bluuebunny/crossref_metadata_2025_split huggingface dataset:
Scale space calibrates present and subsequent spatial learning in Barnes maze in mice
Authors: Tachiki Yuto , Suzuki Yusuke , Kurahashi Mutsumi , Oki Keisuke , Mavuk Özgün , Nakagawa Takuma , Ishihara Shogo , Gyoten Yuichiro , Yamamoto Akira , Imayoshi Itaru 
Published: December 2022

AbstractAnimals including humans are capable of representing different scale spaces from smaller to larger ones. However, most laboratory animals live their life in a narrow range of scale spaces like home-cages and experimental setups, making it hard to extrapolate the spatial representation and learning process in large scale spaces from those in conventional scale spaces. Here, we developed a 3-meter diameter Barnes maze (BM3), then explored whether spatial learning in Barnes maze (BM) is calibrated by scale spaces. In the BM3, mice exhibited lower learning rate compared to a conventional 1-meter diameter Barnes maze (BM1), suggesting that the BM3 requires more trial-and-error and larger computational resources to solve the task than the BM1. Analyzing network structures of moving trajectories, betweenness centrality would contrast spatial learning in a larger scale space with that in a smaller one, as it diverges between the BM1 and the BM3 along with the learning progression. We then explored whether prior learning in either BM scale calibrates subsequent spatial learning in the other BM scale, and found asymmetric facilitation such that the prior learning in the BM3 facilitated the subsequent learning in the BM1, but notvice versa. Network structures of trajectories in the subsequent BM scale were changed by both prior and subsequent BM scale. These results suggest that scale space calibrates both the present and subsequent BM learning. This is the first study to explore and demonstrate scale-dependent spatial learning in Barnes maze in mice.Significance StatementAnimals are capable of representing different scale spaces. However, whether scale space calibrates goal-directed spatial learning remains unclear. The Barnes maze is a well-established experimental paradigm to evaluate spatial learning in rodents. Here, we developed a larger scale 3-meter diameter Barnes maze (BM3) then compared various navigation features in mice between the BM3 and a conventional 1-meter diameter Barnes maze (BM1). We demonstrated that learning on the BM3 required more computational resources than in the BM1, prompting mice to exploit unique navigation patterns. Such learning experiences in the BM3 facilitated subsequent spatial learning in the BM1, but notvice versa. These results suggest that scale space calibrates immediate and subsequent spatial learning.
Survival of people with untreated tuberculosis: effects of time, geography and setting
Authors: Rodriguez Carly A , Leavitt Sarah V , Bouton Tara C. , Horsburgh C Robert , zur Wiesch Pia Abel , Nichols Brooke , Jenkins Helen E , White Laura F 
Published: December 2022

ABSTRACTBackgroundAn estimated 40% of people who developed tuberculosis in 2021 were not diagnosed or treated. Pre-chemotherapy era data are a rich resource on survival for people with untreated TB. We aimed to identify heterogeneities in these data to inform more precise use of them.MethodsWe extracted survival data from pre-chemotherapy era papers reporting TB specific mortality and/or natural recovery data. We used Bayesian parametric survival analysis to model the survival distribution, stratifying by geography (North America versus Europe), time (pre-1930 versus post-1930), and setting (sanitoria versus non-sanitoria).ResultsWe found 12 studies with TB-specific mortality data. Ten-year survival was 69% in North America (95 CI: 54%-81%) and 36% in Europe (95% CI: 10%-71%). Only 38% (95% CI: 18%-63%) of non-sanitorium individuals survived to 10 years compared to 69% (95% CI: 41%-87%) of sanitoria/hospitalized patients. There were no significant differences between people diagnosed pre-1930 and post-1930 (five-year survival pre-1930: 65%; 95% CI: 44%-88% versus post-1930: 72%; 95% CI: 41%-94%).ConclusionsMortality and natural recovery risks vary substantially by location and setting. These heterogeneities need to be considered when using pre-chemotherapy data to make inferences about expected survival of people with undiagnosed TB.
Associations of inflammation-related proteome with demographic and clinical characteristics of people with HIV in South Africa
Authors: Chen Junyu , Hui Qin , Liu Chang , Brijkumar Jaysingh , Edwards Johnathan A. , Ordóñez Claudia E. , Dudgeon Mathew R. , Sunpath Henry , Pillay Selvan , Moodley Pravi , Kuritzkes Daniel R. , Moosa Mohamed Y. S. , Nemoto Tooru , Marconi Vincent C. , Sun Yan V. 
Published: December 2022

AbstractElevated levels of inflammation associated with HIV infection are considered one of the primary causes for the excess burden of age-related morbidity and mortality among people with HIV (PWH). Circulating protein levels can be used to investigate biological pathways contributing to persistent inflammation among PWH. In this study, we profiled 73 inflammation-related protein markers and assessed their associations with chronological age, sex and CD4+ cell count among 87 black South African PWH prior to initiating ART. We identified 1, 1 and 14 inflammatory proteins significantly associated with sex, CD4+ T-cell count, and age respectively among PWH. Twelve out of 14 age-associated proteins have been reported to be associated with age in the general population, and 4 have previously shown significant associations with age for PWH. Furthermore, many of the age-associated proteins such as CST5, CCL23, SLAMF1, MMP-1, MCP-1, and CDCP1 have been linked to chronic diseases such as cardiovascular disease and neurocognitive decline in the general population. We also found a synergistic interaction between male sex and older age accounting for excessive expression of CST5. In conclusion, we found that age may lead to the elevation of multiple inflammatory proteins among PWH. We also demonstrated the potential utility of proteomics for evaluating and characterizing the inflammatory status among PWH.
Polygenic score for sleep duration in relation to risk of Alzheimer’s disease: results from the UK Biobank
Authors: Wong Angel TY , Floud Sarah , Reeves Gillian K , Holmes Michael V , Travis Ruth , van Duijn Cornelia M , Doherty Aiden , Smith-Byrne Karl 
Published: December 2022

AbstractINTRODUCTIONStudies have suggested sleep duration may be associated with Alzheimer’s disease risk, but findings based on self-reported sleep duration are likely to be influenced by reverse causation and residual confounding bias.METHODSA polygenic score (PGS) for device-measured sleep duration was constructed using LDpred2-auto in 77,770 white British UK Biobank participants. We applied the PGS to 264,746 white British participants independent of the sample from which the PGS was developed. We assessed the association of fifths of genetically predicted sleep duration with Alzheimer’s disease risk (1,451 cases/264,746 individuals over median 12.5y of follow-up).RESULTSThe PGS explained ∼2% of variation in device-measured sleep duration. Compared to individuals in the middle fifth of PGS, those in the highest fifth (indicating ∼15 mins/day longer sleep) had a lower risk of Alzheimer’s disease (HR=0.79[95%CI,0.67-0.94]).DISCUSSIONOur results indicate that genetic predisposition to relatively long sleep duration is associated with a lower Alzheimer’s disease risk.
Using Computer Vision and Artificial Intelligence to Track the Healing of Severe Burns
Authors: Ethier Olivier , Chan Hannah O. , Abdolahnejad Mahla , Morzycki Alexander , Tchango Arsene Fansi , Joshi Rakesh , Wong Joshua N. , Hong Collin 
Published: December 2022

AbstractBurn care management includes assessing the severity of burns accurately, especially distinguishing superficial partial thickness (SPT) burns from deep partial thickness (DPT) burns, in the context of providing definitive, downstream treatment. Moreover, the healing of the wound in the sub-acute care setting requires continuous tracking to avoid complications. Artificial intelligence (AI) and computer vision (CV) provide a unique opportunity to build low-cost and accessible tools to classify burn severity and track changes of wound parameters, both in the clinic by physicians and nurses, and asynchronously in the remote setting by the patient themselves. Wound assessments can be achieved by AI-CV using the principles of Image-Guided Therapy (IGT) using high-quality 2D colour images. Wound parameters can include wound 2D spatial dimension and the characterization of wound colour changes which demonstrates physiological changes such as presentation of eschar/necrotic tissue, pustulence, granulation tissue and scabbing. Here we present the development of AI-CV-based Skin Abnormality Tracking Algorithm (SATA) pipeline. Additionally we provide proof-of-concept results on a severe localized burn tracked for a 6-week period in clinic, and an additional 2-week period of home monitoring.
Molecular identification of SARS-CoV-2 variants of concern at urban wastewater treatment plants across South Africa
Authors: Yousif Mukhlid , Rachida Said , Taukobong Setshaba , Ndlovu Nkosenhle , Iwu-Jaja Chinwe , Howard Wayne , Moonsamy Shelina , Mhlambi Nompilo , Gwala Sipho , Levy Joshua I. , Andersen Kristian G. , Scheepers Cathrine , Gottberg Anne von , Wolter Nicole , Ismail Arshad , Suchard Melinda , McCarthy Kerrigan ,   the SACCESS network
Published: December 2022

AbstractThe use of wastewater for SARS-CoV-2 surveillance is a useful complementary tool to clinical surveillance. The aims of this study were to characterize SARS-CoV-2 from wastewater samples, and to identify variants of concern present in samples collected from wastewater treatment plants in South African urban metros from April 2021 to January 2022. A total of 325 samples were collected from 15 wastewater treatment plants. Nucleic acids were extracted from concentrated samples, and subjected to amplicon-based whole genome sequencing. To identify variants of concerns and lineages, we used the Freyja tool (https://github.com/andersen-lab/Freyja), which assigns each sample with the prevalence of each variant present. We also used signature mutation analysis to identify variants in each wastewater treatment site. A heatmap was generated to identify patterns of emerging mutations in the spike gene using Excel conditional formatting. Using the Freyja tool, the Beta variant was detected and became predominate from April to June 2021 followed by the Delta variant and lastly the Omicron variant. Our heatmap approach was able to identify a pattern during the changes of predominate variant in wastewater with the emergence of mutations and the loss of others. In conclusion, sequencing of SARS-CoV-2 from wastewater largely corresponded with sequencing from clinical specimens. Our heatmap has the potential to detect new variants prior to emergence in clinical samples and this may be particularly useful during times of low disease incidence between waves, when few numbers of positive clinical samples are collected and submitted for testing. A limitation of wastewater sequencing is that it is not possible to identify new variants, as variants are classified based on known mutations in clinical strains.
Endogenous oxytocin levels in children with autism: Associations with cortisol levels and oxytocin receptor gene methylation
Authors: Margaux Evenepoel , Matthijs Moerkerke , Nicky Daniels , Viktoria Chubar , Stephan Claes , Jonathan Turner , Bart Vanaudenaerde , Lynn Willems , Johan Verhaeghe , Jellina Prinsen , Jean Steyaert , Bart Boets , Kaat Alaerts 
Published: December 2022

AbstractBackgroundAlterations in the brain’s oxytocinergic system have been suggested to play an important role in the pathophysiology of autism spectrum disorder (ASD), but insights from pediatric populations are sparse.MethodsWe examined salivary oxytocin in school-aged children with (n=80) and without (n=40) ASD (boys/girls 4/1), as well as characterizations of DNA methylation (DNAm) of the oxytocin receptor gene (OXTR). Cortisol levels were also assessed to examine links between the oxytocinergic system and hypothalamic-pituitary-adrenal (HPA) axis signaling.ResultsChildren with ASD displayed altered (diminished) oxytocin levels in the morning, but not in the afternoon, after a mildly stress-inducing social interaction session. Notably, in the control group, higher oxytocin levels were predictive of lower stress-induced cortisol, likely reflective of aprotectivestress-regulatory mechanism for buffering HPA stress activity. In children with ASD, on the other hand, a morereactivestress regulatory mechanism was evident, involving a significant rise in oxytocin levels from the morning to the afternoon upon stress-induced cortisol release, i.e., to reactively cope with heightened HPA activity.Regarding epigenetic modifications, no overall pattern ofOXTRhypo- or hypermethylation was evident in ASD. In control children, a notable association betweenOXTRmethylation and levels of cortisol was evident, likely indicative of a compensatory downregulation ofOXTRmethylation (higher oxytocin receptor expression) in children with heightened HPA axis activity.ConclusionTogether, these observations bear important insights into altered oxytocinergic signaling in ASD, which may aid in establishing relevant biomarkers for diagnostic and/or treatment evaluation purposes targeting the oxytocinergic system in ASD.
Health Outcome Predictive Modelling in Intensive Care Units
Authors: Xian Chengqian , de Souza Camila P. E. , Rodrigues Felipe F. 
Published: December 2022

AbstractThe literature in Intensive Care Units (ICUs) data analysis focuses on predictions of length-of-stay (LOS) and mortality based on patient acuity scores such as Acute Physiology and Chronic Health Evaluation (APACHE), Sequential Organ Failure Assessment (SOFA), to name a few. Unlike ICUs in other areas around the world, ICUs in Ontario, Canada, collect two primary intensive care scoring scales, a therapeutic acuity score called the “Multiple Organs Dysfunctional Score” (MODS) and a nursing workload score called the “Nine Equivalents Nursing Manpower Use Score” (NEMS). The dataset analyzed in this study contains patients’ NEMS and MODS scores measured upon patient admission into the ICU and other characteristics commonly found in the literature. Data were collected between January 1st, 2015 and May 31st, 2021, at two teaching hospital ICUs in Ontario, Canada. In this work, we developed logistic regression, random forests (RF) and neural networks (NN) models for mortality (discharged or deceased) and LOS (short or long stay) predictions. Considering the effect of mortality outcome on LOS, we also combined mortality and LOS to create a new categorical health outcome called LMClass (short stay & discharged, short stay & deceased, or long stay without specifying mortality outcomes), and then applied multinomial regression, RF and NN for its prediction. Among the models evaluated, logistic regression for mortality prediction results in the highest area under the curve (AUC) of 0.795 and also for LMClass prediction the highest accuracy of 0.630. In contrast, in LOS prediction, RF outperforms the other methods with the highest AUC of 0.689. This study also demonstrates that MODS and NEMS, as well as their components measured upon patient arrival, significantly contribute to health outcome prediction in ICUs.
Synthesizing evidence on the impacts of COVID-19 regulatory changes on methadone treatment for opioid use disorder: Implications for U.S. federal policy
Authors: Krawczyk Noa , Rivera Bianca D. , Levin Emily , Dooling Bridget C.E. 
Published: December 2022

AbstractAs the U.S. faces a worsening overdose crisis, improving access to evidence-based treatment for opioid use disorder (OUD) remains a central policy priority. Federal regulatory changes in response to the COVID-19 pandemic significantly expanded flexibilities on take-home doses for methadone treatment for OUD. These changes have fueled critical questions about the impact of new regulations on OUD outcomes, and the potential health impact of permanently integrating these flexibilities into treatment policy going forward. To aide US policy makers as they consider implementing permanent methadone regulatory changes, we conducted a review synthesizing peer-reviewed research evidence on the impact of the COVID-19 methadone-take-home flexibilities on methadone program operations, OUD patient and provider experiences, and patient health outcomes. We interpret this evidence in the context of the federal rulemaking process and discuss avenues by which these important findings can be incorporated and implemented into U.S. substance use treatment policy going forward.
First-Line Systemic Treatment Strategies for unresectable hepatocellular carcinoma : a cost-effectiveness analysis
Authors: wang Liting , Peng Ye , Qin Shuxia , Wan Xiaomin , Zeng Xiaohui , Li Sini , Liu Qiao , Tan Chongqing 
Published: December 2022

AbstractBackgroundOral multikinase inhibitors and immune checkpoint inhibitors (ICIs) are effective in advanced hepatocellular carcinoma (aHCC) but may increase cost. This study compared the cost-effectiveness of oral multikinase inhibitors and ICIs in first-line patients with aHCC.MethodsA three-state Markov model is established to study the cost-effectiveness of drug treatment from the perspective of Chinese payers. The key outcomes were total cost, quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER) in this study.ResultsThe total costs and QALYs of sorafenib, sunitinib, donafenib, lenvatinib, sorafenib plus erlotinib, linifanib, brivanib, sintilimab plus IBI305, and atezolizumab plus bevacizumab were $9070 and 0.25, $9362 and 0.78, $33814 and 0.45, $49120 and 0.83, $63064 and 0.81, $74814 and 0.82, $81995 and 0.82, $74083 and 0.85, $104188 and 0.84, the drug regimen with the lowest ICER was sunitinib ($551 per QALY), followed by lenvatinib($68869 per QALY). For oral multikinase inhibitors, ICER of levatinib, sorafenib plus erlotinib, linifanib and brivanib compared with sunitinib was $779576, $1534347, $1768971, $1963064, respectively. For ICIs, sintilimab plus IBI305 is more cost effective than atezolizumab plus bevacizumab. The model was most sensitive to the price of sorafenib, the utility of PD, and the price of second-line drugs.ConclusionFor oral multikinase inhibitors, the order of possible treatment options is: sunitinib > lenvatinib > sorafenib plus erlotinib > linifanib > brivanib > donafinb. For ICIs, the order of possible treatment options is: sintilimab plus IBI305 > atezolizumab plus bevacizumab.
Simultaneous inhibition of DNA-PK and Polϴ improves integration efficiency and precision of genome editing
Authors: Wimberger Sandra , Akrap Nina , Firth Mike , Brengdahl Johan , Engberg Susanna , Schwinn Marie K. , Slater Michael R. , Lundin Anders , Hsieh Pei-Pei , Li Songyuan , Cerboni Silvia , Sumner Jonathan , Bestas Burcu , Schiffthaler Bastian , Magnusson Björn , Castro Silvio Di , Iyer Preeti , Mohammad Bohlooly-Y , Machleidt Thomas , Rees Steve , Engkvist Ola , Norris Tyrell , Cadogan Elaine , Forment Josep V. , Šviković Saša , Akcakaya Pinar , Taheri-Ghahfarokhi Amir , Maresca Marcello 
Published: December 2022

ABSTRACTGenome editing tools, especially CRISPR/Cas9-based strategies, have transformed biomedical research and opened opportunities for developing curative treatments for genetic diseases. Despite rapid progress, low efficiency of targeted DNA integration and generation of undesired mutations represent major limitations for genome editing applications. Both issues arise from the interplay between the main DNA Double-Strand Break (DSB) repair pathways, Homology-Directed Repair (HDR), Non-Homologous End Joining (NHEJ), and Microhomology-Mediated End Joining (MMEJ). To improve efficiencies of targeted CRISPR-Cas9 genome editing, we screened a large compound library. This led to the discovery of AZD7648, a DNA-dependent protein kinase (DNA-PK) inhibitor and potent enhancer of CRISPR-Cas9-mediated integration. We demonstrated that AZD7648 increased HDR and decreased mutagenic NHEJ repair, thus resulting in improved performance of precise gene editing. Furthermore, we observed additional improvement of integration efficiency by impairing MMEJ repair through DNA polymerase ⊖ (Pol⊖) inhibition. Combined treatment with AZD7648 and Pol⊖ inhibitors (which we named 2iHDR) substantially increased precision of templated insertions, with efficiencies of up to 80%, and nearly no formation of undesired Insertion-Deletions (InDels). Importantly, 2iHDR also decreased Cas9-associated off-target activity, dramatically improving the performance and fidelity of CRISPR-Cas9 gene editing.
Gba1 deletion causes immune hyperactivation and microbial dysbiosis through autophagic defects
Authors: Atilano Magda Luciana , Hull Alexander , Romila Catalina-Andreea , Adams Mirjam L , Wildfire Jacob , Ureña Enric , Dyson Miranda , Ivan-Castillo-Quan Jorge , Partridge Linda , Kinghorn Kerri J. 
Published: December 2022

AbstractMutations in theGBA1gene cause the lysosomal storage disorder Gaucher disease (GD) and are the greatest genetic risk factor for Parkinson’s disease (PD). Communication between gut and brain and immune dysregulation are increasingly being implicated in neurodegenerative disorders such as PD. Here, we show that flies lacking theGba1bgene, the main fly orthologue ofGBA1, display widespread innate immune up-regulation, including gut inflammation and brain glial activation. We also demonstrate gut dysfunction in flies lackingGba1b, with increased intestinal transit time, gut barrier permeability and microbiome dysbiosis. Remarkably, modulating the microbiome ofGba1bknockout flies, by raising them under germ-free conditions, can partially ameliorate lifespan, locomotor and some neuropathological phenotypes. Lastly, direct stimulation of autophagy by rapamycin treatment achieves similar beneficial effects. Overall, our data reveal that the gut microbiome drives systemic immune activation inGba1bknockout flies and that reducing innate immune response activation either by eliminating the microbiota or clearance of immunogens by autophagy may represent potential therapeutic avenues forGBA1-associated neurodegenerative disease.
Lunaemycins, new cyclic hexapeptide antibiotics from the cave moonmilk-dwellerStreptomyces lunaelactisMM109T
Authors: Martinet Loïc , Naômé Aymeric , Rezende Lucas C. D. , Tellatin Déborah , Pignon Bernard , Docquier Jean-Denis , Sannio Filomena , Baiwir Dominique , Mazzucchelli Gabriel , Frédérich Michel , Rigali Sébastien 
Published: December 2022

AbstractStreptomyces lunaelactisstrains have been isolated from moonmilk deposits which are calcium carbonate speleothems used for centuries in traditional medicine for their antimicrobial properties. Genome mining revealed that these strains are a remarkable example of aStreptomycesspecies with huge heterogeneity regarding their content in biosynthetic gene clusters (BGCs) for specialized metabolite production. BGC 28a is one of the cryptic BGCs that is only carried by a subgroup ofS. lunaelactisstrains for whichin silicoanalysis predicted the production of nonribo-somal peptide antibiotics containing the non-proteogenic amino acid piperazic acid (Piz). Comparative metabolomics of culture extracts ofS. lunaelactisstrains either or not holding BGC 28a combined with MS/MS-guided peptidogenomics and1H/13C NMR allowed to identify the cyclic hexapeptide with the amino acid sequence (D-Phe)-(L-HO-Ile)-(D-Piz)-(L-Piz)-(D-Piz)-(L-Piz), called lunaemycin A, as the main compound synthesized by BGC 28a. Molecular networking further identified 18 additional lunaemycins, 14 of them having their structure elucidated by HRMS/MS. Antimicrobial assays demonstrated a huge bactericidal activity of lunaemycins against Gram-positive bacteria including multi-drug resistant clinical isolates. Our work demonstrates how accuratein silicoanalysis of a cryptic BGC can highly facilitate the identification, the structural elucidation, and the bioactivity of its associated specialized metabolites.