bluuebunny/crossref_metadata_2025_split huggingface dataset:
First GWAS on Alzheimer’s Disease in Argentina and Chile populations
Authors: Dalmasso Maria Carolina , de Rojas Itziar , Olivar Natividad , Muchnik Carolina , Angel Bárbara , Gloger Sergio , Sanchez Abalos Mariana Soledad , Chacón M.Victoria , Aránguiz Rafael , Orellana Paulina , Cuesta Carolina , Galeano Pablo , Campanelli Lorenzo , Novack Gisela Vanina , Martinez Luis Eduardo , Medel Nancy , Lisso Julieta , Sevillano Zulma , Irureta Nicolás , Castaño Eduardo Miguel , Montrreal Laura , Thoenes Michaela , Hanses Claudia , Heilmann-Heimbach Stefanie , Kairiyama Claudia , Mintz Ines , Villella Ivana , Rueda Fabiana , Romero Amanda , Wukitsevits Nancy , Quiroga Ivana , Gona Cristina ,   EADB, Lambert Jean-Charles , Solis Patricia , Politis Daniel Gustavo , Mangone Carlos Alberto , Gonzalez-Billault Christian , Boada Mercè , Tàrraga Lluís , Slachevsky Andrea , Albala Cecilia , Fuentes Patricio , Kochen Silvia , Brusco Luis Ignacio , Ruiz Agustín , Morelli Laura , Ramírez Alfredo 
Published: January 2023

AbstractINTRODUCTIONGenome-wide association studies (GWAS) are fundamental for identifying loci associated with diseases. However, they require replication in other ethnicities.METHODSwe performed a GWAS on sporadic Alzheimer’s disease (AD) including 540 patients and 852 controls from Argentina and Chile. We explored the variants associated with AD in European GWAS from European Alzheimer’s and Dementia Biobank (EADB) and tested their genetic risk score (GRS) performance in this admixed population.RESULTSwe detectedAPOE4as single genome-wide significant signal (OR=2.93[2.37-3.63], p=2.6×10−23), and fifteen additional suggestive signals previously undetected. Nine of the 83 variants reported by EADB in Europeans were replicated, and the AD-GRS presented similar performance in this Latin population, despite the score diminishes when the Native American ancestry rises.DISCUSSIONwe report the first GWAS on AD in a population from South America. It shows shared genetics that modulate AD risk between the European and the Latin American populations.
Enhanced physician performance when using an artificial intelligence model to detect ischemic stroke on computed tomography
Authors: Hillis James M , Bizzo Bernardo C , Gauriau Romane , Bridge Christopher P , Chin John K , Hakamy Buthaina , Mercaldo Sarah , Conklin John , Dutta Sayon , Mehan William A , Regenhardt Robert W , Singh Ajay , Singhal Aneesh B , Sonis Jonathan D , Succi Marc D , Zhang Tianhao , Xing Bin , Kalafut John F , Dreyer Keith J , Lev Michael H , González R Gilberto 
Published: January 2023

AbstractAcute ischemic stroke can be subtle to detect on non-contrast computed tomography imaging. We show that a novel artificial intelligence model significantly improves the performance of physicians, including ED physicians, neurologists and radiologists, in identifying and quantifying the volume of acute ischemic stroke lesions. This model may lead to improved clinical decision-making for stroke patients.
Post-pandemic modeling of COVID-19: Waning immunity determines recurrence frequency
Authors: Calvetti D , Somersalo E 
Published: January 2023

AbstractThere are many factors in the current phase of the COVID-19 pandemic that signal the need for new modeling ideas. In fact, most traditional infectious disease models do not address adequately the waning immunity, in particular as new emerging variants have been able to brake the immune shield acquired either by previous infection by a different strain of the virus, or by inoculation of vaccines not effective for the current variant. Furthermore, in a post-pandemic landscape in which reporting is no longer a default, it is impossible to have reliable quantitative data at the population level. Our contribution to COVID-19 post-pandemic modeling is a simple mathematical predictive model along the age-distributed population framework, that can take into account the waning immunity in a transparent and easily controllable manner. Numerical simulations show that under static conditions, the model produces periodic solutions that are qualitatively similar to the reported data, with the period determined by the immunity waning profile. Evidence from the mathematical model indicates that the immunity dynamics is the main factor in the recurrence of infection spikes, however, irregular perturbation of the transmission rate, due to either mutations of the pathogen or human behavior, may result in suppression of recurrent spikes, and irregular time intervals between consecutive peaks. The spike amplitudes are sensitive to the transmission rate and vaccination strategies, but also to the skewness of the profile describing the waning immunity, suggesting that these factors should be taken into consideration when making predictions about future outbreaks.
Combinatorial gene inactivation of aldehyde dehydrogenases mitigates aldehyde oxidation catalyzed by resting cells ofE. coliRARE strains
Authors: Butler Neil D. , Anderson Shelby R. , Dickey Roman M. , Nain Priyanka , Kunjapur Aditya M. 
Published: January 2023

AbstractAldehydes are attractive chemical targets given applications as end products in the flavors and fragrances industry and as intermediates due to their propensity for C-C bond formation. While biosynthetic routes to diverse aldehydes have been designed, a common challenge is the stability of these aldehydes in the presence of microbial hosts of engineered pathways. Here, we identify and address unexpected oxidation of a model collection of aromatic aldehydes, including many that originate from biomass degradation, in the presence ofEscherichia colistrains that were engineered to minimize aldehyde reduction. Of heightened interest to us were resting cell conditions as they offer numerous advantages for the bioconversion of toxic metabolites. Surprisingly, when diverse aldehydes are supplemented toE. coliRARE cells grown under aerobic conditions, they remain stabilized on the timescale of days, whereas when these same aldehydes are supplemented to resting cell preparations ofE. coliRARE that had been grown under the same conditions, we observe substantial oxidation. By performing combinatorial inactivation of six candidate aldehyde dehydrogenase genes in theE. coligenome using multiplexed automatable genome engineering (MAGE), we demonstrate that this oxidation can be substantially slowed, with greater than 50% retention of 6 out of 8 aldehydes when assayed 4 hours after their addition. Given that our newly engineered strain exhibitsReducedOxidationAndReduction of aromatic aldehydes, we dubbed it theE. coliROAR strain. Seeking to apply this new strain to resting cell biocatalysis, we compared the capability to synthesis the aldehyde furfural from 2-furoic acid via the carboxylic acid reductase enzyme fromNocardia iowensis. Here, we found that use of ROAR resting cells achieved 2-fold enhancement in furfural titer after 4 h and nearly 9-fold enhancement after 20 h as compared to resting cells of the RARE strain. Moving forward, the use of this strain to generate resting cells should allow aldehyde product isolation, further enzymatic conversion, or chemical reactivity under cellular contexts that better accommodate aldehyde toxicity.HighlightsWhen genes that encode aldehyde reductases are knocked out inEscherichia colistrains, supplemented aldehydes can experience oxidation instead of reduction, which is catalyzed by a different set of endogenous enzymes.Interestingly, we show for a collection of aromatic aldehydes that this oxidation is far more substantial when using resting cell preparations than during aerobic fermentation.We investigate the identity of the responsible genes by performing combinatorial gene inactivation using multiplex automatable genome engineering.The strain that we engineer exhibits Reduced Oxidation And Reduction (theE. coliROAR strain) and thereby enables design of more efficient aldehyde bioconversion processes under diverse formats.
Development, validation, and usage of metrics to evaluate the quality of clinical research hypotheses
Authors: Jing Xia , Zhou Yuchun , Cimino James J. , Shubrook Jay H. , Patel Vimla L. , De Lacalle Sonsoles , Weaver Aneesa , Liu Chang 
Published: January 2023

AbstractObjectivesMetrics and instruments can provide guidance for clinical researchers to assess their potential research projects at an early stage before significant investment. Furthermore, metrics can also provide structured criteria for peer reviewers to assess others’ clinical research manuscripts or grant proposals. This study aimed to develop, test, validate, and use evaluation metrics and instruments to accurately, consistently, and conveniently assess the quality of scientific hypotheses for clinical research projects.Materials and MethodsMetrics development went through iterative stages, including literature review, metrics and instrument development, internal and external testing and validation, and continuous revisions in each stage based on feedback. Furthermore, two experiments were conducted to determine brief and comprehensive versions of the instrument.ResultsThe brief version of the instrument contained three dimensions: validity, significance, and feasibility. The comprehensive version of metrics included novelty, clinical relevance, potential benefits and risks, ethicality, testability, clarity, interestingness, and the three dimensions of the brief version. Each evaluation dimension included 2 to 5 subitems to evaluate the specific aspects of each dimension. For example, validity included clinical validity and scientific validity. The brief and comprehensive versions of the instruments included 12 and 39 subitems, respectively. Each subitem used a 5-point Likert scale.ConclusionThe validated brief and comprehensive versions of metrics can provide standardized, consistent, and generic measurements for clinical research hypotheses, allow clinical researchers to prioritize their research ideas systematically, objectively, and consistently, and can be used as a tool for quality assessment during the peer review process.
Design and Retrospective Cohort Validation of an Algorithm for Surgical Site Infection Surveillance after Hip Replacement Surgery Using Natural Language Processing and Extreme Gradient Boosting
Authors: Flores-Balado Alvaro , Méndez Carlos Castresana , González Antonio Herrero , Gutierrez Raúl Mesón , Arcos Javier , Martín-Ríos María Dolores 
Published: January 2023

AbstractBackgroundSurgical site infection (SSI) surveillance is a labor-intensive endeavor. We present the design and retrospective cohort validation of a multivariable algorithm to screen for SSI in patients undergoing hip replacement surgery, permitting real-time case detection, and reducing the number of clinical records to be reviewed manually.MethodsWe designed a multivariable algorithm using extreme gradient-boosting (XGBoost) to screen for SSI in patients undergoing hip replacement surgery. The development and validation cohort included all healthcare episodes dating from the initial hospital admission for surgery until 90 days after joint replacement (n=19661) between January 2014 and December 2021 from four hospitals in Madrid, Spain. A NLP pipeline was implemented to obtain text variables from free-text fields of the EHR. Clinical, prescription, microbiology, and laboratory variables were also collected. Episodes were split randomly into training (70%) and testing (30%) datasets. Hyperparameters were adjusted to penalize false negatives.FindingsThe presence of positive microbiological cultures, the text variable “infection”, and the prescription of clindamycin were strong markers of SSI. Statistical analysis of the final model indicated a high sensitivity (99·18%) and specificity (91·01%) with an F1-score of 0·32, AUC of 0·989 and accuracy of 91·27%. The model correctly classified 5129 episodes as negative for SSI, with only one case of SSI escaping detection (NPV 99·98%).InterpretationWe conclude that the combination of NLP and extreme gradient boosting is a sensitive tool for SSI surveillance in hip replacement surgery, permitting real-time, semi-automatic surveillance. In practice, our results translate as an 88·95% reduction in the total volume of clinical records to be reviewed manually. To the best of our knowledge, this is the first time that an algorithm incorporating data from multiple sources using NLP and extreme gradient boosting has been developed for orthopedic SSI surveillance.FundingThis study did not receive any funding.
Autophagy mediates cancer cell resistance to doxorubicin induced by the Programmed Death 1/Programmed Death Ligand 1 immune checkpoint axis
Authors: Minassian Lori , Sanwalka Daniel , Paré Jean-François , Macdonald-Goodfellow Shannyn , Sutherland R. Liam , Ghaffari Abdi , Margerum Chelsea L. , Koti Madhuri , Craig Andrew W.B. , Cotechini Tiziana , Siemens D. Robert , Chan Edmond , Graham Charles H. 
Published: January 2023

ABSTRACTBackgroundWhile the Programmed Death 1/Programmed Death Ligand 1 (PD-1/PD-L1) immune checkpoint is an important mechanism of immune evasion in cancer, recent studies have shown that it can also lead to resistance to chemotherapy in cancer cells via reverse signaling. Here we describe a novel mechanism by which autophagy mediates cancer cell drug resistance induced by PD-1/PD-L1 signaling.MethodsHuman and mouse breast cancer cells were treated with recombinant PD-1 (rPD-1) to stimulate PD-1/PD-L1 signaling. Activation of autophagy was assessed by immunoblot analysis of microtubule-associated protein 1A/1B-light chain 3 (LC3)-II and Beclin 1 protein levels, two important markers of autophagy. Moreover, autophagosome formation was assessed in human breast cancer cells using green fluorescence protein (GFP)-tagged LC3. Cells were either treated with Beclin 1 or Atg7 shRNA to assess the role of autophagy on resistance to doxorubicin mediated by PD-1/PD-L1 signalling. We then investigated signaling mechanisms upstream of PD-1/PD-L1 induced autophagy by assessing phosphorylation of extracellular signal-related kinase (ERK).ResultsTreatment of cells with rPD-1 resulted in a time-dependent increase in LC3-II as well as Beclin 1, and an increase in autophagosome formation. Knockdown of Beclin 1 or Atg7 prevented drug resistance induced by PD-1/PD-L1 signaling. Exposure of breast cancer cells to rPD-1 resulted in increased ERK phosphorylation and inhibition of ERK activation abolished autophagy induced by PD-1/PD-L1 signaling.ConclusionsThese studies provide a rationale for the use of PD-1/PD-L1 immune checkpoint blockers and autophagy inhibitors as potential chemosensitizers in cancer therapy.
Establishment of aMycoplasma hyorhinischallenge model in five-week-old piglets
Authors: Földi Dorottya , Nagy Zsófia Eszter , Belecz Nikolett , Szeredi Levente , Földi József , Kollár Anna , Tenk Miklós , Kreizinger Zsuzsa , Gyuranecz Miklós 
Published: January 2023

SummaryMycoplasma hyorhinisis an emerging swine pathogen bacterium with high prevalence worldwide. The main lesions caused are arthritis and polyserositis and the clinical manifestation of the disease may result in significant economic losses due to the decreased weight gain and enhanced medical costs.Our aim was to compare two challenge routes to induceM. hyorhinisinfection using the same clinical isolate. Five-week-old, Choice hybrid pigs were inoculated on two consecutive days by intravenous route (Group IV-IV) or by intravenous and intraperitoneal route (Group IV-IP). Mock infected animals were used as control (Control Group). After challenge, the clinical signs were recorded for 28 days, after which the animals were euthanized. Gross pathological and histopathological examinations, PCR detection, isolation and genotyping of the re-isolatedMycoplasmasp. and culture of bacteria other thanMycoplasmasp. were carried out. ELISA test was used to detect anti-M. hyorhinisimmunoglobulins in the sera of all animals. Pericarditis and polyarthritis were observed in both challenge groups, however the serositis was more severe in Group IV-IV. Statistically significant differences were detected between the challenged groups and the control group regarding the average daily weight gain, pathological scores and ELISA titres. Additionally, histopathological scores in Group IV-IV differed significantly from the scores in the Control Group. All re-isolated strains were the same or a close genetic variant of the original challenge strain. Our results indicate that both challenge routes are suitable for modelling the disease. However, due to the more severe pathological lesions and the more natural-like route of infection in Group IV-IV, the two-dose intravenous challenge is recommended by the authors to induce serositis and arthritis associated withM. hyorhinisinfection.
Activation-induced cytidine deaminase-basedin vivocontinuous evolution system enables rapid protein engineering
Authors: Zhang Xinyu , Liu Zhanzhi , Xu Ying , Rao Deming , Chen Xiaoqian , Li Zhigang , Huang Yan , Wu Jing 
Published: January 2023

ABSTRACTDirected evolution is a powerful tool to modify the properties of proteins. However, due to multi-round and stage combinations, directed evolution usually requires time- and labor-intensive manual intervention, which limits the efficiency of protein modification to some extent. Therefore,in vivocontinuous evolution system is highly preferred because it can couple the multiple rounds and steps of direction evolution with the host growth cycle, leading to the advantages of effort-saving and accuracy. However, the existing types of this kind of systems can not meet the booming demand. Herein, this paper describes promotedEscherichia coli-assisted continuous evolution (PEACE) that allows forin vivocontinuous evolution of target genes. This system polymorphisms the target gene by activation-induced cytidine deaminase-T7 RNA polymerase (AID-T7 PNAP) fusion protein, then it couples the enzymatic properties of desired variants with the expression of antitoxins to achieve efficient growth-coupled screen using the toxin-antitoxin system (TAS). In this study, T7 RNAP was finally employed for validation of PEACE system, and its specificity to the promoter was successfully altered. These results demonstrated the feasibility and further application potential of PEACE.
Primate superior colliculus is engaged in abstract higher-order cognition
Authors: Peysakhovich Barbara , Tetrick Stephanie M. , Silva Alessandra A. , Li Sihai , Zhu Ou , Ibos Guilhem , Johnston W. Jeffrey , Freedman David J. 
Published: January 2023

AbstractCategorization is a fundamental cognitive process by which the brain assigns stimuli to behaviorally meaningful groups. Investigations of visual categorization in primates have identified a hierarchy of cortical areas that are involved in the transformation of sensory information into abstract category representations. However, categorization behaviors are ubiquitous across diverse animal species, even those without a neocortex, motivating the possibility that subcortical regions may contribute to abstract cognition in primates. One candidate structure is the superior colliculus (SC), an evolutionarily conserved midbrain region that, although traditionally thought to mediate only reflexive spatial orienting, is involved in cognitive tasks that require spatial orienting. Here, we reveal a novel role of the primate SC in abstract, higher-order visual cognition. We compared neural activity in the SC and the posterior parietal cortex (PPC), a region previously shown to causally contribute to category decisions, while monkeys performed a visual categorization task in which they report their decisions with a hand movement. The SC exhibits stronger and shorter-latency category encoding than the PPC, and inactivation of the SC markedly impairs monkeys’ category decisions. These results extend SC’s established role in spatial orienting to abstract, non-spatial cognition.
A Systematic Survey of Reversibly Covalent Dipeptidyl Inhibitors of the SARS-CoV-2 Main Protease
Authors: Geng Zhi Zachary , Atla Sandeep , Shaabani Namir , Vulupala Veerabhadra R. , Yang Kai S. , Alugubelli Yugendar R. , Khatua Kaustav , Chen Peng-Hsun Chase , Xiao Jing , Blankenship Lauren R. , Ma Xinyu R. , Vatansever Erol C. , Cho Chia-Chuan , Ma Yuying , Allen Robert , Ji Henry , Xu Shiqing , Liu Wenshe Ray 
Published: January 2023

AbstractSARS-CoV-2 is the coronavirus pathogen of the currently prevailing COVID-19 pandemic. It relies on its main protease (MPro) for replication and pathogenesis. MProis a demonstrated target for the development of antivirals for SARS-CoV-2. Past studies have systematically explored tripeptidyl inhibitors such as nirmatrelvir as MProinhibitors. However, dipeptidyl inhibitors especially those with a spiro residue at their P2 position have not been systematically investigated. In this work, we synthesized about 30 reversibly covalent dipeptidyl MProinhibitors and characterized them onin vitroenzymatic inhibition potency, structures of their complexes with MPro, cellular MProinhibition potency, antiviral potency, cytotoxicity, andin vitrometabolic stability. Our results indicated that MProhas a flexible S2 pocket that accommodates dipeptidyl inhibitors with a large P2 residue and revealed that dipeptidyl inhibitors with a large P2 spiro residue such as (S)-2-azaspiro[4,4]nonane-3-carboxylate and (S)-2-azaspiro[4,5]decane-3-carboxylate have optimal characteristics. One compound MPI60 containing a P2 (S)-2-azaspiro[4,4]nonane-3-carboxylate displayed high antiviral potency, low cellular cytotoxicity, and highin vitrometabolic stability and can be potentially advanced to further preclinical tests.
The spirit of the fruit: contextual and transituational motives for consumption
Authors: Arboleda Ana M. , Manfredi Luciana C. , Marcazzo Giuseppina , Arroyo Christian 
Published: January 2023

PurposeThis research aims to reach meaningful insights into fruit consumption motives. The study articulates contextual motives observed through inherent fruit characteristics (i.e. attributes and benefits) with personal motives that transcend the situation (i.e. emotions and cultural values).Design/methodology/approachThis qualitative study used the focus group technique comprising eight groups of eight to 10 subjects (n = 94). The participants were frequent fresh-fruit consumers.FindingsThe analysis differentiates contextual motives from transituational ones. Older participants are motivated by taking care of health matters. They value fruit as an expression of their determination to take action and care for others. Younger participants are motivated by the experience of pleasure. Fruits have a hedonic value related to joy, being refreshing and tasteful.Practical implicationsResults serve marketers and decision-makers to better target motivations for fruit consumption enhancement. These motivations could be implemented by communicating specific fruit attributes that respond to short-term needs. In the long run, marketers could create fruit consumption campaigns that respond to deeper consumer values.Social implicationsDesigning fruit consumption campaigns aligned with individuals' motives could effectively strengthen the adoption of a healthy lifestyle. This study is helpful from the aspect of a public-policy approach expected to improve public health.Originality/valueConsumers' fruit preference transcends tangible product characteristics to motives aligned with their goals, emotions and human values. This path merges two approaches: contextual motivations and the Means-end chain model. The first approach recognises short-term observable product characteristics, whereas the latter works on long-term values.