bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of lower tiers of government healthcare facilities on unmet need for contraception and contraception use in Bangladesh
Authors: Khan Md Nuruzzaman , Khanam Shimlin Jahan , Khan Md Mostaured Ali , Islam M Mofizul , Harris Melissa L. 
Published: April 2023

AbstractBackgroundIn low- and middle-income countries (LMICs), including Bangladesh, modern contraception use remains lower than desired, resulting in a higher unmet need. A potential factor contributing to lower contraceptive use is reduced access to and use of lower tiers of government healthcare facilities, including home visits by family welfare assistants (FWAs), as well as women’s visits to community and satellite clinics. These relationships, however, are still unexplored in Bangladesh and LMICs more broadly. The aim of this study was to explore effects of lower tiers of government healthcare facilities on unmet need for contraception and contraception use in Bangladesh.MethodsData from 17,585 sexually active married women were analyzed from the 2017 Bangladesh Demographic and Health Survey. The outcome variables were any contraceptive use, modern contraceptive use, unmet need for contraception, and unmet need for modern contraception. The explanatory variables considered were respondent’s home visits by FWAs, respondent’s visits to a community clinic, and respondent’s visits to a satellite clinic. Multilevel mixed-effect Poisson regression with robust variance was used to determine the association between the outcome and explanatory variables, adjusted for individual-, household-, and community-level factors.ResultsApproximately 18% of respondents were visited by FWAs in the three months prior to the survey date and only 3.4% and 3.1% of women attended community and satellite clinics, respectively. Women who reported being visited by FWAs in the three months prior to the survey were approximately 36% less likely to report an unmet need for modern contraception and 42% more likely to report using modern contraception than women who did not report such a visit. A higher likelihood of unmet need for contraception and a lower likelihood of contraception use was found among women who did not visit these community or satellite clinics or visited these clinics for other reasons than collecting contraception as compared to women who visited these clinics to collect contraception.ConclusionFWAs’ visits to respondents’ homes to provide contraception, as well as respondent’s visits to satellite and community clinics play a major role in Bangladesh to ensure contraception use and reduce the unmet need for contraception. However, their coverage is quite low in Bangladesh. The findings suggest an urgent need for greater government initiatives to increase the number of FWAs and engage in proper monitoring them at the field level.
Effects of dietary interventions focused on adding base in the management of metabolic acidosis in adults with chronic kidney disease: A protocol for systematic review and meta-analysis of randomized clinical trials
Authors: Mahboobi Sepideh , Mollard Rebecca , Tangri Navdeep , Askin Nicole , Rabbani Rasheda , Abou-Setta Ahmed M. , Mackay Dylan 
Published: April 2023

AbstractBackgroundMetabolic acidosis is a common complication of chronic kidney disease (CKD) which can impair the function of multiple organs and accelerate CKD progression to kidney failure. The condition is usually treated with sodium bicarbonate (NaHCO3), which is an alkali salt. Although effective, alkali therapy has numerous side effects including gastric discomfort and bloating, with many people having difficulty tolerating higher doses. Research has shown that base producing fruit and vegetables may have the ability to increase serum bicarbonate concentrations similar to what is achieved with alkali therapy, but also provides added benefits. This systematic review aims to identify, critically-appraise and meta-analyze findings from randomized clinical trials (RCTs) comparing the effects of dietary interventions, including base producing fruit and vegetables, on serum bicarbonate concentrations as well as other factors related to kidney function in adult patients with CKD.MethodsRCTs (in adult participants (18 years of age or older), with CKD will be included in the study. Studies will be excluded if participants are undergoing dialysis or have chronic obstructive pulmonary disease (COPD) requiring oxygen therapy. The interventions of interest are any dietary intervention aimed at manipulating dietary acid load, compared with usual care, no treatment or placebo. Our primary outcome measure will be changes in serum bicarbonate concentration, while other parameters related to kidney function will be considered as secondary outcomes. A knowledge synthesis librarian developed a literature search strategy for MEDLINE (Ovid). The search strategy was then adjusted for use in Cochrane Central (Ovid), Embase (Ovid), Web of Science Core Collection (Clarivate) and CINAHL (EBSCO). Two independent reviewers will select studies for eligibility in Covidence and data extraction will be conducted using a custom MS Excel worksheet. We are planning to perform meta-analysis wherever possible using random effects model. Standardized mean difference (95% confidence interval) and risk ratio will be used to present continuous and dichotomous data, respectively. The assessment of publication bias will be performed using funnel plots and Egger’s regression test while I2statistics will be used to assess heterogeneity. We are planning to perform subgroup analysis to deal with potential heterogeneity.DiscussionThe results of this systematic review and meta-analysis will be useful in designing effective dietary strategies for the management of CKD-related metabolic acidosis.Systematic review registrationThe present systematic review is registered in International Prospective Register of Systematic Reviews (PROSPERO) (https://www.crd.york.ac.uk/, registration ID: CRD42022342612).
Integrated Metabolomics and Transcriptomics Analysis Identifies Molecular Subtypes within the Early and Late Mild Cognitive Impairment Stages of Alzheimer’s Disease
Authors: Yadev Shashank , Zhou Shu , Karas Zachary , Zhang Yueyang , Garmire Lana X ,   Alzheimer’s Disease Neuroimaging Initiative
Published: April 2023

AbstractAlzheimer’s disease (AD) is a highly heterogeneous neurodegenerative condition. The current study identified clinically relevant molecular subtypes of the early and late mild cognitive impairment (EMCI and LMCI) stages of AD using 401 patients’ data from the ADNI consortium. We integrated patients’ metabolomics data with the PBMC transcriptomics data using an unsupervised clustering method called Similarity Network Fusion (SNF), and identified two subtypes in early and late MCI patients, respectively. The differences between these subtypes’ metabolite concentrations and gene expression well correlate with physio-pathogenesis for AD, based on cognitive measurements, pseudo-trajectory analysis, and longitudinal analysis of dementia diagnosis. We detected many dysregulated processes between subtypes, such as aminoacyl-tRNA biosynthesis, immune system activity, zinc imbalances. While immune-related pathways are commonly dysregulated pathways in EMCI and LMCI stages, oxidative stress is prevalent in EMCI, whereas metabolic abnormality is enriched in LMCI. Refined subtypes within EMCI and LMCI are a step-forward toward more personalized treatment strategies for progressing patients before AD diagnosis.
Low-dose cytokine immunotherapy of solid cancers enabled by phagocytic-competent protein co-crystals
Authors: Jones Michael H , Quispe Calla Nirk E , Smith Robert , Talbot-Cooper Callum , Rudge Simon , Kusano Hiroyuki , Shiomi Takayuki , Ishikawa Yuichi , Zeng Hong , Best Jonathan 
Published: April 2023

AbstractProtein therapeutics are often compromised by sub-optimal biodistribution contributing to poor efficacy and adverse events. Drug delivery mechanisms better able to target protein drugs to the disease site and provide localized, sustained release have the potential to transform therapeutic standards. PODS®crystals (PODS) are natural-mimetic, micron-scale protein co-crystals engineered to incorporate a protein cargo that can be sustainably released under the action of resident proteases. PODS are efficiently taken up by phagocytic cells with the cargo protein subsequently released in a bioactive form. Since blood-circulating phagocytic cells, including monocytes, are actively recruited into diseased and inflamed tissue, such as the tumour microenvironment, we postulated that monocyte/macrophage-mediated PODS delivery could be used as a molecular “Trojan horse” to efficiently deliver therapeutic proteins to target cells. This could improve the pharmacodynamics and pharmacokinetics of protein drug delivery to treat systemic and disseminated diseases. Interleukin-2 (IL-2) is notoriously toxic at the high doses required for therapeutic efficacy. Here, we demonstrate the therapeutic efficacy and tolerability of low doses of PODS containing IL-2 cargo (PODS-IL-2) administered intravenously in a mouse model of melanoma. We further demonstrate the therapeutic benefit of PODS delivering IL-2, interleukin-15 (IL-15) and interferon gamma (IFN-γ) in a mouse model of renal cell carcinoma at two doses. Efficacy was seen in both doses with the higher dose generating rapid and complete rejection of the tumour in some of the mice treated with each cytokine. This study provides proof-of-concept for the utility of intravenously administered PODS to provide a generalised and widely applicable mechanism to effectively deliver protein drugs for the therapy of cancer and potentially other diseases.
Latent evolution of biofilm formation depends on life-history and genetic background
Authors: Nucci Amandine , Rocha Eduardo P.C. , Rendueles Olaya 
Published: April 2023

ABSTRACTAdaptation to one environment can often generate phenotypic and genotypic changes which impact the future ability of an organism to thrive in other environmental conditions. In the context of host-microbe interactions, biofilm formation can increase survival ratesin vivoupon exposure to stresses, like the host’s immune system or antibiotic therapy. However, how the generic process of adaptation impacts the ability to form biofilm and how it may change through time has seldomly been studied. To do so, we used a previous evolution experiment with three strains of theKlebsiella pneumoniaespecies complex, in which we did not specifically select for biofilm formation. We observed that changes in the ability to form biofilm happened very fast at first and afterwards reverted to ancestral levels in many populations. Biofilm changes were associated to phenotypic changes in population yield and surface polysaccharide production. Genotypically, mutational targets in the tip adhesin of type III fimbriae (mrkD) or thefimswitch of type I fimbriae were driven by nutrient availability during evolution, and their impact on biofilm formation was dependent on capsule production. Analyses of natural isolates revealed similar mutations inmrkD, suggesting that they also play an important role in adaptation outside the laboratory. Our work reveals that the latent evolution of biofilm formation, and its evolutionary dynamics, depend on nutrient availability, the genetic background and other intertwined phenotypic and genotypic changes. Ultimately, it suggests that small differences in the environment can alter an organism’s fate in more complex niches like the host.
Coding Sequence Insertions in Fungal Genomes are Intrinsically Disordered and can Impart Functionally-Important Properties on the Host Protein
Authors: Lemire Bernard D. , Uppuluri Priya 
Published: April 2023

ABSTRACTInsertion and deletion mutations (indels) are important mechanisms of generating protein diversity. Indels in coding sequences are under considerable selective pressure to maintain reading frames and to preserve protein function, but once generated, indels provide raw material for the acquisition of new protein properties and functions. We reported recently that coding sequence insertions in theCandida albicansNDU1 protein, a mitochondrial protein involved in the assembly of the NADH:ubiquinone oxidoreductase are imperative for respiration, biofilm formation and pathogenesis. NDU1 inserts are specific to CTG-clade fungi, absent in human ortholog and successfully harnessed as drug targets. Here, we present the first comprehensive report investigating indels and clade-defining insertions (CDIs) in fungal proteomes. We investigated 80 ascomycete proteomes encompassing CTG clade species, the Saccharomycetaceae family, the Aspergillaceae family and the Herpotrichiellaceae (black yeasts) family. We identified over 30,000 insertions, 4,000 CDIs and 2,500 clade-defining deletions (CDDs). Insert sizes range from 1 to over 1,000 residues in length, while maximum deletion length is 19 residues. Inserts are strikingly over-represented in protein kinases, and excluded from structural domains and transmembrane segments. Inserts are predicted to be highly disordered. The amino acid compositions of the inserts are highly depleted in hydrophobic residues and enriched in polar residues. An indel in theSaccharomyces cerevisiaeSth1 protein, the catalytic subunit of the RSC (Remodel the Structure of Chromatin) complex is predicted to be disordered until it forms a ß-strand upon interaction. This interaction performs a vital role in RSC-mediated transcriptional regulation, thereby expanding protein function.
Therapeutic strategy for spinal muscular atrophy by combining gene supplementation and genome editing
Authors: Hatanaka Fumiyuki , Suzuki Keiichiro , Shojima Kensaku , Yu Jingting , Takahashi Yuta , Sakamoto Akihisa , Prieto Javier , Shokhirev Maxim , Esteban Concepcion Rodriguez , Nuñez-Delicado Estrella , Belmonte Juan Carlos Izpisua 
Published: April 2023

AbstractDefect in theSMN1gene causes spinal muscular atrophy (SMA), which shows loss of motor nerve cells, muscle weakness and atrophy. While current treatment strategies, including small molecules or viral vectors, have been reported to improve motor function and survival, an ultimate and long-term treatment to correct SMA endogenous mutations and improve its phenotypes is still highly challenging. We have previously developed a CRISPR-Cas9 based homology-independent targeted integration (HITI) strategy, which allowed for unidirectional DNA knock-in in both dividing and non-dividing cellsin vivo. Here, we demonstrated its utility by correcting a SMA mutation in mice, and when combined withSmn1cDNA supplementation show SMA long-term therapeutic benefits in mice. Our observations may provide new avenues for long term and efficient treatment of inherited diseases.SummaryThe Gene-DUET strategy by combining cDNA supplementation and genome editing was sufficient to ameliorate SMA phenotypes in mouse modelin vivo.
Butyrate prevents visceral adipose tissue inflammation and metabolic alterations in a mouse model of Friedreich’s ataxia
Authors: Turchi Riccardo , Sciarretta Francesca , Tiberi Marta , Audano Matteo , Pedretti Silvia , Panebianco Concetta , Nesci Valentina , Pazienza Valerio , Ferri Alberto , Carotti Simone , Chiurchiù Valerio , Mitro Nico , Lettieri-Barbato Daniele , Aquilano Katia 
Published: April 2023

ABSTRACTFriedreich’s ataxia (FA) is a genetic neurodegenerative disease caused by mutation inFXNgene encoding for the mitochondrial protein frataxin (FXN). Patients with FA display an increased risk of developing diabetes that may aggravate disease prognosis. Recent studies have indicated that in addition to increased visceral adiposity, FA patients undergo a low-grade inflammatory state. The expansion of white adipose tissue (WAT) plays a fundamental role in the development of type 2 diabetes as it becomes insulin-resistant and a source of inflammatory molecules (adipokines). In this work, we have characterized visceral WAT (vWAT) at metabolic and immunological level in a murine FA model (KIKO) to test whether dysfunction of vWAT could be involved in FA metabolic complications. Through RNAseq analyses we found an alteration of inflammatory, angiogenesis and fibrosis genes in vWAT of KIKO mice. We also found other diabetes-related hallmarks such as increased lipid droplet size, immune cell infiltration and increased expression of pro-inflammatory cytokines. In addition, by targeted metabolomics we disclosed a raise in lactate production, an event usually associated with obesity and diabetes and that triggers activation of vWAT resident macrophages. To reproduce anin vitromodel of FA, we downregulated FXN protein in cultured white adipocytes and recapitulated the diabetes-like features observed in vWAT. Real time monitoring of adipocyte metabolism evidenced metabolic rewiring towards glycolysis according to increased lactate production. Analysis of fecal samples revealed a reduction of some butyrate-producing bacteria in KIKO mice. As this microbiota derived short-chain fatty was demonstrated to exert anti-diabetic function, we fed KIKO mice with a butyrate-enriched diet for 16 weeks. This dietary approach limited vWAT alterations and mitigated other diabetes-like signatures both inin vitroandin vivomodels.In conclusion, this study identified vWAT as an important player in the onset of metabolic complications typical of FA and suggests butyrate as safe and promising adjuvant tool to treat metabolic complications in FA.
Strain-specific changes in nucleus accumbens transcriptome and motivation for food reward in mice exposed to maternal separation
Authors: Benoit Simon , Henry Mathilde , Fneich Sara , Mathou Alexia , Xia Lin , Foury Aline , Jouin Mélanie , Junien Claudine , Capuron Lucile , Jouneau Luc , Moisan Marie-Pierre , Delpierre Cyrille , Gabory Anne , Darnaudery Muriel 
Published: April 2023

AbstractAdversity in childhood exerts enduring effects on brain and increases the vulnerability to psychiatric diseases. It also leads to a higher risk for eating disorders and obesity. We hypothesised that neonatal stress in mice affects motivation to obtain palatable food in adulthood and changes gene expression in reward system. Male and female pups from C57Bl/6J and C3H/HeN mice strains were subjected to a daily maternal separation (MS) protocol from PND2 to PND14. In adulthood, their motivation for palatable food reward was assessed in operant cages. Compared to control mice, male and female C3H/Hen mice exposed to MS significantly did more lever presses to obtain palatable food especially when the effort required to obtain the reward is high. Transcriptional analysis reveals 375 genes differentially expressed in the nucleus accumbens of male MS C3H/HeN mice compared to the control group, some of these being associated with the regulation of the reward system (e.g.Gnas, Pnoc). Interestingly, C57Bl/6J mice exposed to MS did not show any alteration in their motivation to obtain a palatable reward nor significant changes in gene expression in the nucleus accumbens. In conclusion, neonatal stress produces lasting changes in motivation for palatable food in C3H/HeN offspring but has no impact in C57Bl/6J offspring. These behavioural alterations are accompanied by drastic changes in gene expression specifically within the nucleus accumbens, a key structure in the regulation of motivational processes.
Virological characteristics of the SARS-CoV-2 Omicron XBB.1.16 variant
Authors: Yamasoba Daichi , Uriu Keiya , Plianchaisuk Arnon , Kosugi Yusuke , Pan Lin , Zahradnik Jiri ,   The Genotype to Phenotype Japan (G2P-Japan) Consortium, Ito Jumpei , Sato Kei 
Published: April 2023

AbstractAt the end of March 2023, XBB.1.16, a SARS-CoV-2 omicron XBB subvariant, emerged and was detected in various countries. Compared to XBB.1.5, XBB.1.16 has two substitutions in the S protein: E180V is in the N-terminal domain, and T478R in the receptor-binding domain (RBD). We first show that XBB.1.16 had an effective reproductive number (Re) that was 1.27- and 1.17-fold higher than the parental XBB.1 and XBB.1.5, respectively, suggesting that XBB.1.16 will spread worldwide in the near future. In fact, the WHO classified XBB.1.16 as a variant under monitoring on March 30, 2023. Neutralization assays demonstrated the robust resistance of XBB.1.16 to breakthrough infection sera of BA.2 (18-fold versus B.1.1) and BA.5 (37-fold versus B.1.1). We then used six clinically-available monoclonal antibodies and showed that only sotrovimab exhibits antiviral activity against XBB subvariants, including XBB.1.16. Our results suggest that, similar to XBB.1 and XBB.1.5, XBB.1.16 is robustly resistant to a variety of anti-SARS-CoV-2 antibodies. Our multiscale investigations suggest that XBB.1.16 that XBB.1.16 has a greater growth advantage in the human population compared to XBB.1 and XBB.1.5, while the ability of XBB.1.16 to exhibit profound immune evasion is comparable to XBB.1 and XBB.1.5. The increased fitness of XBB.1.16 may be due to (1) different antigenicity than XBB.1.5; and/or (2) the mutations in the non-S viral protein(s) that may contribute to increased viral growth efficiency.
Correcting PCR amplification errors in unique molecular identifiers to generate absolute numbers of sequencing molecules
Authors: Sun Jianfeng , Philpott Martin , Loi Danson , Li Shuang , Monteagudo-Mesas Pablo , Hoffman Gabriela , Robson Jonathan , Mehta Neelam , Gamble Vicki , Brown Tom , Sr Tom Brown , Canzar Stefan , Oppermann Udo , Cribbs Adam P 
Published: April 2023

AbstractUnique Molecular Identifiers (UMIs) are random oligonucleotide sequences that remove PCR amplification biases. However, the impact that PCR associated sequencing errors have on the accuracy of generating absolute counts of RNA molecules is underappreciated. We show that PCR errors are the main source of inaccuracy in both bulk and single-cell sequencing data, and synthesizing UMIs using homotrimeric nucleotide blocks provides an error correcting solution, that allows absolute counting of sequenced molecules.
Data driven and cell specific determination of nuclei-associated actin structure
Authors: Nikitina Nina , Bursa Nurbanu , Goelzer Matthew , Goldfeldt Madison , Crandall Chase , Howard Sean , Rubin Janet , Satici Aykut , Uzer Gunes 
Published: April 2023

AbstractQuantitative and volumetric assessment of filamentous actin fibers (F-actin) remains challenging due to their interconnected nature, leading researchers to utilize threshold based or qualitative measurement methods with poor reproducibility. Here we introduce a novel machine learning based methodology for accurate quantification and reconstruction of nuclei-associated F-actin. Utilizing a Convolutional Neural Network (CNN), we segment actin filaments and nuclei from 3D confocal microscopy images and then reconstruct each fiber by connecting intersecting contours on cross-sectional slices. This allowed measurement of the total number of actin filaments and individual actin filament length and volume in a reproducible fashion. Focusing on the role of F-actin in supporting nucleocytoskeletal connectivity, we quantified apical F-actin, basal F-actin, and nuclear architecture in mesenchymal stem cells (MSCs) following the disruption of the Linker of Nucleoskeleton and Cytoskeleton (LINC) Complexes. Disabling LINC in mesenchymal stem cells (MSCs) generated F-actin disorganization at the nuclear envelope characterized by shorter length and volume of actin fibers contributing a less elongated nuclear shape. Our findings not only present a new tool for mechanobiology but introduce a novel pipeline for developing realistic computational models based on quantitative measures of F- actin.