bluuebunny/crossref_metadata_2025 huggingface dataset:
The Semantics of Clause Linking A Cross-Linguistic Typology
Authors: Dixon R M W , Aikhenvald Alexandra Y
Published: November 2023

This book is a cross-linguistic examination of the different grammatical means languages employ to represent a general set of semantic relations between clauses. The investigations focus on ways of combining clauses other than through relative and complement clause constructions. These span a number of types of semantic linking. Three, for example, describe varieties of consequence - cause, result, and purpose - which may be illustrated in English by, respectively: Because John has been studying German for years, he speaks it well; John has been studying German for years, thus he speaks it well; and John has been studying German for years, in order that he should speak it well. Syntactic descriptions of languages provide a grammatical analysis of clause types. The chapters in this book add the further dimension of semantics, generally in the form of focal and supporting clauses, the former referring to the central activity or state of the biclausal linking; and the latter to the clause attached to it. The supporting clause may set out the temporal milieu for the focal clause or specify a condition or presupposition for it or a preliminary statement of it, as in Although John has been studying German for years (the supporting clause), he does not speak it well (the focal clause). Professor Dixon's extensive opening discussion is followed by fourteen case studies of languages ranging from Korean and Kham to Iquito and Ojibwe. The book's concluding synthesis is provided by Professor Aikhenvald.
The Semantics of Clause Linking in Manambu
Authors: Aikhenvald Alexandra Y
Published: November 2023

Linking clauses in Manambu involves a variety of means, including clause chaining, speech reports, conjoined dependent clauses, nominalizations, connectives, and apposition. Many clause linking techniques are polysemous; and some can be disambiguated if necessary. I start with an outline of typological features of Manambu, focusing on the parameters relevant for clause linking. I then turn to the clause linking techniques and their correlations with semantic types. The last section contains a brief summary.
The Semantics of Clause Linking in Mali
Authors: Stebbins Tonya N
Published: November 2023

Clause linking in Mali is striking for the fact that there are no strategies of nominalization, no contrasts between finite and non-finite verbs, and no switch-reference marking, which would invite an analysis of clause linking in terms of subordination or make it possible to speak in terms ofstructurally distinctive main versus non-main clauses. Nevertheless there are functional differences between clauses, and a rich range of semantic contrasts in relations between clauses may be marked by grammatical words or clitics within the clause, generally in initial position. In the main these relations are marked by specialized particles but adverbs also play a significant role in organizing the semantic relations between clauses.
Theoretical methods for analysing biosensor performance
Authors: Eddowes Mark J
Published: November 2023

Theory, along with experiment, forms a vital part of a practical scientific approach. Though perhaps redundant on its own, theory enables the most efficient use of time spent performing experiments. This is important since experiments are often difficult and time consuming and will not always be successful. Proper use of theory assists effective planning of experiments and enables the researcher to gain the maximum amount of information from each experiment performed. In applied work, such as biosensor research and development, theory used in a predictive manner can identify which, of perhaps a multitude of approaches, is most likely to yield the desired result. It is therefore important that proper consideration be given to theory and its application to the solution of practical problems involving real systems. The aim of this chapter is to demonstrate how, in practice, the problem of the provision of a theoretical description of biosensors may be approached and illustrate this approach by way of some examples commonly encountered.
Genetics and molecular biology
Authors: Wren B W , Mullany P , Lamb F I
Published: November 2023

Genetic and molecular techniques used for the study of anaerobes are essentially the same as those used for aerobes. The major obstacles to the molecular characterization of anaerobes arc their stringent growth requirements and the lack of appropriate host-vector systems for the genetic manipulation of cloned determinants.
Methods for the study of anaerobic microflora
Authors: Drasar B S , Roberts April K
Published: November 2023

This chapter is about the study of the microbial ecology of the bacteria associated with the human body. This is among the most intensively studied of microbial habitats and includes a number of distinct ecosystems of particular interest. Attention has focused on the microbial flora of the mouth (1), the skin (2), the genital tract (3), and the intestine (4 6). These themes have on occasion been drawn together in more systematic treatments of the whole system (7-9). Systematic studies of animals other than man have concentrated on the bovine rumen (10, l l). Many studies have been concerned to describe these habitats in terms of their bacterial inhabitants while others have concentrated on examining the metabolic potential of the bacterial microflora and its impact on the host (12, 13).
The combinatorial approach
Authors: Cohen Fred E , Presnell scott R
Published: November 2023

With the advent of protein X-ray crystallography in the 1950s and the more recent use of multidimensional NMR spectroscopy, biologists have become familiar with the detailed organization of protein structures at the atomic level. These structures have fundamentally changed our understanding of mechanistic enzymology and molecular recognition in the immune system. More recently, the ability of structural studies to influence drug discovery and design has become clear (1). In spite of these advances, the rate of pro tein sequence determination via DNA sequencing vastly exceeds the rate of structure determination. How can this gap between sequence and structure be bridged? With an increase in the number of proteins of known structure, the likelihood that a new sequence will be similar to a known structure increases. Currently, ∼20% of the sequences identified in genome sequencing efforts are related to well-characterized proteins (2).
Recent developments in affinity separation technologies
Authors: Mohan Sudesh B , Lyddiatt Andrew
Published: November 2023

Since the innovative work of Porath et al. (1) in the 1960s, and the seminal texts of Lowe and Dean (2) and Dean et al. (3), the technologies of affinity separation have become widely accepted-perhaps now to the extent of being taken for granted. Practitioners range widely from laboratories interested in the isolation of bioactive probes and tools for biological research, to large manufacturing plants active in the production of diagnostic and therapeutic agents.
Immunoaffinity arid IgG receptor technologies
Authors: Godfrey Miguel A J
Published: November 2023

Historically, affinity chromatographic techniques have exploited the presence of naturally occurring biospecific interactions found in nature. Perhaps the most useful of these to biomedical science is the binding of antibodies to antigens, especially as the presence and binding specificities of antibodies may be manipulated by selective operator intervention. This chapter aims to introduce the laboratory scientist to affinity chromatographic methods of purifying antibodies and to demonstrate the use of immobilized antibodies as a tool in preparative affinity chromatography.
Designer affinity purifications of recombinant proteins
Authors: Sharma Satish K
Published: November 2023

During the last five years, tailoring recombinant proteins to facilitate their purification has proven to be a very useful strategy in recombinant DNA technology. DNA encoding peptide or protein tags (also called, among other names, affinity tails, cleavable linkers, and marker sequences) is attached to the gene of interest at its 5’ or 3’ end. The resulting gene fusions are expressed in a host and the encoded recombinant protein can be isolated from contaminating host proteins based on properties of the engineered tag. A schematic representation of this genetic approach, called designer affinity purification, is shown in Figure 1.
Counting integral numbers of residues by chemical modification
Authors: Hollecker Michelle
Published: November 2023

Proteins have integral numbers of each of the 20 amino adds, hut all the currently accepted methods of determining this number measure only a nonintegral ratio of moles of amino acid per mole of protein. This value is rarely found to be close to an integer, due to experimental error and uncertainty about the molecular weight of the protein (1-3).
Analysis of protein conformation by gel electrophoresis
Authors: Goldenberg David P
Published: November 2023

Electrophoresis through polyacrylamide gels (PAGE) is one of the simplest and most commonly used methods for characterizing protein molecules (1,2). As described in Chapter l, gel electrophoresis in the presence of the detergent sodium dodecyl sulfate (SOS) is widely used to determine the molecular weights of polypeptides. Electrophoretic methods can also be used to determine the isoelectric point of a protein and to count the number of reactive groups (Chapter 6). This chapter describes the use of non-denaturing, or ‘native’, gel electrophoresis to analyse the conformations of proteins as well as a method for studying protein folding-unfolding reactions using gels containing transverse gradients of denaturants.
How to determine the molar absorbance coefficient of a protein
Authors: Pace C Nick , Schmid Franz X
Published: November 2023

It is frequently essential to know the concentration of a protein solution. Protein concentrations are most conveniently and accurately measured by absorbance spectroscopy.
The design, synthesis, and characterization of molecular mimetics
Authors: Matthews Ian T W
Published: November 2023

This chapter is concerned with practical approaches to the design, synthesis, and characterization of synthetic organic compounds that attempt to mimic bioactive natural molecules. The chapter will concentrate on the preparation of peptoids as peptidomimetics and discuss the design and synthesis of other amino acid/ peptide surrogates.
Glutathione Transferase Photoaffinity Labeling Displays GST Induction by Safeners and Pathogen Infection
Authors: Font Farre Maria , Brown Daniel , König Maurice , Killinger Brian J , Kaschani Farnusch , Kaiser Markus , Wright Aaron T , Burton Jonathan , van der Hoorn Renier A L
Published: November 2023

Glutathione transferases (GSTs) represent a large and diverse enzyme family involved in the detoxification of small molecules by glutathione conjugation in crops, weeds and model plants. In this study, we introduce an easy and quick assay for photoaffinity labeling of GSTs to study GSTs globally in various plant species. The small-molecule probe contains glutathione, a photoreactive group and a minitag for coupling to reporter tags via click chemistry. Under UV irradiation, this probe quickly and robustly labels GSTs in crude protein extracts of different plant species. Purification and mass spectrometry (MS) analysis of labeled proteins from Arabidopsis identified 10 enriched GSTs from the Phi(F) and Tau(U) classes. Photoaffinity labeling of GSTs demonstrated GST induction in wheat seedlings upon treatment with safeners and in Arabidopsis leaves upon infection with avirulent bacteria. Treatment of Arabidopsis with salicylic acid (SA) analog benzothiadiazole (BTH) induces GST labeling independent of NPR1, the master regulator of SA. Six Phi- and Tau-class GSTs that are induced upon BTH treatment were identified, and their labeling was confirmed upon transient overexpression. These data demonstrate that GST photoaffinity labeling is a useful approach to studying GST induction in crude extracts of different plant species upon different types of stress.
Real-world comparative study of the efficacy of Janus kinase inhibitors in patients with rheumatoid arthritis: the ANSWER cohort study
Authors: Hayashi Shinya , Tachibana Shotaro , Maeda Toshihisa , Yamashita Mai , Shirasugi Iku , Yamamoto Yuzuru , Yamada Hirotaka , Okano Takaichi , Nishimura Keisuke , Ueda Yo , Jinno Sadao , Saegusa Jun , Yamamoto Wataru , Murata Koichi , Fujii Takayuki , Hata Kenichiro , Yoshikawa Ayaka , Ebina Kosuke , Etani Yuki , Yoshida Naofumi , Amuro Hideki , Hashimoto Motomu , Hara Ryota , Katayama Masaki , Okano Tadashi , Kuroda Ryosuke
Published: November 2023

Objective

This multicentre, retrospective study compared the efficacy and safety of tofacitinib, baricitinib, peficitinib and upadacitinib in real-world clinical settings after minimizing selection bias and adjusting the confounding patient characteristics.

Method

The 622 patients were selected from the ANSWER cohort database and treated with tofacitinib (TOF), baricitinib (BAR), peficitinib (PEF) or upadacitinib (UPA). The patient’s background was matched using propensity score-based inverse probability of treatment weighting (IPTW) among four treatment groups. The values of Clinical Disease Activity Index (CDAI), C-reactive protein (CRP), and modified Health Assessment Questionnaire (mHAQ) after drug initiation and the remission or low disease activity (LDA) rates of CDAI at 6 months after drug initiation were compared among the four groups. Further, the predictive factor for TOF and BAR efficacy was analysed.

Results

The retention and discontinuation rates until 6 months after drug initiations were not significantly different among the four JAK inhibitors treatment groups. Mean CDAI value, CDAI remission rate, and CDAI-LDA rate at 6 months after drug initiation were not significantly different among treatment groups. Baseline CDAI (TOFA: OR 1.09, P < 0.001; BARI: OR 1.07, P < 0.001), baseline CRP (TOFA: OR 1.32, P = 0.049), baseline glucocorticoid dose (BARI: OR 1.18, 95% CI 1.01–1.38, P = 0.035), a number of previous biological or targeted synthetic disease-modifying antirheumatic drugs (biological/targeted synthetic DMARDs) (BARI: OR 1.36, P = 0.004) were predictive factors for resistance to CDAI-LDA achievement to JAK inhibitor treatment.

Conclusion

The efficacy and safety of TOF, BAR, PEF and UPA were not significantly different for the treatment of patients with rheumatoid arthritis.
Correlations between inflammatory cytokine levels and degree of pigmentation in acral melanomas
Authors: Kim Hong Euy , Kim Jinkyeong , Park Hyung Keon , Lee Jee-Bum , Yun Sook Jung
Published: November 2023

Cutaneous melanoma, a highly aggressive skin tumor, is characterized by complex signaling pathways in terms of its pathogenesis and progression. Although the degree of pigmentation in melanoma determines its progression, metastasis, and prognosis, its association with inflammatory cytokines remains unclear. Thus, we evaluated the associations between melanoma pigmentation and plasma levels of inflammatory cytokines; furthermore, we investigated the potential variations in this relationship across the primary anatomic sites of melanoma. We enrolled patients with cutaneous melanoma who visited Chonnam National University Hwasun Hospital between January 2021 and December 2021. The anatomical sites of melanoma were categorized as acral and non-acral sites. The degree of pigmentation was quantified using computer software. In total, nine inflammatory cytokines were analyzed, including interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α). This study included 80 melanoma patients. Of these, 53 had acral melanoma and 27 had non-acral melanoma. Overall, plasma concentrations of IL-2, IL-4, IL-5, GM-CSF, and IFN-γ demonstrated significant correlations with diminished pigmentation. Furthermore, in the acral melanoma patients group, plasma concentrations of IL-2, IL-4, IL-5, GM-CSF, IFN-γ, and TNF-α revealed significant correlations with diminished pigmentation. Our results reveal significant associations between melanoma pigmentation and various cytokine levels, particularly in acral melanoma patients; these associations can be influenced by factors related to acral melanoma, such as physical stress or trauma. These correlations may also provide directions for the treatment of acral melanoma.
Comparison of short-term outcomes between robotic and laparoscopic liver resection: a meta-analysis of propensity score-matched studies
Authors: Gao Feng-wei , Zhao Xin , Xie Qing-yun , Jiang Kang-yi , Mao Tian-yang , Yang Man-yu , Wu Hong
Published: November 2023

Objective:

This meta-analysis aimed to compare short-term outcomes between robotic liver resection (RLR) and laparoscopic liver resection (LLR) using data collected from propensity score-matched studies (PSM).

Methods:

The PubMed, Cochrane Library, and Embase databases were searched to collect propensity score-matched studies comparing RLR and LLR. Relevant data were extracted and analyzed. Odds ratios (OR) and standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated using fixed-effect or random-effect models. Meta-regression analysis was performed for primary outcome measures. Subgroup analyses and sensitivity analyses were performed for outcomes exhibiting high heterogeneity. Quality of evidence was evaluated using the Grading of Recommendations, Assessment, Development and Evaluation framework.

Results:

Twenty-two propensity score-matched studies were included to comprise 5272 patients (RLR group, 2422 cases; LLR group, 2850 cases). Intraoperative blood loss (SMD=−0.31 mL, 95% CI −0.48 to −0.14; P=0.0005), open conversion (OR= 0.46, 95% CI 0.37 to 0.58; P<0.0001), and severe complications (OR=0.76, 95% CI 0.61 to 0.95; P=0.02) were significantly lower in the RLR group. Operation time, odds of use and duration of Pringle maneuver, length of hospital stay, and odds of intraoperative blood transfusion, overall complications, R0 resection, reoperation, 30-day readmission, 30-day mortality, and 90-day mortality did not significantly differ between the groups. Further subgroup and sensitivity analyses suggested that the results were stable. Meta regression analysis did not suggest a correlation between primary outcomes and study characteristics. The quality of evidence for the primary outcomes was medium or low, while that for the secondary outcomes was medium, low, or very low.

Conclusion:

Although some short-term outcomes are similar between RLR and LLR, RLR is superior in terms of less blood loss and lower odds of open conversion and severe complications. In the future, RLR may become a safe and effective replacement for LLR.
Natural History of Pediatric Patients With Crohn’s Disease Treated With Mesalamine Therapy
Authors: Young Denise D. , Perry Sharon , Malay Sindhoosha , Sferra Thomas J. , Finkler Michael , Moses Jonathan
Published: November 2023

Background:

5-aminosalicylates (5-ASA) are used to treat mild to moderate ulcerative colitis. Despite their lack of efficacy in Crohn disease (CD), they are still used in real-world practice. Additionally, when patients have progressive disease, they may escalate to biologic therapy, at which time 5-ASA may or may not be discontinued.

Objectives:

The aim of this study is to assess the clinical outcomes of patients started on 5-ASA for the treatment of pediatric CD. The secondary aims were to evaluate the outcomes of those who continue 5-ASA to those who discontinue 5-ASA upon biologic escalation.

Methods:

We performed a single-center retrospective chart review of pediatric CD patients from 2010 to 2019 who were initially treated with 5-ASA. Demographics, medication and laboratory data, and clinical disease activity were collected.

Results:

Sixty-one patients were included in the study; the majority had inflammatory CD with ileocolonic involvement. Twenty-four patients were on a concomitant immunomodulator. The majority of patients (85.2%) required escalation to biologics. Thirty-two patients (61.5%) who escalated to biologic therapy continued on 5-ASA. Eighty percent of patients achieved clinical remission at 1 year, and there was no difference between those who continued 5-ASA at time of biologic initiation compared to those who did not continue the medication. Patients who discontinued 5-ASA had an average annual cost savings of $6741.

Conclusion:

5-ASA is not a durable monotherapy for the treatment of pediatric CD. Patients who require escalation from 5-ASA to biologic therapy do not benefit from concomitant 5-ASA therapy. Further prospective studies are needed to confirm these findings.
Development and validation of a multivariable risk prediction model for hepatic steatosis in patients with HIV infection
Authors: Wirth Marielle , Ruckes Christian , Michel Maurice , Schattenberg Jörn M.
Published: November 2023

Objective:

Early detection of hepatic steatosis in people with HIV (PWH) could prevent progression and inflammation. The aim was to develop and validate a multivariable risk prediction model for hepatic steatosis in German PWH.

Design:

In this cohort study, 282 PWH were prospectively enrolled, and hepatic steatosis was defined via controlled attenuation parameter (CAP; ≥275 dB/m) using vibration-controlled transient elastography.

Methods:

Three multivariable logistic regression models were conducted. Missing values were imputed with multiple imputation. Cut-offs were derived based on Youden-Indices. Performance was assessed via discriminatory and calibrative ability and accuracy via Brier Skill Score. Sensitivity, specificity, and predictive values were calculated. Internal validation was performed via bootstrapping.

Results:

The prevalence of hepatic steatosis was 35.3% (100/282). Univariate analyses revealed associations with age, waist circumference, BMI, hypertension, hyperlipidemia and gamma-gt. In multivariable analyses, male sex [odds ratio (OR) 2.07, 95% confidence interval (CI) 1.42–3.00, P = 0.001] and BMI (OR 1.27, 95% CI 1.18–1.36, P < 0.001) were identified as independent predictors of hepatic steatosis. The naive and optimism-corrected c-statistic of 79% showed a good discriminatory ability, the calibration was well with a slight tendency for overestimation for predicted probabilities above 70%. At the cutoff of 1.95, the specificity was 71% and the negative-predictive value 82.3%. Twenty-seven percent of the 282 patients would be misclassified, 17% as false positives and 10% as false negatives.

Conclusion:

The developed prediction model contributes to the lack of validated noninvasive tools to predict hepatic steatosis in people with HIV. Future studies should include more candidate predictors and externally validate the model.
SimReadUntil for Benchmarking Selective Sequencing Algorithms on ONT Devices
Authors: Mordig Maximilian , Rätsch Gunnar , Kahles André
Published: November 2023

Motivation

The Oxford Nanopore Technologies (ONT) ReadUntil API enables selective sequencing, which aims to reduce time spent on sequencing uninteresting reads in favor of more interesting reads, e.g., to deplete or enrich certain genomic regions. The performance gain depends on the selective sequencing decision-making algorithm (SSDA) which decides whether to reject a read, stop receiving a read or wait for more data. Since real runs are time-consuming and costly (at scale), simulating the ONT device with support for the ReadUntil API is highly beneficial to compare and optimize the parameters of SSDAs. Existing software like MinKNOW and UNCALLED only return raw signal data, are memory-intensive, require huge and often unavailable multi-fast5 files (≥100GB) and are not clearly documented.

Results

We present the ONT device simulatorSimReadUntilthat takes a set of full (real or simulated) reads as input, distributes them to channels and plays them back in real time including mux scans, channel gaps and blockages, and allows to unblock (reject) reads as well as stop receiving data from them (imitating the ReadUntil API). Our modified ReadUntil API provides the basecalled reads rather than the raw signal to reduce computational load and focus on the SSDA rather than basecalling. Tuning the parameters of tools like ReadFish and ReadBouncer becomes easier because no GPU is required anymore for basecalling. We offer various methods to extract simulation parameters from a sequencing summary file and compare them.SimReadUntil‘s gRPC interface allows standardized interaction with a wide range of programming languages.

Availability

The code is freely available on GitHub (https://github.com/ratschlab/sim_read_until) along with a fully worked use case that combines the simulator with ReadFish (and optionally NanoSim).

Supplementary information

Supplementary data are available at Bioinformatics online.
Senescent cells impair fracture repair through elevating ubiquitin-proteasome system activity in aged mice
Authors: Zhang Jun , Xu Jiongnan , Liu Jiatong , Lipe Brea , Wu Tao , Boyce Brendan F. , Shen Jie , Xing Lianping , Zhang Hengwei
Published: November 2023

Senescent cells accumulate in multiple tissues with aging. Depletion of senescent cells benefits the aging related disease, such as aging bone fracture. However, the molecular mechanisms by which senescent cells regulate their neighboring bone cells are still not well-known. We reported that proteasome inhibitor enhanced fracture repair in aged mice. Senescent cells are major source of chronic inflammatory cytokines, which in turn induced protein ubiquitination. We reported that PDGFRβ was one of the highly ubiquitinated proteins in mesenchymal progenitors (MPCs) and TGFβ was the most increased SASP. In the current study, we found TGFβ induced PDGFRβ ubiquitination and proteasomal degradation through its E3 ligases. TGFβ neutralizing antibody blocked the inhibited callus derived MPC growth and increased Ub-PDGFRβ by senescent cells, which could be further prevented PDGFRβ inhibitor. These findings suggested senescent cells derived TGFβ impaired fracture repair in aged mice through elevating ubiquitination of PDGFRβ. The discovery of TGFβ-PDGFRβ pathway triggered by senescent cells opens avenues for optimizing treatment strategies for aging related disease by combination with the ligand of PDGFRβ.
Melanophilin mediates the association of myosin-5a with melanosome via three distinct interactions
Authors: Pan Jiabin , Zhou Rui , Yao Lin-Lin , Zhang Jie , Zhang Ning , Cao Qin-Juan , Sun Shaopeng , Li Xiang-dong
Published: November 2023

Transport and localization of melanosome at the periphery region of melanocyte are depended on myosin-5a (Myo5a), which associates with melanosome by interacting with its adaptor protein melanophilin (Mlph). Mlph contains four functional regions, including Rab27a-binding domain, Myo5a GTD-binding motif (GTBM), Myo5a exon F-binding domain (EFBD), and actin-binding domain (ABD). The association of Myo5a with Mlph is known to be mediated by two specific interactions: the interaction between the exon-F-encoded region of Myo5a and Mlph-EFBD and that between Myo5a-GTD and Mlph-GTBM. Here, we identify a third interaction between Myo5a and Mlph, i.e., the interaction between the exon-G-encoded region of Myo5a and Mlph-ABD. The exon-G/ABD interaction is independent from the exon-F/EFBD interaction and is required for the association of Myo5a with melanosome. Moreover, we demonstrate that Mlph-ABD interacts with either the exon-G or actin filament, but cannot interact with both of them simultaneously. Based on above findings, we propose a new model for the Mlph-mediated Myo5a transportation of melanosomes.
Extralimital Terrestrials: A reassessment of range limits in Alaska’s land mammals
Authors: Baltensperger A. P. , Lanier H. C. , Olson L. E.
Published: November 2023

Understanding and mitigating the effects of anthropogenic climate change and development on species requires the ability to track distributional changes over time. This is particularly true for species occupying high-latitude regions, which are experiencing a greater magnitude of climate change than the rest of the world. In North America, ranges of many mammals reach their northernmost extent in Alaska, positioning this region at the leading edge of climate-induced distribution change. Over a decade has elapsed since the publication of the last spatial assessments of terrestrial mammals in the state. We compared public occurrence records against commonly referenced range maps to evaluate potential extralimital records and develop repeatable baseline range maps. We compared occurrence records from the Global Biodiversity Information Facility for 64 terrestrial mammals native to mainland Alaska against a variety of range estimates (International Union for the Conservation of Nature, Alaska Gap Analysis Project, and the published literature). We mapped extralimital records and calculated proportions of occurrences encompassed by range extents. We also evaluated extralimital records against published species models, highlighted extralimital observations on U.S. Department of Interior lands, and report on two species of bats new to Alaska since 2014. Range comparisons identified 6,848 extralimital records belonging to 39 of 112 (34.8%) Alaskan species. On average, the Alaska Gap Analysis Project encompassed 95.5% of occurrence records and ranges were deemed accurate (> 90.0% correct) for 31 of 37 species, but overestimated extents for 13 species. International Union for Conservation of Nature range maps encompassed 68.1% of occurrence records and were > 90% accurate for 17 of 39 species. Results are either the product of improved sampling and digitization or represent actual geographic range expansions. Here we provide new data-driven range maps, update standards for the archival of museum-quality locational records and offer recommendations for mapping range changes for monitoring and conservation.
Alteration in Gut Microbiome and Intestinal Barrier Function caused by Efavirenz versus Dolutegravir Treatments in Mice
Authors: Tang Qin , Pan Hai-en , Liu Zhe , Deng Zhou , Zhong Qing-Yang , Cao Huan-huan , Ye Jun-yan , Li Jin , Li Xue-ying , Zhu Hai-peng , Chen Song
Published: November 2023

Dolutegravir (DTG) is replacing efavirenz (EFV) as first-line antiretroviral therapy because of its better tolerance. However, DTG cause similar, but milder, gastrointestinal and neurological side effects as EFV does. We speculated that impaired gut barrier function contributes to their side effects. For this purpose, the mice were intragastrically administered EFV, DTG, or vehicle for 60 consecutive days. The plasma levels of FITC-dextran were determined to evaluate gut barrier integrity. Colonic contents were collected for 16S rRNA sequencing. Adipose, liver, ileum, and colon tissues were collected for pathological examination, and intestinal zona occludens-1 (ZO-1) immunofluorescence staining and goblet cell staining were performed. We found that EFV significantly retarded body weight gain, decreased glucose uptake, and caused lipodystrophy and hepatocyte necrosis. EFV also decreased species richness of gut microbiota, increased Verrucomicrobia and Proteobacteria, and decreased Patescibacteria and Cyanobacteria. Moreover, it caused crypt damage, goblet cell loss, reduced ZO-1 expression, impaired gut barrier function, and suppressed expressions of Pdha1 and Ndufv1. Interestingly, DTG impaired barrier function similar to EFV, but the impairment was milder. DTC also inhibited MPC1, MPC2, and Pdha1 expression. Our results suggest a link between abnormal energy metabolism, impaired gut barrier integrity and side effects of EFV and DTG.
Insights intoKIF11pathogenesis in Microcephaly-Lymphedema-Chorioretinopathy syndrome: a lymphatic perspective
Authors: Ogmen Kazim , Dobbins Sara , Martinez-Corral Ines , Behncke Rose Yinghan , Brown Ryan C.S. , Ulferts Sascha , Hansmeier Nils Rouven , Sackey Ege , Alqahtani Ahlam , Karapouliou Christina , Grigoriadis Dionysios , Oberlin Michael , Williams Denise , Ekici Arzu , Karaer Kadri , Jeffery Steve , Mortimer Peter , Gordon Kristiana , Hogan Benjamin M. , Mäkinen Taija , Hägerling René , Mansour Sahar , Martin-Almedina Silvia , Ostergaard Pia
Published: November 2023

Pathogenic variants in kinesinKIF11underlie microcephaly-lymphedema-chorioretinopathy (MLC) syndrome. Although well known for regulating spindle dynamics ensuring successful cell division, the association ofKIF11(encoding EG5) with development of the lymphatic system, and howKIF11pathogenic variants lead to lymphatic dysfunction and lymphedema remain unknown.

Using patient-derived lymphoblastoid cells, we demonstrate that MLC patients carrying pathogenic stop-gain variants inKIF11have reduced mRNA and protein levels. Lymphoscintigraphy showed reduced tracer absorption, and intestinal lymphangiectasia was detected in one patient, pointing to impairment of lymphatic function caused byKIF11haploinsufficiency.

We reveal thatKIF11is expressed in early human and mouse development with the lymphatic markers VEGFR3, Podoplanin and PROX1. In zebrafish, scRNA-seq identifiedKIF11specifically expressed in endothelial precursors. In human lymphatic endothelial cells (LECs), EG5 inhibition with Ispinesib, reduces VEGFC-driven AKT phosphorylation, migration and spheroid sprouting.KIF11knockdown reducesPROX1andVEGFR3expression, providing for the first time a link betweenKIF11and drivers of lymphangiogenesis and lymphatic identity.
Sex-stratified phenotyping of comorbidities associated with an inpatient delirium diagnosis using real world data
Authors: Kodama Lay , Woldemariam Sarah , Tang Alice , Li Yaqiao , Oskotsky Tomiko , Raphael Eva , Sirota Marina
Published: November 2023

Delirium is a heterogeneous and detrimental mental condition often seen in older, hospitalized patients and is currently hard to predict. In this study, we leverage large-scale, real- world data using the electronic health records (EHR) to identify two cohorts comprised of 7,492 UCSF patients and 19,417 UC health system patients (excluding UCSF patients) with an inpatient delirium diagnosis and the same number of propensity score-matched control patients without delirium. We found significant associations between comorbidities or laboratory test values and an inpatient delirium diagnosis which were validated independently. Most of these associations were those previously-identified as risk factors for delirium, including metabolic abnormalities, mental health diagnoses, and infections. Some of the associations were sex- specific, including those related to dementia subtypes and infections. We further explored the diagnostic associations with anemia and bipolar disorder by conducting longitudinal analyses from the time of first diagnosis of the risk factor to development of delirium demonstrating a significant relationship across time. Finally, we show that an inpatient delirium diagnosis leads to dramatic increases in mortality outcome across both cohorts. These results demonstrate the powerful application of leveraging EHR data to shed insights into prior diagnoses and laboratory test values that could help predict development of inpatient delirium and emphasize the importance of considering patient demographic characteristics including documented sex when making these assessments.

One Sentence Summary

Longitudinal analysis of electronic health record data reveals associations between inpatient delirium, comorbidities, and mortality.
Genomic fingerprints of the world’s soil ecosystems
Authors: Graham Emily B. , Garayburu-Caruso Vanessa A. , Wu Ruonan , Zheng Jianqiu , McClure Ryan , Jones Gerrad
Published: November 2023

Despite the explosion of soil metagenomic data, we lack a synthesized understanding of patterns in the distribution and functions of soil microorganisms. These patterns are critical to predictions of soil microbiome responses to climate change and resulting feedbacks that regulate greenhouse gas release from soils. To address this gap, we assay 1512 manually-curated soil metagenomes using complementary annotation databases, read-based taxonomy, and machine learning to extract multidimensional genomic fingerprints of global soil microbiomes. Our objective is to uncover novel biogeographical patterns of soil microbiomes across environmental factors and ecological biomes with high molecular resolution. We reveal shifts in the potential for (1) microbial nutrient acquisition across pH gradients; (2) stress, transport, and redox-based processes across changes in soil bulk density; and (3) greenhouse gas emissions across biomes. We also use an unsupervised approach to reveal a collection of soils with distinct genomic signatures, characterized by coordinated changes in soil organic carbon, nitrogen, and cation exchange capacity and in bulk density and clay content that may ultimately reflect soil environments with high microbial activity. Genomic fingerprints for these soils highlight the importance of resource scavenging, plant-microbe interactions, fungi, and heterotrophic metabolisms. Across all analyses, we observed phylogenetic coherence in soil microbiomes –– more closely related microorganisms tended to move congruently in response to soil factors. Collectively, the genomic fingerprints uncovered here present a basis for global patterns in the microbial mechanisms underlying soil biogeochemistry and help beget tractable microbial reaction networks for incorporation into process-based models of soil carbon and nutrient cycling.

Importance

We address a critical gap in our understanding of soil microorganisms and their functions, which have a profound impact on our environment. We analyzed 1512 global soils with advanced analytics to create detailed genetic profiles (fingerprints) of soil microbiomes. This reveals novel patterns in how microorganisms are distributed across different soil environments. For instance, we discovered shifts in microbial potential to acquire nutrients in relation to soil acidity, as well as changes in stress responses and potential greenhouse gas emissions linked to soil structure. We also identified soils with putative high activity that had unique genomic characteristics surrounding resource acquisition, plant-microbe interactions, and fungal activity. Finally, we observed that closely related microorganisms tend to respond in similar ways to changes in their surroundings. Our work is a significant step towards comprehending the intricate world of soil microorganisms and its role in the global climate.
Orsay virus infection increasesCaenorhabditis elegansresistance to heat-shock
Authors: Castiglioni Victoria G. , Elena Santiago F.
Published: November 2023

The heat shock response plays a role in the immune defense against viruses across various organisms. Studies on model organisms show that inducing this response prior to viral exposure enhances host resistance to infections, while deficient responses make individuals more vulnerable. Moreover, viruses rely on components of the heat shock response for their own stability and viral infections improve thermal tolerance in plants, giving infected individuals an advantage in extreme conditions, which aids the virus in replication and transmission. Here, we examine the interaction between the nematodeCaenorhabditis elegansand its natural pathogen the Orsay virus (OrV) under heat stress. We found that OrV infection leads to differential gene expression related to heat stress, and infected populations showed increased resistance to heat shock. This resistance was associated with increased expression of argonautesalg-1andalg-2, which are crucial for survival after heat shock and for OrV replication. Overall, our study suggests an environmental-dependent mutualistic relationship between the worm and OrV, potentially expanding the worm’s ecological niche and providing the virus with extra opportunities for replication and adaptation to extreme conditions.

IMPORTANCE

Viruses have traditionally been viewed as self-serving pathogens that harm their hosts to ensure their own survival. However, recent studies are painting a different picture, revealing that viruses are ubiquitous and not always linked to diseases. In the realm of plant pathology, it has been long noted that the outcome of an infection hinges on environmental factors. Here, we show that the interaction between an animal virus and its natural host can be mutualistic under harsh temperature conditions. Our research highlights that this shift towards mutualism hinges on the expression of argonaute proteins.
The evolution of multiply substituted isotopologues of methane during microbial aerobic oxidation
Authors: Li Jiawen , Chiu Beverly K. , Piasecki Alison M. , Feng Xiahong , Landis Joshua D. , Marcum Sarah , Young Edward D. , Leavitt William D.
Published: November 2023

Aerobic methane oxidation (AeOM) is an important biological sink of methane on Earth. Stable isotopes are critical tools in tracking the sources and sinks of Earth’s surface methane budget. However, the major factors that influence the two multiply-substituted (clumped) isotope signatures of AeOM, Δ13CH3D and Δ12CH2D2, are not well known. Here we quantify the influence of kinetics as a function of temperature, and different methane monooxygenase (MMO) enzymes as a function of copper, on the isotopologue concentrations of residual methane by the obligate aerobic methanotroph,Methylococcus capsulatus(Bath). We observe deviations from traditional closed-system distillation (Rayleigh) fractionation during exponential growth at high oxidation rates. We model this as a reservoir effect controlled by the ratio of oxidation rate in the cells to transport rate of methane into the cells, where environmental temperature affects both rates. We also test whether clumped isotope fractionation values vary for the particulate versus soluble MMOs, but the results show minimal differences. We further determine that the back reaction (re-equilibration) of methane with medium water is unlikely. Together, the observations and model demonstrate that at low oxidation-to-transport ratios, the clumped isotope signatures follow canonical Rayleigh fractionation, whereas at high ratios, more positive Δ12CH2D2values result, deviating from simple Rayleigh-like trajectories. This study shows that the methane oxidation-to-transport ratio is a critical influence on clumped isotope signatures of AeOM that should be considered when interpreting the isotopic data of natural methane samples in both open and closed systems.
A review on human gut microbial diversity in 21 tribal populations from India
Authors: Chakraborty Sayak , Mollick Sahid Afrid , Roy Bidyut
Published: November 2023

From the earlier to modern times, the human populations passed through stages of subsistence such as foraging, rural farming and industrialized urban life. Till date various tribal people are living in geographically isolated areas depending on their traditional (gathering/rural farming) food sources. The long term cultural practices and food habits shaped the gut microbiome composition in these populations and contributed to health. However, the population-level study of the gut microbiota in Indian tribes with representative sampling across its geography and subsistence are limited. So, it is important to understand the complexity and diversity of the gut microbiome in healthy tribal populations, studied so far, to explore relationship among food, gut microbiome and health. Here, we reviewed gut microbiome studies which included 21 Indian tribal populations from different geographical regions to understand the role of food, ecology and cultural habits on variation of gut microbiota.
Educational Impact of a Research and Mentoring Symposium Emphasizing Formative Feedback for Medical Students and Early Career Doctors in Africa
Authors: Nowbuth Avis A , Muwowo Mwiza , Makashinyi Mwitupa , Kumwenda Andrew , Mwanamwampula Sheila J , Kaluba Tamara , Mazimba Sula , Bloom Seth M , Asombang Akwi W
Published: November 2023

Research training is a core component of medical education, but many African medical schools lack resources to support student research, impeding global health progress. Conferences offer alternate venues to learn about research, network, and receive scientific feedback, but conference access for African trainees is limited. We hypothesized that a research and mentorship symposium for African medical trainees could promote research knowledge and interest among attendees.

Methods

We co-organized a symposium attended by medical students and early career doctors from African institutions in-person (Lusaka, Zambia) and virtually. The program featured trainee abstract presentations, keynote lectures, and networking. Abstracts received written reviews and judges provided live formative feedback on presentations. Participants completed a post-symposium survey on demographics, institutional research support, and benefits of symposium participation.

Results

Respondents included 87 trainees from 7 African countries, including 28 presenters from 11 schools. Most had never attended or presented at a conference, interacted with peers in a research forum, or received formal research training. The majority reported key unmet needs in research training and resources at their institutions. Trainees praised the symposium’s judging format and said attendance inspired them, increased their interest in research, improved quality of their projects, and motivated them to initiate new studies.

Interpretation

A volunteer-organized research and mentorship symposium emphasizing formative feedback enhanced research knowledge and interest among African medical trainees, many of whom had limited access to institutional research training and support. Such initiatives can inspire and nurture new generations of African scientists to advance global health.

Funding

None
A Comprehensive Study of GPT-4V’s Multimodal Capabilities in Medical Imaging
Authors: Li Yingshu , Liu Yunyi , Wang Zhanyu , Liang Xinyu , Liu Lingqiao , Wang Lei , Cui Leyang , Tu Zhaopeng , Wang Longyue , Zhou Luping
Published: November 2023

Abstract

This paper presents a comprehensive evaluation of GPT-4V’s capabilities across diverse medical imaging tasks, including Radiology Report Generation, Medical Visual Question Answering (VQA), and Visual Grounding. While prior efforts have explored GPT-4V’s performance in medical imaging, to the best of our knowledge, our study represents the first quantitative evaluation on publicly available benchmarks. Our findings highlight GPT-4V’s potential in generating descriptive reports for chest X-ray images, particularly when guided by well-structured prompts. However, its performance on the MIMIC-CXR dataset benchmark reveals areas for improvement in certain evaluation metrics, such as CIDEr. In the domain of Medical VQA, GPT-4V demonstrates proficiency in distinguishing between question types but falls short of prevailing benchmarks in terms of accuracy. Furthermore, our analysis finds the limitations of conventional evaluation metrics like the BLEU score, advocating for the development of more semantically robust assessment methods. In the field of Visual Grounding, GPT-4V exhibits preliminary promise in recognizing bounding boxes, but its precision is lacking, especially in identifying specific medical organs and signs. Our evaluation underscores the significant potential of GPT-4V in the medical imaging domain, while also emphasizing the need for targeted refinements to fully unlock its capabilities.