bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improved Indicators for Subnational Unmet Antiretroviral Therapy Need in the Health System: Updates to the Naomi Model in 2023
Authors: Esra Rachel , Mmelesi Mpho , Ketlogetswe Akeem T. , Wolock Timothy M. , Howes Adam , Nong Tlotlo , Matlhaga Matshelo Tina , Ratladi Siphiwe , Ramaabya Dinah , Imai-Eaton Jeffrey W. 
Published: January 2024

Background:
Quantifying subnational need for antiretroviral therapy (ART) for HIV is challenging because people living with HIV (PLHIV) access health facilities in areas that may differ from their residence. We defined and demonstrated new indicators for PLHIV treatment needed to guide health system target setting and resource allocation.

Setting:
Botswana.

Methods:
We extended Naomi, a Bayesian small-area model for estimating district-level HIV indicators from national household survey and HIV service delivery data. We used model outputs for ART seeking probabilities in neighboring districts to define the “PLHIV (attending)” indicator representing the estimated number of PLHIV who would seek treatment at health facilities in a district, and “Untreated PLHIV attending” representing gaps in ART service provision. Botswana 2021 district HIV estimates were used to demonstrate new outputs and assess the sensitivity to uncertainty in district population sizes.

Results:
Across districts of Botswana, estimated adult ART coverage in December 2021 ranged 90%–96%. In the capital city Gaborone, there were 50,400 resident PLHIV and 64,200 receiving ART, of whom 24% (95% CI: 20 to 32) were estimated to reside in neighboring districts. Applying ART attendance probabilities gave a “PLHIV attending” denominator of 68,300 and unmet treatment need of 4100 adults (95% CI: 3000 to 5500) for Gaborone health facilities. The facility-based “PLHIV attending” denominator was less-sensitive to fluctuations in district population size assumptions.

Conclusions:
New indicators provided more consistent targets for HIV service provision, but are limited by ART data quality. This challenge will increase as treatment coverage reaches high levels and treatment gaps are smaller.
Impact of Genetic Variants in ABCG2, NR1I2, and UGT1A1 on the Pharmacokinetics of Dolutegravir in Children
Authors: Spector Stephen A. , Brummel Sean S. , Chang Audrey , Wiznia Andrew , Ruel Theodore D. , Acosta Edward P. ,   for IMPAACT P1093 Team
Published: January 2024

Background:
Dolutegravir plasma concentrations and pharmacokinetic (PK) parameters in children display considerable variability. Here, the impact of genetic variants in ABCG2 421C>A (rs2231142), NR1I2 63396 C>T (rs2472677), and UGT1A1 (rs5839491) on dolutegravir PK was examined.

Methods:
Children defined by age and administered dolutegravir formulation had AUC24 at steady state, Cmax and C24h determined. Associations between genetic variants and PK parameters were assessed using the dominant inheritance model.

Results:
The 59 children studied had a median age of 4.6 years, log10 plasma HIV RNA of 4.79 (copies/mm3), and CD4+ lymphocyte count of 1041 cells/mm3; 51% were female. For ABCG2, participants with ≥1 minor allele had lower adjusted mean AUC difference (hr*mg/L) controlling for weight at entry, cohort and sex (−15.7, 95% CI: [−32.0 to 0.6], P = 0.06), and log10Cmax adjusted mean difference (−0.15, 95% CI: [−0.25 to −0.05], P = 0.003). Participants with ≥1 minor allele had higher adjusted mean AUC difference (11.9, 95% CI: [−1.1 to 25.0], P = 0.07). For UGT1A1,poor metabolizers had nonsignificant higher concentrations (adjusted log10Cmax mean difference 11.8; 95% CI: [−12.3 to 36.0], P = 0.34) and lower mean log10 adjusted oral clearance −0.13 L/h (95% CI: [−0.3 to 0.06], P = 0.16). No association was identified between time-averaged AUC differences by genotype for adverse events, plasma HIV RNA, or CD4+ cell counts.

Conclusions:
Dolutegravir AUC24 for genetic variants in ABCG2, NR1l2, and UGT1A1 varied from −25% to +33%. These findings help to explain some of the variable pharmacokinetics identified with dolutegravir in children.
Ictal EEG Source Imaging
Authors: Knowlton Robert C. 
Published: January 2024

Summary:
Ictal EEG source imaging (ESI) is an advancing and growing application for presurgical epilepsy evaluation. For far too long, localization of seizures with scalp EEG has continued to rely on visual inspection of tracings arranged in a variety of montages allowing, at best, rough estimates of seizure onset regions. This most critical step is arguably the weakest point in epilepsy localization for surgical decision-making in clinical practice today. This review covers the methods and strategies that have been developed and tested for the performance of ictal ESI. It highlights practical issues and solutions toward sound implementation while covering differing methods to tackle the challenges specific to ictal ESI—noise and artifact reduction, component analysis, and other tools to increase seizure-specific signal for analysis. Further, validation studies to date—those with both high and low density numbers of electrodes—are summarized, providing a glimpse at the relative accuracy of ictal ESI in all types of focal epilepsy patients. Finally, given the added noninvasive information (greater degree of spatial resolution compared with standard ictal EEG review), the role of ictal ESI and its clinical utility in the presurgical evaluation is discussed.
Enhancing Antibody Language Models with Structural Information
Authors: Barton Justin , Galson Jacob D. , Leem Jinwoo 
Published: January 2024

AbstractThe central tenet of molecular biology is that a protein’s amino acid sequence determines its three-dimensional structure, and thus its function. However, proteins with similar sequences do not always fold into the same shape, and vice-versa, dissimilar sequences can adopt similar folds. In this work, we explore antibodies, a class of proteins in the immune system, whose local shapes are highly unpredictable, even with small variations in their sequence. Inspired by the CLIP method [1], we propose a multimodal contrastive learning approach, contrastive sequence-structure pre-training (CSSP), which amalgamates the representations of antibody sequences and structures in a mutual latent space. Integrating structural information leads both antibody and protein language models to show better correspondence with structural similarity and improves accuracy and data efficiency in downstream binding prediction tasks. We provide an optimised CSSP-trained model, AntiBERTa2-CSSP, for non-commercial use athttps://huggingface.co/alchemab.
Predictive coding in the auditory brainstem
Authors: de Cheveigné Alain 
Published: January 2024

AbstractPredictive coding is an influential concept in sensory and cognitive neuroscience. It is often understood as involving top-down prediction of bottom-up sensory patterns, but the term also applies to feed-forward predictive mechanisms, for example in the retina. Here, I discuss a recent model of low-level predictive processing in the auditory brainstem that is of the feed-forward flavor. Past sensory input from the cochlea is delayed and compared with the current input, via a predictive model that is tuned with the objective of minimizing prediction error. This operation is performed independently within each peripheral channel, with parameters determined from information within that channel. The result is a sensory representation that is invariant to a certain class of interfering sounds (harmonic, quasi-harmonic, or spectrally sparse), thus contributing to Auditory Scene Analysis. The purpose of this paper is to discuss that model in the light of predictive coding, and examine how it might fit within a wider hierarchical model that supports the perceptual representation of objects and events in the world.
Rapid and specific detection of single nanoparticles and viruses in microfluidic laminar flow via confocal fluorescence microscopy
Authors: Drori Paz , Mouhadeb Odelia , Muñoz Gabriel G. Moya , Razvag Yair , Alcalay Ron , Klocke Philipp , Cordes Thorben , Zahavy Eran , Lerner Eitan 
Published: January 2024

AbstractMainstream virus detection relies on the specific amplification of nucleic acids via polymerase chain reaction, a process that is slow and requires extensive laboratory expertise and equipment. Other modalities, such as antigen-based tests, allow much faster virus detection but have reduced sensitivity. In this study, we report the development of a flow virometer for the specific and rapid detection of single nanoparticles based on confocal microscopy. The combination of laminar flow and multiple dyes enable the detection of correlated fluorescence signals, providing information on nanoparticle volumes and specific chemical composition properties, such as viral envelope proteins. We evaluated and validated the assay using fluorescent beads and viruses, including SARS-CoV-2. Additionally, we demonstrate how hydrodynamic focusing enhances the assay sensitivity for detecting clinically-relevant virus loads. Based on our results, we envision the use of this technology for clinically relevant bio-nanoparticles, supported by the implementation of the assay in a portable and user-friendly setup.
Orally delivered biodegradable targeted inflammation resolving pectin-coated nanoparticles induce anastomotic healing post intestinal surgery
Authors: Lee Jong Hyun , Reischl Stefan , Walter Robert Leon , Vieregge Vincent , Weber Marie-Christin , Xu Runxin , Chen Hao , Kasajima Atsuko , Friess Helmut , Neumann Philipp-Alexander , Kamaly Nazila 
Published: January 2024

ABSTRACTAlthough medical treatment is sucessful in most cases in patients with inflammatory bowel diseases (IBD), a percentage of patients require surgical resection of diseased bowel segments at least once in their lifetime. Healing success of the intestinal anastomosis is at high risk, especially in presence of acute inflammation. Failure of anastomotic healing is a life-threatening complication and causes high socioeconomic costs. Common anti-inflammatory medications can have detrimental effects on wound healing. Thus, targeted perioperative therapeutics supporting anastomotic healing during colitis are an urgent medical need. Here, we develop a novel basal membrane targeted controlled release, pectin-coated polymeric nanoparticle (NP) encapsulating a highly potent inflammation resolving mediator, the peptide Ac2-26. These NPs can undergo gastric passage and facilitate localized release of the therapeutic peptide in the colon via degradation of their pectin-chitosan coating by microbial pectinases, which subsequently exposes a collagen IV targeted NP surface, allowing for further binding and retention of the NPs at the intestinal wound. To test these NPs, we used a murine surgical model combining the formation of an intestinal anastomosis with the induction of a preoperative colitis by dextran sodium sulfate. In this model, perioperative administration of pectin-chitosan coated NPs containing Ac2-26 (P-C-Col IV-Ac2-26-NP) led to the reduction of colitis activity in the postoperative phase. Macroscopic wound closure was improved by P-C-Col IV-Ac2-26-NP treatment as evaluated by endoscopy and intraabdominal adhesion scoring. Microscopic analysis of the healing process showed an improved semiquantitative healing score in the treatment group. In this proof-of-concept study we demonstrate that novel P-C-Col IV-Ac2-26-NP could be a promising and clinically feasible perioperative treatment strategy for IBD patients.TOC graphic
ExploreTurns: A web tool for the exploration, analysis, and classification of beta turns and structured loops in proteins; application to beta-bulge and Schellman loops, Asx helix caps, beta hairpins and other hydrogen-bonded motifs
Authors: Newell Nicholas E. 
Published: January 2024

AbstractThe most common type of protein secondary structure after the alpha helix and beta sheet is the four-residue beta turn, which plays many key structural and functional roles. Existing tools for the study of beta turns operate in backbone dihedral-angle (Ramachandran) space, which presents challenges for the visualization, comparison and analysis of the wide range of turn conformations. In this work, a new turn-local coordinate system and structural alignment, together with a set of geometric descriptors for turn backbone shape, are incorporated into ExploreTurns, a web facility for the exploration, analysis, geometric tuning and retrieval of beta turns and their contexts which combines the advantages of Ramachandran- and Euclidean-space representations. Due to the prevalence of beta turns in proteins, this facility, supported by its interpreter for a new general nomenclature which classifies H-bonded loop motifs and beta hairpins, serves as an exploratory browser and analysis tool for most loop structure. The tool is applied to the detection of new H-bonded loops, including short and “double” Schellman loops, a large family of beta-bulge loops with a range of geometries and H-bond topologies, and other motifs. Other applications presented here include the mapping of sequence preferences in Asx helix N-caps and an investigation of the depth dependence of beta-turn geometry. ExploreTurns, available atwww.betaturn.com, should prove useful in research, education, and applications such as protein design, in which an enhanced Euclidean-space picture of turn and motif structure and the ability to identify and tune structures suited to particular requirements may improve performance.
Valine Catabolism Drives Bioenergetic and Lipogenic Fuel Plasticity in Prostate Cancer
Authors: Bidgood Charles L. , Philp Lisa K. , Rockstroh Anja , Lehman Melanie , Nelson Colleen C. , Sadowski Martin C. , Gunter Jennifer H. 
Published: January 2024

AbstractMetabolic reprogramming is a hallmark of cancer and fundamental for disease progression. The remodelling of oxidative phosphorylation and enhanced lipogenesis are key characteristics of prostate cancer (PCa). Recently, succinate-dependent mitochondrial reprogramming was identified in high-grade prostate tumours with upregulation of enzymes associated with branched-chain amino acid (BCAA) catabolism. We hypothesised that the degradation of BCAAs, particularly valine may play a critical role in anapleurotic refuelling of the mitochondrial succinate pool. Through suppression of valine availability, we report strongly reduced lipid content despite compensatory upregulation of fatty acid uptake, indicating valine is an important lipogenic fuel in PCa. Inhibition of the enzyme 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) also resulted in selective inhibition of cellular proliferation of malignant but not benign prostate cells and impaired succinate production. In combination with a comprehensive multi-omic investigation of patient and cell line data, our work highlights a therapeutic target for selective inhibition of metabolic reprogramming in PCa.
Long-Term Monolayer Cultivation Captures Homeostatic and Regenerative Features of Human Colonic Epithelial Cells
Authors: Fujii Satoru , Wang Yi , Meng Shanshan , Musich Ryan J. , Espenschied Scott T. , Newhall Kevin , Han Yi , Sekiguchi Shuhei , Matsumoto Ryoma , Ciorba Matthew A. , Sibley L. David , Okamoto Ryuichi , Stappenbeck Thaddeus S. 
Published: January 2024

SUMMARYWhile organoid culture technique has significantly advanced research on intestinal epithelial cells (IECs), reproducing the homeostatic and regenerative processes of human IECs in vitro remains challenging. We previously established a unique long-term 2-dimensional (2D) cultivation for mouse IECs using the air-liquid interface (ALI) technique, successfully recapitulating homeostasis and regeneration. Here, applying this to human IECs, we developed a long-term, self-organizing 2D cultivation for human IECs. During the culture, we observed a dynamic transition in cellular shape from squamous to columnar, resembling in vivo regeneration. RNA sequencing indicated that intestinal stem cells (SCs) with canonical SC markers like LGR5 may play a main role in both homeostasis and regeneration. Moreover, we identified minor populations, including deep crypt secretory (DCS)-like cells, CA7-positive cells, and non-canonical Goblet cells, previously overlooked in vitro. This novel technique holds promise for not only broadening our understanding of homeostasis, regeneration, and the functions of minor populations as well as SCs in human intestinal mucosa, but also facilitating future studies such as analyzing host-microbe interactions.
Structural Basis of Conformational Dynamics in the PROTAC-Induced Protein Degradation
Authors: Zhao Hongtao 
Published: January 2024

AbstractPronounced conformational dynamics is unveiled upon analyzing multiple crystal structures of the same proteins recruited to the same E3 ligases by PROTACs, and yet, is largely permissive for targeted protein degradation due to the intrinsic mobility of E3 assemblies creating a large ubiquitylation zone. Mathematical modelling of ternary dynamics on ubiquitylation probability confirms the experimental finding that ternary complex rigidification need not correlate with enhanced protein degradation. Salt bridges are found to prevail in the PROTAC-induced ternary complexes, and may contribute to a positive cooperativity and prolonged half-life. The analysis highlights the importance of presenting lysines close to the active site of the E2 enzyme while constraining ternary dynamics in PROTAC design to achieve high degradation efficiency.Abstract Figure
Macrophage- and CD4+T cell-derived SIV differ in glycosylation, infectivity and neutralization sensitivity
Authors: Karsten Christina B. , Buettner Falk F.R. , Cajic Samanta , Nehlmeier Inga , Roshani Berit , Klippert Antonina , Sauermann Ulrike , Stolte-Leeb Nicole , Reichl Udo , Gerardy-Schahn Rita , Rapp Erdmann , Stahl-Hennig Christiane , Pöhlmann Stefan 
Published: January 2024

AbstractThe human immunodeficiency virus (HIV) envelope protein (Env) mediates viral entry into host cells and is the primary target for the humoral immune response. Env is extensively glycosylated, and these glycans shield underlying epitopes from neutralizing antibodies. The glycosylation of Env is influenced by the type of host cell in which the virus is produced. Thus, HIV is distinctly glycosylated by CD4+T cells, the major target cells, and macrophages. However, the specific differences in glycosylation between viruses produced in these cell types have not been explored at the molecular level. Moreover, the impact of these differences on viral spread and neutralization sensitivity remains largely unknown. To address these questions, we employed the simian immunodeficiency virus (SIV) model. Glycan analysis revealed higher relative levels of oligomannose-typeN-glycans in SIV from CD4+T cells (T-SIV) compared to SIV from macrophages (M-SIV), and the complex-typeN-glycans profiles differed between the two viruses. Notably, M-SIV demonstrated greater infectivity than T-SIV, even when accounting for Env incorporation, suggesting that host cell-dependent factors influence infectivity. Further, M-SIV was more efficiently disseminated by HIV binding cellular lectins. We also evaluated the influence of cell type-dependent differences on SIV’s vulnerability to carbohydrate binding agents (CBAs) and neutralizing antibodies. T-SIV demonstrated greater susceptibility to mannose-specific CBAs, possibly due to its elevated expression of oligomannose-typeN-glycans. In contrast, M-SIV exhibited higher susceptibility to neutralizing sera in comparison to T-SIV. These findings underscore the importance of host cell-dependent attributes of SIV, such as glycosylation, in shaping both infectivity and the potential effectiveness of intervention strategies.
PCA-Plus: Enhanced principal component analysis with illustrative applications to batch effects and their quantitation
Authors: Zhang Nianxiang , Casasent Tod D. , Casasent Anna K. , Kumar Shwetha V. , Wakefield Chris , Broom Bradley M. , Weinstein John N. , Akbani Rehan 
Published: January 2024

ABSTRACTBackgroundPrincipal component analysis (PCA), a standard approach to analysis and visualization of large datasets, is commonly used in biomedical research for detecting similarities and differences among groups of samples. We initially used conventional PCA as a tool for critical quality control of batch and trend effects in multi-omic profiling data produced by The Cancer Genome Atlas (TCGA) project of the NCI. We found, however, that conventional PCA visualizations were often hard to interpret when inter-batch differences were moderate in comparison with intra-batch differences; it was also difficult to quantify batch effects objectively. We, therefore, sought enhancements to make the method more informative in those and analogous settings.ResultsWe have developed algorithms and a toolbox of enhancements to conventional PCA that improve the detection, diagnosis, and quantitation of differences between or among groups, e.g., groups of molecularly profiled biological samples. The enhancements include (i) computed group centroids; (ii) sample-dispersion rays; (iii) differential coloring of centroids, rays, and sample data points; (iii) trend trajectories; and (iv) a novel separation index (DSC) for quantitation of differences among groups.ConclusionsPCA-Plus has been our most useful single tool for analyzing, visualizing, and quantitating batch effects, trend effects, and class differences in molecular profiling data of many types: mRNA expression, microRNA expression, DNA methylation, and DNA copy number. An early version of PCA-Plus has been used as the central graphical visualization in our MBatch package for near-real-time surveillance of data for analysis working groups in more than 70 TCGA, PanCancer Atlas, PanCancer Analysis of Whole Genomes, and Genome Data Analysis Network projects of the NCI. The algorithms and software are generic, hence applicable more generally to other types of multivariate data as well. PCA-Plus is freely available in a down-loadable R package at our MBatch website.
Cognitive and molecular characterization of the Ts66Yah murine model of Down syndrome: deepening on hippocampal changes associated with genotype and aging
Authors: Lanzillotta Chiara , Baniowska Monika Rataj , Prestia Francesca , Sette Chiara , Nalesso Valérie , Perluigi Marzia , Barone Eugenio , Duchon Arnaud , Tramutola Antonella , Herault Yann , Di Domenico Fabio 
Published: January 2024

ABSTRACTDown syndrome (DS) is the most common condition with intellectual disability and is caused by trisomy ofHomo sapienschromosome 21 (HSA21). The increased dosage of genes on HSA21 is the cause for the initial neurodevelopmental disorder and for further development of cognitive decline, however the molecular mechanisms promoting brain pathology along ageing are still missing. One of the major challenges in the study of DS is the lack of reliable murine model able to accurately replicate genotypic and phenotypic aspects observed in humans along ageing. Preclinical studies in DS were pioneered using the Ts65Dn murine model, which despite its genetic limitations, has been extremely helpful in characterising the progression of brain degeneration. The novel Ts66Yah model represents an evolution of the Ts65Dn, with phenotypes only induced by trisomic HSA21 homologous genes, closer to human DS condition. In this study, we confirmed the behavioural features of Ts66Yah mice with improvement in the detection of spatial memory defects and also a new anxiety-related phenotype. The molecular characterisation of Ts66Yah demonstrated the aberrant regulation of redox balance, proteostasis, stress response, metabolic pathways, programmed cell death and synaptic plasticity. Intriguingly, the genotype-related alterations of those pathways occur early promoting the alteration of brain development and the onset of a condition of premature aging. Overall, data collected in Ts66Yah provide novel and consolidated insights, devoid of genome bias, concerning trisomy-driven processes that contribute to brain pathology in conjunction with aging. This, in turn, aids in bridging the existing gap in comprehending the intricate nature of DS phenotypes.