bluuebunny/crossref_metadata_2025 huggingface dataset:
PD-L1 signaling selectively regulates T cell lymphatic transendothelial migration
Authors: Piao Wenji , Li Lushen , Saxena Vikas , Iyyathurai Jegan , Lakhan Ram , Zhang Yigang , Lape Isadora Tadeval , Paluskievicz Christina , Hippen Keli L. , Lee Young , Silverman Emma , Shirkey Marina W. , Riella Leonardo V. , Blazar Bruce R. , Bromberg Jonathan S.
Published: April 2022

Programmed death-1 (PD-1) and its ligand PD-L1 are checkpoint molecules which regulate immune responses. Little is known about their functions in T cell migration and there are contradictory data about their roles in regulatory T cell (Treg) function. Here we show activated Tregs and CD4 effector T cells (Teffs) use PD-1/PD-L1 and CD80/PD-L1, respectively, to regulate transendothelial migration across lymphatic endothelial cells (LECs). Antibody blockade of Treg PD-1, Teff CD80 (the alternative ligand for PD-L1), or LEC PD-L1 impairs Treg or Teff migration in vitro and in vivo. PD-1/PD-L1 signals through PI3K/Akt and ERK to regulate zipper junctional VE-cadherin, and through NFκB-p65 to up-regulate VCAM-1 expression on LECs. CD80/PD-L1 signaling up-regulates VCAM-1 through ERK and NFκB-p65. PD-1 and CD80 blockade reduces tumor egress of PD-1high fragile Tregs and Teffs into draining lymph nodes, respectively, and promotes tumor regression. These data provide roles for PD-L1 in cell migration and immune regulation.
R-loops at microRNA encoding loci promote co-transcriptional processing of pri-miRNAs in plants
Authors: Gonzalo Lucia , Tossolini Ileana , Gulanicz Tomasz , Cambiagno Damian A. , Kasprowicz-Maluski Anna , Smolinski Dariusz Jan , Mammarella María Florencia , Ariel Federico D. , Marquardt Sebastian , Szweykowska-Kulinska Zofia , Jarmolowski Artur , Manavella Pablo A.
Published: April 2022

In most organisms, the maturation of nascent RNAs is coupled to transcription. Unlike in animals, the RNA polymerase II (RNAPII) transcribes microRNA genes (MIRNAs) as long and structurally variable pri-miRNAs in plants. Current evidence suggests that the miRNA biogenesis complex assembly initiates early during the transcription of pri-miRNAs in plants. However, it is unknown whether miRNA processing occurs co-transcriptionally. Here, we used native elongating transcript sequencing data and imaging techniques to demonstrate that plant miRNA biogenesis occurs coupled to transcription. We found that the entire biogenesis occurs co-transcriptionally for pri-miRNAs processed from the loop of the hairpin but requires a second nucleoplasmic step for those processed from the base. Furthermore, we found that co- and post-transcriptional miRNA processing mechanisms co-exist for most miRNAs in a dynamic balance. Notably, we discovered that R-loops, formed near the transcription start site region of MIRNAs, promote co-transcriptional pri-miRNA processing. Furthermore, our results suggest the neofunctionalization of co-transcriptionally processed miRNAs, boosting countless regulatory scenarios.
Association of treatment-emergent symptoms identified by patient-reported outcomes with adjuvant endocrine therapy discontinuation
Authors: Smith Karen Lisa , Verma Neha , Blackford Amanda L. , Lehman Jennifer , Westbrook Kelly , Lim David , Fetting John , Wolff Antonio C. , Jelovac Daniela , Miller Robert S. , Connolly Roisin , Armstrong Deborah K. , Nunes Raquel , Visvanathan Kala , Riley Carol , Papathakis Katie , Zafman Nelli , Sheng Jennifer Y. , Snyder Claire , Stearns Vered
Published: April 2022

Many patients discontinue endocrine therapy for breast cancer due to intolerance. Identification of patients at risk for discontinuation is challenging. The minimal important difference (MID) is the smallest change in a score on a patient-reported outcome (PRO) that is clinically significant. We evaluated the association between treatment-emergent symptoms detected by worsening PRO scores in units equal to the MID with discontinuation. We enrolled females with stage 0-III breast cancer initiating endocrine therapy in a prospective cohort. Participants completed PROs at baseline, 3, 6, 12, 24, 36, 48, and 60 months. Measures included PROMIS pain interference, fatigue, depression, anxiety, physical function, and sleep disturbance; Endocrine Subscale of the FACT-ES; and MOS-Sexual Problems (MOS-SP). We evaluated associations between continuous PRO scores in units corresponding to MIDs (PROMIS: 4-points; FACT-ES: 5-points; MOS-SP: 8-points) with time to endocrine therapy discontinuation using Cox proportional hazards models. Among 321 participants, 140 (43.6%) initiated tamoxifen and 181 (56.4%) initiated aromatase inhibitor (AI). The cumulative probability of discontinuation was 23% (95% CI 18–27%) at 48 months. For every 5- and 4-point worsening in endocrine symptoms and sleep disturbance respectively, participants were 13 and 14% more likely to discontinue endocrine therapy respectively (endocrine symptoms HR 1.13, 95% CI 1.02–1.25, p = 0.02; sleep disturbance HR 1.14, 95% CI 1.01–1.29,p = 0.03). AI treatment was associated with greater likelihood of discontinuation than tamoxifen. Treatment-emergent endocrine symptoms and sleep disturbance are associated with endocrine therapy discontinuation. Monitoring for worsening scores meeting or exceeding the MID on PROs may identify patients at risk for discontinuation.
Clinical relevance of pathogenic germline variants in mismatch repair genes in Chinese breast cancer patients
Authors: Hu Li , Sun Jie , Li Zhongwu , Qu Ziwei , Liu Yan , Wan Qiting , Liu Jiaming , Ding Xinyun , Zang Fan , Zhang Juan , Yao Lu , Xu Ye , Wang Yin , Xie Yuntao
Published: April 2022

The prevalence and clinical relevance of pathogenic germline variants in MMR genes have not been investigated in large series of breast cancers. In this study, we screened the germline variants in MMR genes in 8085 consecutive Chinese breast cancer patients, and investigated the MMR/PD-L1 protein expression and tumor mutation burden (TMB) of breast tumors from MMR variant carriers. We found that 15 of 8085 patients (0.19%) carried a pathogenic germline variant in MMR genes. Compared with non-carriers, MMR variant carriers might have worse recurrence-free survival (unadjusted hazard ratios [HR] = 2.70, 95% CI: 1.12–6.49, P = 0.027) and distant recurrence-free survival (unadjusted HR = 3.24, 95% CI: 1.45–7.22, P = 0.004). More importantly, some of the breast cancers from MMR carriers displayed MMR protein loss (5/13), TMB-high (2/10), and PD-L1 positive expression (9/13). This study showed that MMR variant carriers were rare in breast cancer. They might have worse survival and part of them might benefit from immunotherapy.
Unconventional dual 1D–2D quantum spin liquid revealed by ab initio studies on organic solids family
Authors: Ido Kota , Yoshimi Kazuyoshi , Misawa Takahiro , Imada Masatoshi
Published: April 2022

Organic solids host various electronic phases. Especially, a milestone compound of organic solid, $$\beta ^{\prime}$$

β

′

-X[Pd(dmit)2]2 with X=EtMe3Sb shows quantum spin-liquid (QSL) properties suggesting a novel state of matter. However, the nature of the QSL has been largely unknown. Here, we computationally study five compounds comprehensively with different X using 2D ab initio Hamiltonians and correctly reproduce the experimental phase diagram with antiferromagnetic order for X=Me4P, Me4As, Me4Sb, Et2Me2As and a QSL for X=EtMe3Sb without adjustable parameters. We find that the QSL for X=EtMe3Sb exhibits 1D nature characterized by algebraic decay of spin correlation along one direction, while exponential decay in the other direction, indicating dimensional reduction from 2D to 1D. The 1D nature indeed accounts for the experimental specific heat, thermal conductivity and magnetic susceptibility. The identified QSL, however, preserves 2D nature as well consistently with spin fractionalization into spinon with Dirac-like gapless excitations and reveals duality bridging the 1D and 2D QSLs.
Neural alterations of emotion processing in atypical trajectories of psychotic-like experiences
Authors: Assaf Roxane , Ouellet Julien , Bourque Josiane , Stip Emmanuel , Leyton Marco , Conrod Patricia , Potvin Stéphane
Published: April 2022

The aim of this study was to investigate the neural bases of facial emotion processing before the onset of clinical psychotic symptoms in youth belonging to well-defined developmental trajectories of psychotic-like experiences (PLEs). A unique sample of 86 youths was recruited from a population-based sample of over 3800 adolescents who had been followed from 13 to 17 years of age. Three groups were identified based on validated developmental trajectories: a control trajectory with low and decreasing PLEs, and two atypical trajectories with moderate to elevated baseline PLEs that subsequently decreased or increased. All had functional magnetic resonance imaging data collected during a facial emotion processing task. Functional activation and connectivity data were analyzed for different contrasts. The increasing PLE trajectory displayed more positive psychotic symptoms while the decreasing trajectory exhibited more negative symptoms relative to the control group. During face processing, both atypical trajectories displayed decreased activations of the right inferior frontal gyrus (IFG), while the increasing trajectory displayed a negative signal in the precentral gyrus. The increasing PLE trajectory also displayed impaired connectivity between the amygdala, ventromedial prefrontal cortex, and cerebellum, and between the IFG, precuneus, and temporal regions, while the decreasing trajectory exhibited reduced connectivity between the amygdala and visual regions during emotion processing. Both atypical PLE trajectories displayed alterations in brain regions involved in attention salience. While the increasing trajectory with more positive symptoms exhibited dysconnectivity in areas that influence emotion salience and face perception, the decreasing trajectory with more negative symptoms had impairments in visual information integration areas. These group-specific features might account for the differential symptom expression.
Increased memory B cell potency and breadth after a SARS-CoV-2 mRNA boost
Authors: Muecksch Frauke , Wang Zijun , Cho Alice , Gaebler Christian , Ben Tanfous Tarek , DaSilva Justin , Bednarski Eva , Ramos Victor , Zong Shuai , Johnson Brianna , Raspe Raphael , Schaefer-Babajew Dennis , Shimeliovich Irina , Daga Mridushi , Yao Kai-Hui , Schmidt Fabian , Millard Katrina G. , Turroja Martina , Jankovic Mila , Oliveira Thiago Y. , Gazumyan Anna , Caskey Marina , Hatziioannou Theodora , Bieniasz Paul D. , Nussenzweig Michel C.
Published: April 2022

The Omicron variant of SARS-CoV-2 infected many vaccinated and convalescent individuals1–3. Despite the reduced protection from infection, individuals who received three doses of an mRNA vaccine were highly protected from more serious consequences of infection4. Here we examine the memory B cell repertoire in a longitudinal cohort of individuals receiving three mRNA vaccine doses5,6. We find that the third dose is accompanied by an increase in, and evolution of, receptor-binding domain (RBD)-specific memory B cells. The increase is due to expansion of memory B cell clones that were present after the second dose as well as the emergence of new clones. The antibodies encoded by these cells showed significantly increased potency and breadth when compared with antibodies obtained after the second dose. Notably, the increase in potency was especially evident among newly developing clones of memory cells, which differed from persisting clones in targeting more conserved regions of the RBD. Overall, more than 50% of the analysed neutralizing antibodies in the memory compartment after the third mRNA vaccine dose neutralized the Omicron variant. Thus, individuals receiving three doses of an mRNA vaccine have a diverse memory B cell repertoire that can respond rapidly and produce antibodies capable of clearing even diversified variants such as Omicron. These data help to explain why a third dose of a vaccine that was not specifically designed to protect against variants is effective against variant-induced serious disease.
Hippocampal place codes are gated by behavioral engagement
Authors: Pettit Noah L. , Yuan Xintong C. , Harvey Christopher D.
Published: April 2022

As animals explore an environment, the hippocampus is thought to automatically form and maintain a place code by combining sensory and self-motion signals. Instead, we observed an extensive degradation of the place code when mice voluntarily disengaged from a virtual navigation task, remarkably even as they continued to traverse the identical environment. Internal states, therefore, can strongly gate spatial maps and reorganize hippocampal activity even without sensory and self-motion changes.
GEOM, energy-annotated molecular conformations for property prediction and molecular generation
Authors: Axelrod Simon , Gómez-Bombarelli Rafael
Published: April 2022

Machine learning (ML) outperforms traditional approaches in many molecular design tasks. ML models usually predict molecular properties from a 2D chemical graph or a single 3D structure, but neither of these representations accounts for the ensemble of 3D conformers that are accessible to a molecule. Property prediction could be improved by using conformer ensembles as input, but there is no large-scale dataset that contains graphs annotated with accurate conformers and experimental data. Here we use advanced sampling and semi-empirical density functional theory (DFT) to generate 37 million molecular conformations for over 450,000 molecules. The Geometric Ensemble Of Molecules (GEOM) dataset contains conformers for 133,000 species from QM9, and 317,000 species with experimental data related to biophysics, physiology, and physical chemistry. Ensembles of 1,511 species with BACE-1 inhibition data are also labeled with high-quality DFT free energies in an implicit water solvent, and 534 ensembles are further optimized with DFT. GEOM will assist in the development of models that predict properties from conformer ensembles, and generative models that sample 3D conformations.
An anatomical classification of congenital proximal radioulnar synostosis based on retrospective MRI measurement combined with radiography
Authors: Li Jin , Chen Kailei , Wang Jing , Guo Yueming , Rai Saroj , Tang Xin ,   Chinese Multi-center Pediatric Orthopedic Study Group (CMPOS), Li Jin , Tang Xin , Guo Yueming
Published: April 2022

Existed classifications of congenital proximal radioulnar synostosis (PRUS) mainly focus on osseous changes and do not cover all types of congenital PRUS, ignoring the role and developing status of the supinator. This study aims to explore the correlation between supinator development and radiographic deformity of congenital PRUS. Pediatric patients diagnosed with congenital PRUS in two pediatric Orthopedic centers were evaluated retrospectively. MRI and radiographic images of their bilateral forearms (including normal ones) were collected. The area of supinator, extensor carpi radialis longus (ECRL), extensor carpi radialis brevis (ECRB), brachioradialis (BRAR) muscle and extensor indicis (EI) muscle were measured on each forearm. The ratios of these muscles were calculated and regarded as an indicator of the developing status of supinator muscle. Twenty-seven congenital PRUS forearms of 16 patients (average 3.45 years) were included. A new MRI & X-ray classification system was proposed to cover all types of radiographic deformity and provide a comprehensive description of supinator development. This study revealed the relation between MRI measured supinator volume and radiographic deformity of congenital PRUS. Supinator muscles were observed in all congenital PRUS cases. A novel classification was proposed, providing a more comprehensive understanding of congenital PRUS.
Costly avoidance of Pavlovian fear stimuli and the temporal dynamics of its decision process
Authors: Boschet Juliane M. , Scherbaum Stefan , Pittig Andre
Published: April 2022

Conflicts between avoiding feared stimuli versus approaching them for competing rewards are essential for functional behavior and anxious psychopathology. Yet, little is known about the underlying decision process. We examined approach-avoidance decisions and their temporal dynamics when avoiding Pavlovian fear stimuli conflicted with gaining rewards. First, a formerly neutral stimulus (CS+) was repeatedly paired with an aversive stimulus (US) to establish Pavlovian fear. Another stimulus (CS−) was never paired with the US. A control group received neutral tones instead of aversive USs. Next, in each of 324 trials, participants chose between a CS−/low reward and a CS+/high reward option. For the latter, probability of CS+ presentation (Pavlovian fear information) and reward magnitude (reward information) varied. Computer mouse movements were tracked to capture the decision dynamics. Although no more USs occurred, pronounced and persistent costly avoidance of the Pavlovian fear CS+ was found. Time-continuous multiple regression of movement trajectories revealed a stronger and faster impact of Pavlovian fear compared to reward information during decision-making. The impact of fear information, but not reward information, modestly decreased across trials. These findings suggest a persistently stronger weighting of fear compared to reward information during approach-avoidance decisions, which may facilitate the development of pathological avoidance.
Social capital's impact on COVID-19 outcomes at local levels
Authors: Fraser Timothy , Page-Tan Courtney , Aldrich Daniel P.
Published: April 2022

Over the past thirty years, disaster scholars have highlighted that communities with stronger social infrastructure—including social ties that enable trust, mutual aid, and collective action—tend to respond to and recover better from crises. However, comprehensive measurements of social capital across communities have been rare. This study adapts Kyne and Aldrich’s (Risk Hazards Crisis Public Policy11, 61–86, 2020) county-level social capital index to the census-tract level, generating social capital indices from 2011 to 2018 at the census-tract, zipcode, and county subdivision levels. To demonstrate their usefulness to disaster planners, public health experts, and local officials, we paired these with the CDC’s Social Vulnerability Index to predict the incidence of COVID-19 in case studies in Massachusetts, Wisconsin, Illinois, and New York City. We found that social capital predicted 41–49% of the variation in COVID-19 outbreaks, and up to 90% with controls in specific cases, highlighting its power as diagnostic and predictive tools for combating the spread of COVID.
Einstein–Roscoe regression for the slag viscosity prediction problem in steelmaking
Authors: Saigo Hiroto , KC Dukka B. , Saito Noritaka
Published: April 2022

In classical machine learning, regressors are trained without attempting to gain insight into the mechanism connecting inputs and outputs. Natural sciences, however, are interested in finding a robust interpretable function for the target phenomenon, that can return predictions even outside of the training domains. This paper focuses on viscosity prediction problem in steelmaking, and proposes Einstein–Roscoe regression (ERR), which learns the coefficients of the Einstein–Roscoe equation, and is able to extrapolate to unseen domains. Besides, it is often the case in the natural sciences that some measurements are unavailable or expensive than the others due to physical constraints. To this end, we employ a transfer learning framework based on Gaussian process, which allows us to estimate the regression parameters using the auxiliary measurements available in a reasonable cost. In experiments using the viscosity measurements in high temperature slag suspension system, ERR is compared favorably with various machine learning approaches in interpolation settings, while outperformed all of them in extrapolation settings. Furthermore, after estimating parameters using the auxiliary dataset obtained at room temperature, an increase in accuracy is observed in the high temperature dataset, which corroborates the effectiveness of the proposed approach.
Ketone-selenoesters as potential anticancer and multidrug resistance modulation agents in 2D and 3D ovarian and breast cancer in vitro models
Authors: Dobiasová Simona , Szemerédi Nikoletta , Kučerová Denisa , Koucká Kamila , Václavíková Radka , Gbelcová Helena , Ruml Tomáš , Domínguez-Álvarez Enrique , Spengler Gabriella , Viktorová Jitka
Published: April 2022

Long-term treatment of cancer with chemotherapeutics leads to the development of resistant forms that reduce treatment options. The main associated mechanism is the overexpression of transport proteins, particularly P-glycoprotein (P-gp, ABCB1). In this study, we have tested the anticancer and multidrug resistance (MDR) modulation activity of 15 selenocompounds. Out of the tested compounds, K3, K4, and K7 achieved the highest sensitization rate in ovarian carcinoma cells (HOC/ADR) that are resistant to the action of the Adriamycin. These compounds induced oxidation stress, inhibited P-gp transport activity and altered ABC gene expression. To verify the effect of compounds, 3D cell models were used to better mimic in vivo conditions. K4 and K7 triggered the most significant ROS release. All selected selenoesters inhibited P-gp efflux in a dose-dependent manner while simultaneously altering the expression of the ABC genes, especially P-gp in paclitaxel-resistant breast carcinoma cells (MCF-7/PAX). K4, and K7 demonstrated sensitization potential in resistant ovarian spheroids. Additionally, all selected selenoesters achieved a high cytotoxic effect in 3D breast and ovarian models, which was comparable to that in 2D cultures. K7 was the only non-competitive P-gp inhibitor, and therefore appears to have considerable potential for the treatment of drug-resistant cancer.
Increased biomarkers of cardiovascular risk in HIV-1 viremic controllers and low persistent inflammation in elite controllers and art-suppressed individuals
Authors: Caetano Diogo Gama , Ribeiro-Alves Marcelo , Hottz Eugênio Damaceno , Vilela Larissa Melo , Cardoso Sandra Wagner , Hoagland Brenda , Grinsztejn Beatriz , Veloso Valdilea Gonçalves , Morgado Mariza Gonçalves , Bozza Patrícia Torres , Guimarães Monick Lindenmeyer , Côrtes Fernanda Heloise
Published: April 2022

HIV controllers (HICs) are models of HIV functional cure, although some studies have shown persistent inflammation and increased rates of atherosclerosis in HICs. Since immune activation/inflammation contributes to the pathogenesis of cardiovascular diseases (CVD), we evaluated clinical data and inflammation markers in HIV-1 viremic controllers (VC), elite controllers (EC), and control groups (HIV positive individuals with virological suppression by antiretroviral therapy—cART; HIV negative individuals—HIVneg) to assess whether they presented elevated levels of inflammation markers also associated with CVD. We observed the highest frequencies of activated CD8+ T cells in VCs, while EC and cART groups presented similar but slightly altered frequencies of this marker when compared to the HIVneg group. Regarding platelet activation, both HICs groups presented higher expression of P-selectin in platelets when compared to control groups. Monocyte subset analyses revealed lower frequencies of classical monocytes and increased frequencies of non-classical and intermediate monocytes among cART individuals and in EC when compared to HIV negative individuals, but none of the differences were significant. For VC, however, significant decreases in frequencies of classical monocytes and increases in the frequency of intermediate monocytes were observed in comparison to HIV negative individuals. The frequency of monocytes expressing tissue factor was similar among the groups on all subsets. In terms of plasma markers, VC had higher levels of many inflammatory markers, while EC had higher levels of VCAM-1 and ICAM-1 compared to control groups. Our data showed that VCs display increased levels of inflammation markers that have been associated with CVD risk. Meanwhile, ECs show signals of lower but persistent inflammation, comparable to the cART group, indicating the potential benefits of alternative therapies to decrease inflammation in this group.
Integrated computer-aided drug design and biophysical simulation approaches to determine natural anti-bacterial compounds for Acinetobacter baumannii
Authors: Almihyawi Raed A. H. , Naman Ziad Tareq , Al-Hasani Halah M. H. , Muhseen Ziyad Tariq , Zhang Sitong , Chen Guang
Published: April 2022

Acinetobacter baumannii is a nosocomial bacterial pathogen and is responsible for a wide range of diseases including pneumonia, necrotizing fasciitis, meningitis, and sepsis. The enzyme 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase (encoded by aroA gene) in ESKAPE pathogens catalyzes the sixth step of shikimate pathway. The shikimate pathway is an attractive drug targets pathway as it is present in bacteria but absent in humans. As EPSP is essential for the A. baumannii growth and needed during the infection process, therefore it was used as a drug target herein for high-throughput screening of a comprehensive marine natural products database (CMNPD). The objective was to identify natural molecules that fit best at the substrate binding pocket of the enzyme and interact with functionally critical residues. Comparative assessment of the docking scores allowed selection of three compounds namely CMNPD31561, CMNPD28986, and CMNPD28985 as best binding molecules. The molecules established a balanced network of hydrophobic and hydrophilic interactions, and the binding pose remained in equilibrium throughout the length of molecular simulation time. Radial distribution function (RDF) analysis projected key residues from enzyme active pocket which actively engaged the inhibitors. Further validation is performed through binding free energies estimation that affirms very low delta energy of <−22 kcal/mol in MM-GBSA method and <−12 kcal/mol in MM-PBSA method. Lastly, the most important active site residues were mutated and their ligand binding potential was re-investigated. The molecules also possess good druglike properties and better pharmacokinetics. Together, these findings suggest the potential biological potency of the leads and thus can be used by experimentalists in vivo and in vitro studies.
Changes in contrast sensitivity after surgery for intermittent exotropia
Authors: Bae Young Hwan , Choi Dong Gyu
Published: April 2022

To determine whether intermittent exotropia (IXT) surgery affects contrast sensitivity (CS), this retrospective study evaluated the changes in monocular and binocular CS and the binocular summation ratio (BSR) quantified as the ratio between the values of the binocular and the better monocular CS score (BSR = binocular CS score/better monocular CS score) after surgery for IXT. The subjects were patients who had undergone IXT-correcting surgery with a postoperative follow-up of > 3 months and had pre- and postoperative records of Mars CS test scores. In total, 64 patients (128 eyes) were evaluated. Both the binocular and monocular CS scores of the operated eyes were significantly worse on postoperative 1 day than the preoperative scores, but they were recovered after 1 week. The monocular CS scores of the operated eyes were significantly worse than those of the non-operated eyes until 1 week. There was no significant difference in monocular CS scores between the one-muscle and two-muscle surgeries and in binocular CS scores between the successful alignment and overcorrection groups even on the first day after surgery. The mean BSR was significantly decreased until postoperative month 1, however, recovered to preoperative levels after month 3. In conclusion, IXT-correcting surgery may temporarily worsen the CS, but it is recovered to preoperative levels. Thus, changes in CS in the immediate postoperative period after strabismus surgery should not be of concern.
Lombard effect, intelligibility, ambient noise, and willingness to spend time and money in a restaurant amongst older adults
Authors: Bottalico Pasquale , Piper Rachael N. , Legner Brianna
Published: April 2022

Dining establishments are an essential part of the social experience. However, they are often characterized by high levels of background noise, which represents a barrier to effective communication. This particularly affects people suffering from hearing problems. Moreover, noise level exceeding normal conversational levels causes a phenomenon called the Lombard Effect, an involuntary tendency to increase the amount of vocal effort when talking in the presence of noise. Adults over 60 years represent the second largest population in the US and the majority of them suffer from some degree of hearing loss. The primary aim of the current study was to understand the effect of noise on vocal effort and speech intelligibility in a restaurant setting for adults over 60 years old with and without hearing loss. The secondary aim was to evaluate their perception of disturbance in communication and their willingness to spend time and money in a restaurant was affected by the varying levels of background noise. The results of this study showed background noise levels lower than 50 dB(A) will allow senior customers to minimize their vocal effort and to maximize their understanding of conversations, even for those with moderate to severe hearing loss. By setting a limit, it will also keep perceived disturbance low and willingness to spend time and money high among dining patrons.
Early indicators of microbial strain dysbiosis in the human gastrointestinal microbial community of certain healthy humans and hospitalized COVID-19 patients
Authors: Koo Hyunmin , Morrow Casey D.
Published: April 2022

Dysbiosis in the human gastrointestinal microbial community could functionally impact microbial metabolism and colonization resistance to pathogens. To further elucidate the indicators of microbial strain dysbiosis, we have developed an analytic method that detects patterns of presence/absence of selected KEGG metabolic pathways for a selected strain (PKS). Using a metagenomic data set consisting of multiple high-density fecal samples from six normal individuals, we found three had unique PKS for important gut commensal microbes, Bacteroides vulgatus and Bacteroides uniformis, at all sample times examined. Two individuals had multiple shared PKS clusters of B. vulgatus or B. uniformis over time. Analysis of a data set of high-density fecal samples from eight COVID-19 hospitalized patients taken over a short period revealed that two patients had shared PKS clusters for B. vulgatus and one shared cluster for B. uniformis. Our analysis demonstrates that while the majority of normal individuals with no B. vulgatus or B. uniformis strain change over time have unique PKS, in some healthy humans and patients hospitalized with COVID-19, we detected shared PKS clusters at the different times suggesting a slowing down of the intrinsic rates of strain variation that could eventually lead to a dysbiosis in the microbial strain community.
The distribution of manta rays in the western North Atlantic Ocean off the eastern United States
Authors: Farmer Nicholas A. , Garrison Lance P. , Horn Calusa , Miller Margaret , Gowan Timothy , Kenney Robert D. , Vukovich Michelle , Willmott Julia Robinson , Pate Jessica , Harry Webb D. , Mullican Timothy J. , Stewart Joshua D. , Bassos-Hull Kim , Jones Christian , Adams Delaney , Pelletier Nicole A. , Waldron Jordan , Kajiura Stephen
Published: April 2022

In 2018, the giant manta ray was listed as threatened under the U.S. Endangered Species Act. We integrated decades of sightings and survey effort data from multiple sources in a comprehensive species distribution modeling (SDM) framework to evaluate the distribution of giant manta rays off the eastern United States, including the Gulf of Mexico. Manta rays were most commonly detected at productive nearshore and shelf-edge upwelling zones at surface thermal frontal boundaries within a temperature range of approximately 20–30 °C. SDMs predicted highest nearshore occurrence off northeastern Florida during April, with the distribution extending northward along the shelf-edge as temperatures warm, leading to higher occurrences north of Cape Hatteras, North Carolina from June to October, and then south of Savannah, Georgia from November to March as temperatures cool. In the Gulf of Mexico, the highest nearshore occurrence was predicted around the Mississippi River delta from April to June and again from October to November. SDM predictions will allow resource managers to more effectively protect manta rays from fisheries bycatch, boat strikes, oil and gas activities, contaminants and pollutants, and other threats.
Quantitative serology for SARS-CoV-2 using self-collected saliva and finger-stick blood
Authors: Campbell Christopher , Padmanabhan Nikhil , Romero Daniel , Joe Jessica , Gebremeskel Mikias , Manjula Navaratnam , Wohlstadter Noah , Wohlstadter Rachel , Goodwin Paul , Quintero Lillian , Debad Jeff , Sigal George , Wohlstadter Jacob
Published: April 2022

Convenient and widespread serology testing may alter the trajectory of the COVID-19 pandemic. This study seeks to leverage high-throughput, multiplexed serologic assays, which have been adopted as benchmarks for vaccine efficacy, to support large-scale surveys of SARS-CoV-2 immunity using finger-stick blood and/or saliva. Specifically, we optimized MSD’s serology assays, which were analytically validated for serum, to test self-collected finger-stick blood and saliva samples to identify prior infection. We show that these assays can be used with FDA-registered specimen collection devices to obtain quantitative measurements for self-collected samples. First, we show that salivary antibodies are stable without refrigeration or preservatives for at least 5 days. We selected classification thresholds for antibodies against SARS-CoV-2 N, RBD and Spike in finger-stick blood and saliva that provided 98% specificity in a set of individuals without known COVID-19 exposure. Using matched samples, we show that testing of saliva and finger-stick blood equivalently identified individuals with humoral responses to CoV-2 antigens. Moreover, we piloted a simple saliva collection kit that can be used to safely send samples through the mail using written instructions only. This work establishes key parameters to robustly assay self-collected finger-stick blood and saliva using quantitative immunoassays that could support large-scale serology testing.
Hydrogel assisted synthesis of gold nanoparticles with enhanced microbicidal and in vivo wound healing potential
Authors: Batool Zahra , Muhammad Gulzar , Iqbal Muhammad Mudassir , Aslam Muhammad Shahbaz , Raza Muhammad Arshad , Sajjad Noreen , Abdullah Muhammad , Akhtar Naeem , Syed Asad , Elgorban Abdallah M. , Al-Rejaie Salim S. , Shafiq Zahid
Published: April 2022

The present study reports a hydrogel-based sunlight-assisted synthesis of gold nanoparticles (Au NPs) with enhanced antimicrobial and wound healing potential. The hydrogel extracted from the seeds of Cydonia oblonga was used as a reducing and capping agent to synthesize Au NPs for the first time. The as-synthesized Au NPs were characterized for an average size, shape, surface functionalization, antimicrobial, and wound healing capabilities. The cubic and rectangular-shaped Au NPs with an average edge length of 74 ± 4.57 nm depicted a characteristic surface plasmon resonance band at 560 nm. The hydrogel-based Au NPs inhibited the growth of microorganisms in zones with 12 mm diameter. In-vitro experiments showed that a minimum inhibitory concentration of Au NPs (16 µg/mL) was sufficient to mimic the 95% growth of pathogenic microorganisms in 24 h. In vivo treatment of wounds with Au NPs in murine models revealed a 99% wound closure within 5 days. Quantitative PCR analysis performed to decipher the role of Au NPs in enhanced wound healing showed an increase in the expression levels of NANOG and CD-34 proteins.
Quadrupedal water launch capability demonstrated in small Late Jurassic pterosaurs
Authors: Pittman Michael , Kaye Thomas G. , Campos Hebert B. , Habib Michael B.
Published: April 2022

Pterosaurs thrived in and around water for 160 + million years but their take-off from water is poorly understood. A purportedly low floating position and forward centre of gravity barred pterosaurs from a bird-like bipedal running launch. Quadrupedal water launch similar to extant water-feeding birds and bats has been proposed for the largest pterosaurs, such asAnhangueraandQuetzalcoatlus. However, quadrupedal water launch has never been demonstrated in smaller pterosaurs, including those living around the Tethys Sea in the Late Jurassic Solnhofen Lagoon. Using Laser-Stimulated Fluorescence, we singled out aurorazhdarchid specimen MB.R.3531 that alone preserved specific soft tissues among more than a dozen well-preserved Solnhofen pterosaur specimens. These soft tissues pertain to primary propulsive contact surfaces needed for quadrupedal water launch (pedal webbing and soft tissues from an articulated forelimb) that permit robust calculations of its dynamic feasibility without the need to make assumptions about contact areas. A first-principles-based dynamics model of MB.R.3531 reveals that quadrupedal water launch was theoretically feasible and that webbed feet significantly impacted launch performance. Three key factors limiting water launch performance in all pterosaurs are identified, providing a foundation for understanding water launch evolution: available propulsive contact area, forelimb extension range and forelimb extension power about the shoulder.
Retrospective genomics highlights changes in genetic composition of tiger sharks (Galeocerdo cuvier) and potential loss of a south-eastern Australia population
Authors: Manuzzi Alice , Jiménez-Mena Belen , Henriques Romina , Holmes Bonnie J. , Pepperell Julian , Edson Janette , Bennett Mike B. , Huveneers Charlie , Ovenden Jennifer R. , Nielsen Einar E.
Published: April 2022

Over the last century, many shark populations have declined, primarily due to overexploitation in commercial, artisanal and recreational fisheries. In addition, in some locations the use of shark control programs also has had an impact on shark numbers. Still, there is a general perception that populations of large ocean predators cover wide areas and therefore their diversity is less susceptible to local anthropogenic disturbance. Here we report on temporal genomic analyses of tiger shark (Galeocerdo cuvier) DNA samples that were collected from eastern Australia over the past century. Using Single Nucleotide Polymorphism (SNP) loci, we documented a significant change in genetic composition of tiger sharks born between ~1939 and 2015. The change was most likely due to a shift over time in the relative contribution of two well-differentiated, but hitherto cryptic populations. Our data strongly indicate a dramatic shift in the relative contribution of these two populations to the overall tiger shark abundance on the east coast of Australia, possibly associated with differences in direct or indirect exploitation rates.
Establishment of a fish model to study gas-bubble lesions
Authors: Velázquez-Wallraf Alicia , Fernández Antonio , Caballero María José , Arregui Marina , González Díaz Óscar , Betancor Mónica B. , Bernaldo de Quirós Yara
Published: April 2022

Decompression sickness (DCS) is a clinical syndrome caused by the formation of systemic intravascular and extravascular gas bubbles. The presence of these bubbles in blood vessels is known as gas embolism. DCS has been described in humans and animals such as sea turtles and cetaceans. To delve deeper into DCS, experimental models in terrestrial mammals subjected to compression/decompression in a hyperbaric chamber have been used. Fish can suffer from gas bubble disease (GBD), characterized by the formation of intravascular and extravascular systemic gas bubbles, similarly to that observed in DCS. Given these similarities and the fact that fish develop this disease naturally in supersaturated water, they could be used as an alternative experimental model for the study of the pathophysiological aspect of gas bubbles. The objective of this study was to obtain a reproducible model for GBD in fish by an engineering system and a complete pathological study, validating this model for the study of the physiopathology of gas related lesions in DCS. A massive and severe GBD was achieved by exposing the fish for 18 h to TDG values of 108–109%, characterized by the presence of severe hemorrhages and the visualization of massive quantities of macroscopic and microscopic gas bubbles, systemically distributed, circulating through different large vessels of experimental fish. These pathological findings were the same as those described in small mammals for the study of explosive DCS by hyperbaric chamber, validating the translational usefulness of this first fish model to study the gas-bubbles lesions associated to DCS from a pathological standpoint.
Baicalin regulates autophagy to interfere with small intestinal acute graft-versus-host disease
Authors: Sun Xiaoqi , Pisano Michael , Xu Longjin , Sun Fumou , Xu Jie , Zheng Wei , Liu Xiujuan , Zhang Yanyu , Sun Runjie , Cui Xing
Published: April 2022

Acute graft-versus-host disease (aGVHD) is the main complication of and cause of death after allogeneic hematopoietic stem cell transplantation. Baicalin can protect the small intestinal epithelial cells of rats against TNF-α-induced injury and alleviate enteritis-related diarrhea. To verify whether baicalin can protect the small intestinal mucosal barrier by regulating abnormal autophagy and interfering with intestinal aGVHD, a mouse model of aGVHD was established. CB6F1 micewere intravenously injected with a suspension of mononuclear cells derived from BALB/c donor mouse bone marrow and splenic tissue after treatment with 60Co X-rays. After treatment with different doses of baicalin for 15 days, the survival time, serum TNF-α and IL-10 levels, and autophagy markers levels in the intestine were assessed. A cell model of intestinal barrier dysfunction was also used to verify the effect of baicalin. The results showed that baicalin significantly prolonged the survival time, significantly reduced the aGVHD pathology score and clinical score by decreasing the TNF-α level with increasing the IL-10 level compared with the control. Transmission electron microscopy examination showed that baicalin treatment increased the number of autophagic vacuoles and led to the recovery of mitochondrial structures in the intestinal mucosal epithelial cells of mice and in Caco-2 cells. Western blotting results showed that baicalin treatment enhanced autophagy in vivo by regulating the AMPK/mTOR autophagy pathway. Similar results were observed in vitro in Caco-2 cells. Furthermore, the effect of baicalin was reduced after combination treatment with the autophagy inhibitor 3-methyladenine(3-MA). Baicalin can decrease the severity of small intestinal aGVHD by regulating autophagy by influencing imbalances in inflammatory cytokine levels and mucosal barrier damage, thus baicalin may have potential as a new treatment for aGVHD.
The influence of contact lenses with different optical designs on the binocular vision and visual behavior of young adults
Authors: Chen Shyan-Tarng , Tung Hsiao-Ching , Chen Yan-Ting , Tien Chuen-Lin , Yeh Chih-Wei , Lian Jheng-Sin , Cheng Ching-Ying
Published: April 2022

Theoretically, contact lenses change the accommodation and vergence demands of the eyes and directly or indirectly influence binocular vision. The purpose of this study was to investigate the influence of different optical designs of contact lenses on binocular vision and visual behavior among young adults. In this randomized, single-blinded experimental study, visual behavioral performance (VBP) and Ocular Surface Disease Index questionnaires were used for preliminary screening. Nineteen myopic subjects aged 20–26 years (21.59 ± 1.40 years) participated in the study. Baseline values for subjective refraction and binocular visual functions were evaluated. All the subjects were randomly grouped to wear different optical designs of single-vision, progressive, and bifocal contact lenses. Eye examinations were performed on the first day (CL baseline), 2nd week, and 4th week of wearing the lenses. In addition, subjects completed the VBP and visual quality questionnaire again at the end of the examination. Single-vision contact lenses (Lens 1) increased accommodative lag, negative relative accommodation, and distant and near vergence; however, vergence facilities, accommodative facilities, heterophoria, and the comfort and posture balance dimensions in the VBP questionnaire were improved. Progressive contact lenses (Lens 2) reduced the lag of accommodation and near vergence; in addition, vergence facilities and accommodative facilities were also improved. Bifocal contact lenses (Lens 3) affected negative and positive relative accommodation, but vergence facilities and accommodative facilities also progressed. Furthermore, both progressive (Lens 2) and bifocal (Lens 3) contact lenses enhanced overall visual behavioral performance. In terms of visual quality, single-vision contact lenses (Lens 1) were the most comfortable, progressive and bifocal contact lenses reduced distant visual acuity and stability, progressive contact lenses (Lens 2) had more complaints about halos at night, and bifocal contact lens (Lens 3) users were more likely to have double vision. Compared with single-vision contact lenses, progressive and bifocal contact lenses relaxed accommodation, reduced the lag of accommodation, and improved visual behavioral performance. Although the vergence function showed a significant change, it did not show worse trends when wearing contact lenses. Contact lenses with different optical designs have a great influence on binocular vision and visual behavioral performance.
Reliable P wave detection in pathological ECG signals
Authors: Saclova Lucie , Nemcova Andrea , Smisek Radovan , Smital Lukas , Vitek Martin , Ronzhina Marina
Published: April 2022

Accurate automated detection of P waves in ECG allows to provide fast correct diagnosis of various cardiac arrhythmias and select suitable strategy for patients’ treatment. However, P waves detection is a still challenging task, especially in long-term ECGs with manifested cardiac pathologies. Software tools used in medical practice usually fail to detect P waves under pathological conditions. Most of recently published approaches have not been tested on such the signals at all. Here we introduce a novel method for accurate and reliable P wave detection, which is success in both normal and pathological cases. Our method uses phasor transform of ECG and innovative decision rules in order to improve P waves detection in pathological signals. The rules are based on a deep knowledge of heart manifestation during various arrhythmias, such as atrial fibrillation, premature ventricular contraction, etc. By involving the rules into the decision process, we are able to find the P wave in the correct location or, alternatively, not to search for it at all. In contrast to another studies, we use three, highly variable annotated ECG databases, which contain both normal and pathological records, to objectively validate our algorithm. The results for physiological records are Se = 98.56% and PP = 99.82% for MIT-BIH Arrhythmia Database (MITDP, with MITDB P-Wave Annotations) and Se = 99.23% and PP = 99.12% for QT database. These results are comparable with other published methods. For pathological signals, the proposed method reaches Se = 96.40% and PP = 91.56% for MITDB and Se = 93.07% and PP = 88.60% for Brno University of Technology ECG Signal Database with Annotations of P wave (BUT PDB). In these signals, the proposed detector greatly outperforms other methods and, thus, represents a huge step towards effective use of fully automated ECG analysis in a real medical practice.