positions, we find that the match between occupations' skill demands and individuals' abilities tends to be specifically close in diverse and competitive urban labor markets. In non-competitive peripheral labor markets, in contrast, graduates with lower school certificates seem to have a higher likelihood of entering VET in segments that are specifically attractive for graduates with upper secondary school degree. The results on the allocation of abilities and the weight of preferences under different labor market conditions have different welfare implications from an individual, regional and general economic perspective.
Real-time monitoring of liver fibrosis through embedded sensors in a microphysiological system
Authors: Farooqi Hafiz Muhammad Umer , Kang Bohye , Khalid Muhammad Asad Ullah , Salih Abdul Rahim Chethikkattuveli , Hyun Kinam , Park Sung Hyuk , Huh Dongeun , Choi Kyung Hyun 
Published: February 2021

AbstractHepatic fibrosis is a foreshadowing of future adverse events like liver cirrhosis, liver failure, and cancer. Hepatic stellate cell activation is the main event of liver fibrosis, which results in excessive extracellular matrix deposition and hepatic parenchyma's disintegration. Several biochemical and molecular assays have been introduced for in vitro study of the hepatic fibrosis progression. However, they do not forecast real-time events happening to the in vitro models. Trans-epithelial electrical resistance (TEER) is used in cell culture science to measure cell monolayer barrier integrity. Herein, we explored TEER measurement's utility for monitoring fibrosis development in a dynamic cell culture microphysiological system. Immortal HepG2 cells and fibroblasts were co-cultured, and transforming growth factor β1 (TGF-β1) was used as a fibrosis stimulus to create a liver fibrosis-on-chip model. A glass chip-based embedded TEER and reactive oxygen species (ROS) sensors were employed to gauge the effect of TGF-β1 within the microphysiological system, which promotes a positive feedback response in fibrosis development. Furthermore, albumin, Urea, CYP450 measurements, and immunofluorescent microscopy were performed to correlate the following data with embedded sensors responses. We found that chip embedded electrochemical sensors could be used as a potential substitute for conventional end-point assays for studying fibrosis in microphysiological systems.
Echocardiographic myocardial strain analysis describes subclinical cardiac dysfunction after craniospinal irradiation in pediatric and young adult patients with central nervous system tumors
Authors: Martinez Hugo R. , Salloum Ralph , Wright Erin , Bueche Lauren , Khoury Philip R. , Tretter Justin T. , Ryan Thomas D. 
Published: February 2021

Abstract
Background
Craniospinal irradiation (CSI) is part of the treatment of central nervous system (CNS) tumors and is associated with cardiovascular disease in adults. Global myocardial strain analysis including longitudinal peak systolic strain (GLS), circumferential peak systolic strain (GCS), and radial peak systolic strain (GRS) can reveal subclinical cardiac dysfunction.

Methods
Retrospective, single-center study in patients managed with CSI vs. age-matched controls. Clinical data and echocardiography, including myocardial strain analysis, were collected at early (< 12 months) and late (≥ 12 months) time points after completion of CSI.

Results
Echocardiograms were available at 20 early and 34 late time points. Patients at the late time point were older (21.7 ± 10.4 vs. 13.3 ± 9.6 years) and further out from CSI (13.1 ± 8.8 vs. 0.2 ± 0.3 years). Standard echocardiographic parameters were normal for both groups. For early, CSI vs. control: GLS was − 16.8 ± 3.6% vs. -21.3 ± 4.0% (p = 0.0002), GCS was − 22.5 ± 5.2% vs. -21.3 ± 3.4% (p = 0.28), and GRS was 21.8 ± 11.0% vs. 26.9 ± 7.7% (p = 0.07). For late, CSI vs. control: GLS was − 16.2 ± 5.4% vs. -21.6 ± 3.7% (p < 0.0001), GCS was − 20.9 ± 6.8% vs. -21.9 ± 3.5% (p = 0.42), and GRS was 22.5 ± 10.0% vs. 27.3 ± 8.3% (p = 0.03). Radiation type (proton vs. photon), and radiation dose (< 30 Gy vs. ≥ 30 Gy) did not impact any parameter, although numbers were small.

Conclusions
Subclinical cardiac systolic dysfunction by GLS is present both early and late after CSI. These results argue for future studies to determine baseline cardiovascular status and the need for early initiation of longitudinal follow-up post CSI.
Identification of zinc-binding peptides in ADAM17-inhibiting whey protein hydrolysates using IMAC-Zn2+ coupled with shotgun peptidomics
Authors: Udechukwu M. Chinonye , Dang Chi , Udenigwe Chibuike C. 
Published: February 2021

Abstract
Food components possessing zinc ligands can be used to inhibit zinc-dependent enzymes. In this study, zinc-binding peptides were derived from whey protein hydrolysates, and their ultrafiltration (> 1 and < 1 kDa) fractions, produced with Esperase (WPH-Esp), Everlase and Savinase. Immobilized metal affinity chromatography (IMAC-Zn2+) increased the zinc-binding capacity of the peptide fraction (83%) when compared to WPH-Esp (23%) and its < 1 kDa fraction (40%). The increased zinc-binding capacity of the sample increased the inhibitory activity against the zinc-dependent “a disintegrin and metalloproteinase 17”. LC-MS/MS analysis using a shotgun peptidomics approach resulted in the identification of 24 peptides originating from bovine β-lactoglobulin, α-lactalbumin, serum albumin, β-casein, κ-casein, osteopontin-k, and folate receptor-α in the fraction. The identified peptides contained different combinations of the strong zinc-binding group of residues, His+Cys, Asp+Glu and Phe+Tyr, although Cys residues were absent in the sequences. In silico predictions showed that the IMAC-Zn2+ peptides were non-toxins. However, the peptides possessed poor drug-like and pharmacokinetic properties; this was possibly due to their long chain lengths (5–19 residues). Taken together, this work provided an array of food peptide-based zinc ligands for further investigation of structure-function relationships and development of nutraceuticals against inflammatory and other zinc-related diseases.

Graphical abstract
Open-Label, Single-Arm, Phase II Study of Pembrolizumab Monotherapy as First-Line Therapy in Patients With Advanced Non–Clear Cell Renal Cell Carcinoma
Authors: McDermott David F. , Lee Jae-Lyun , Ziobro Marek , Suarez Cristina , Langiewicz Przemyslaw , Matveev Vsevolod Borisovich , Wiechno Pawel , Gafanov Rustem Airatovich , Tomczak Piotr , Pouliot Frederic , Donskov Frede , Alekseev Boris Yakovlevich , Shin Sang Joon , Bjarnason Georg A. , Castellano Daniel , Silverman Rachel Kloss , Perini Rodolfo F. , Schloss Charles , Atkins Michael B. 
Published: February 2021

PURPOSE Programmed death 1 (PD-1) pathway inhibitors have not been prospectively evaluated in patients with non–clear cell renal cell carcinoma (nccRCC). The phase II KEYNOTE-427 study (cohort B) was conducted to assess the efficacy and safety of single-agent pembrolizumab, a PD-1 inhibitor, in advanced nccRCC. METHODS Patients with histologically confirmed, measurable (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) nccRCC and no prior systemic therapy received pembrolizumab 200 mg intravenously once every 3 weeks for ≤ 24 months. The primary end point was objective response rate (ORR) per RECIST v1.1. RESULTS Among enrolled patients (N = 165), 71.5% had confirmed papillary, 12.7% had chromophobe, and 15.8% had unclassified RCC histology. Most patients (67.9%) had intermediate or poor International Metastatic RCC Database Consortium risk status and tumors with programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥ 1 (61.8%). The median time from enrollment to database cutoff was 31.5 months (range, 22.7-38.8). In all patients, the ORR was 26.7%. The median duration of response was 29.0 months; 59.7% of responses lasted ≥ 12 months. The ORR by CPS ≥ 1 and CPS < 1 status was 35.3% and 12.1%, respectively. The ORR by histology was 28.8% for papillary, 9.5% for chromophobe, and 30.8% for unclassified. Overall, the median progression-free survival was 4.2 months (95% CI, 2.9 to 5.6); the 24-month rate was 18.6%. The median overall survival was 28.9 months (95% CI, 24.3 months to not reached); the 24-month rate was 58.4%. Overall, 69.7% of patients reported treatment-related adverse events, most commonly pruritus (20.0%) and hypothyroidism (14.5%). Two deaths were treatment related (pneumonitis and cardiac arrest). CONCLUSION First-line pembrolizumab monotherapy showed promising antitumor activity in nccRCC. The safety profile was similar to that observed in other tumor types.
Managing otalgia in general practice
Authors: Perry Margaret Ann 
Published: February 2021

Otalgia is a frequent reason for minor illness consultations in general practice. Margaret Ann Perry provides an overview of the common causes, complications and treatments Otalgia, also known as earache, is a common condition, which has a variety of causes. It is a frequent reason for visits to GP surgeries or walk-in centres and can potentially affect any age. Most of the common causes of otalgia are benign conditions that can be easily treated; however, there are a few more sinister diagnoses that need to be considered in some cases. This article therefore aims to give nurses and non-medical prescribers confidence in assessing and treating patients who present with this common condition.
Health coaching: the role of the practice nurse
Authors: Best Catherine 
Published: February 2021

Health coaching can be used to improve the health of patients. Catherine Best looks at the theory behind health coaching and how the nurse can play a role Health coaching is a concept which focuses on evidence-based clinical interventions, such as motivational interviewing, goal setting, active listening and change management theory, with the aim that patients are supported to self-manage their own health. Health coaching is patient-centred and empowers individuals to make healthcare choices based on what personally matters to them. The practice nurse is in a strong position to utilise their skills, many of which can be attributed to the role of a health coach.
Angular micro-vibration of the Micius satellite measured by an optical sensor and the method for its suppression
Authors: Wang Xu , Li Changkun , Jia Jianjun , Wu Jincai , Shu Rong , Zhang Liang , Wang Jianyu 
Published: February 2021

Satellite angular micro-vibration has an important impact on the efficiency of space quantum communication links. We measured the micro-vibrations on the Micius satellite in orbit using a high-precision optical sensor mounted on the satellite and analyzed the power spectral density. We designed a compound axis acquisition, tracking, and pointing (ATP) system based on a two-axis turntable and tested its suppressive effect on the micro-vibration through in-orbit experiments. The tracking error caused by the angular micro-vibration was found to be 9.3 µrad, with the energy concentrated primarily in the frequencies below 30 Hz; after suppression by the ATP system, the error was 0.47 µrad.
30 GHz GeSn photodetector on SOI substrate for 2 µm wavelength application
Authors: Li Xiuli , Peng Linzhi , Liu Zhi , Zhou Zhiqi , Zheng Jun , Xue Chunlai , Zuo Yuhua , Chen Baile , Cheng Buwen 
Published: February 2021

We report the demonstration of a normal-incidence p-i-n germanium-tin (

Ge

0.951

Sn

0.049

) photodetector on silicon-on-insulator substrate for 2 μm wavelength application. The DC and RF characteristics of the devices have been characterized. A dark current density under

−
1

V

bias of approximately

125

mA/

cm

2

is achieved at room temperature, and the optical responsivity of 14 mA/W is realized for illumination wavelength of 2 μm under

−
1

V

reverse bias. In addition, a 3 dB bandwidth (

f

3

dB

) of around 30 GHz is achieved at

−
3

V

, which is the highest reported value among all group III–V and group IV photodetectors working in the 2 μm wavelength range. This work illustrates that a GeSn photodetector has great prospects in 2 μm wavelength optical communication.