bluuebunny/crossref_metadata_2025_split huggingface dataset:
Factors Associated with Malaria Infection in Under Five Children-Zambia, 2018. A Secondary Analysis of the Malaria Indicator Survey, 2018
Authors: Tembo Lindiwe , Sialubanje Cephas , Malasa Martha , Heilmann Elizabeth Susan , Sinyange Nyambe , Nawa Mukumbuta 
Published: September 2023

AbstractIntroductionMalaria is a public health concern in Zambia. In 2018, Zambia reported a 9% malaria prevalence in under-five children, with some provinces reporting above 20%. Factors still driving malaria infection among the country’s under-five children must be investigated. Factors associated with malaria infection among under-five children were investigated.MethodsThis was a secondary analysis of the cross-sectional study for the Zambia Malaria Indicator Survey 2018 (MIS). Multistage sampling was used in the malaria indicator survey. All children aged 6 to 59 months who received malaria rapid diagnostic tests (RDT) in the data set were considered for the study. Malaria infection: Tested positive or negative for malaria RDT. Sample weights and multivariable logistic regression were used. Backward stepwise regression was used to determine the best model, and the Akaike information criterion was used to select the best model that best fits the data. The Odds ratio measured the association at a 95% confidence level.ResultsA total of 2400 children were analysed. 24.3% (583) tested positive. The median age was 32 (interquartile range (IQR:8-46)) months. Males were 52% (1,249). The odds of malaria infection increased as the child’s age in months increased (aOR=1.004, 95% CI: 1.003, 1.005). Children in the rural had higher odds of malaria than urban children (aOR=1.11,95% CI: 1.05, 1.17). The odds of malaria in children in Copperbelt, Luapula, Muchinga and North-Western Provinces were higher than in children in Central Province (p-value <0.05). Children whose houses did not receive IRS had increased odds of malaria compared to children whose houses received IRS (aOR=1.05, 95%CI: 1.01, 1.09). Sex was not statistically significant.ConclusionAn increase in age, living in the rural and northern parts of Zambia was associated with malaria infection. Increasing malaria prevention and control measures for older children, rural communities, and the northern parts of Zambia may help reduce malaria prevalence.Strengths and LimitationsThe study used a large dataset of the Malaria Indicator Survey 2018 that was powered to be nationally representative of Zambia, urban and rural strata, and provincial levels.The study used a complex data analysis considering household weights, census enumeration areas and provinces, addressing intra-cluster correlations.The study addressed confounding using multivariable regressing and determined the best-fit model using Akaike Information Criteria (AIC) in a backward stepwise regressing.The study’s main limitation is that it is a survey that simultaneously assessed the outcome and exposure variables, eliciting associations only and not causality.
CAR T cells recognizing CD276 and Dual-CAR T cells against CD276/FGFR4 promote rhabdomyosarcoma clearance in orthotopic mouse models
Authors: Timpanaro Andrea , Piccand Caroline , Dzhumashev Dzhangar , Anton-Joseph Stenija , Robbi Andrea , Moser Janine , Rössler Jochen , Bernasconi Michele 
Published: September 2023

AbstractBackgroundRhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood, whose prognosis is still poor especially for metastatic, high-grade, and relapsed RMS. New treatments are urgently needed, especially systemic therapies. Chimeric Antigen Receptor T cells (CAR Ts) are very effective against hematological malignancies, but their efficacy against solid tumors needs to be improved. CD276 is a target upregulated in RMS and detected at low levels in normal tissues. FGFR4 is a very specific target for RMS. Here, we optimized CAR Ts for these two targets, alone or in combination, and tested their anti-tumor activityin vitroandin vivo.MethodsFour different single-domain antibodies were used to select the most specific FGFR4-CAR construct. RMS cell killing and cytokine production by CD276- and FGFR4-CAR Ts expressing CD8α or CD28 HD/TM domains in combination with 4-1BB and/or CD28 co-stimulatory domains were testedin vitro.The most effective CD276- and FGFR4-CAR Ts were used to generate Dual-CAR Ts. Tumor killing was evaluatedin vivoin three orthotopic RMS mouse models.ResultsCD276.V-CAR Ts (276.MG.CD28HD/TM.CD28CSD.3z) showed the strongest killing of RMS cells, and the highest release of IFN-γ and Granzyme Bin vitro. FGFR4.V-CAR Ts (F8-FR4.CD28HD/TM.CD28CSD.3z) showed the most specific killing. CD276-CAR Ts successfully eradicated RD- and Rh4-derived RMS tumorsin vivo, achieving complete remission in 3/5 and 5/5 mice, respectively. In CD276lowJR-tumors, however, they achieved complete remission in only 1/5 mice. FGFR4 CAR Ts instead delayed of Rh4 tumor growth. Dual-CAR Ts promoted Rh4-tumors clearance in 5/5 mice.ConclusionsCD276- and CD276/FGFR4-directed CAR Ts showed effective RMS cell killingin vitroand eradication of CD276highRMS tumorsin vivo. CD276lowtumors escaped the therapy showing a correlation of antigen density and effectiveness. FGFR4-CAR Ts showed specific killingin vitrobut could only delay RMS growthin vivo. Our results show that combined expression of CD276-CAR with other CAR does not reduce its benefit. Introducing immunotherapy with CD276-CAR Ts in RMS seems to be feasible and promising, although CAR constructs design and target combinations have to be further improved to eradicate tumors with low target expression.
Bacterial Sphingolipids Exacerbate Colitis by Inhibiting ILC3-derived IL-22 Production
Authors: Bao Bin , Wang Youyuan , Boudreau Pavl , Song Xinyang , Wu Meng , Chen Xi , Patik Izabel , Tang Ying , Ouahed Jodie , Ringel Amit , Barends Jared , Wu Chuan , Balskus Emily , Thiagarajah Jay , Liu Jian , Wessels Michael R. , Lencer Wayne , Kasper Dennis L. , An Dingding , Horwitz Bruce , Snapper Scott B. 
Published: September 2023

AbstractCommensal bacteria of the Bacteroidetes phylum are the primary producers of sphingolipids in the gut lumen. These lipids serve dual roles as bacterial virulence factors and regulators of the host mucosal immune system, including regulatory T cells and invariant natural killer T cells (iNKT). Sphingolipid composition is significantly altered in fecal samples of patients with inflammatory bowel disease (IBD). However, the specific mechanisms by which bacterial sphingolipids modulate mucosal homeostasis and regulate intestinal inflammation remain unclear. In this study, we investigated the impact of bacterial sphingolipids on intestinal inflammation by mono-colonizing mice withBacteroides fragilisstrains that either express or lack sphingolipids during DSS-induced colitis. We discovered thatB. fragilissphingolipids exacerbate intestinal inflammation. Mice mono-colonized withB. fragilislacking sphingolipids exhibited less severe DSS-induced colitis. This amelioration of colitis was associated with increased production of interleukin-22 (IL-22) by innate lymphoid cell type 3 (ILC3). Consistent with the inhibitory effect of sphingolipids on IL-22 production, mice colonized withB. fragilislacking sphingolipids showed enhanced epithelial STAT3 activity, intestinal cell proliferation, and antimicrobial peptide production following DSS treatment compared to those colonized withB. fragilisproducing sphingolipids. Additionally, colitis severity in mice colonized withB. fragilislacking sphingolipids was exacerbated upon IL-22 blockade. Furthermore, our study reveals that bacterial sphingolipids restrict epithelial IL-18 production following DSS treatment and interfere with IL-22 production by a subset of ILC3 cells expressing both the interleukin-18 receptor (IL-18R) and major histocompatibility complex class II (MHC II). These findings indicate thatB. fragilis-derived sphingolipids exacerbate mucosal inflammation by impeding epithelial IL-18 expression, resulting in compromised production of IL-22 by ILC3 cells.HighlightsB. fragilis-derived sphingolipids exacerbate DSS-induced colitis in mono-colonized C57BL/6 mice.B. fragilis-derived sphingolipids constrain ILC3-derived IL-22, leading to reduced colonic epithelial cell proliferation and compromised barrier function.B. fragilis-derived sphingolipids restrict epithelial NLRC4 inflammasome activation and IL-18 secretion.B. fragilis-derived sphingolipids modulate IL-22 production by IL18R+MHC II+ILC3s.
Rational design of a SOCS1-edited tumor infiltrating lymphocyte therapy for solid tumors using CRISPR/Cas9 screens
Authors: Schlabach Michael R. , Lin Sharon , Collester Zachary , Wrocklage Christopher , Shenker Sol , Calnan Conor , Xu Tianlei , Gannon Hugh , Williams Leila , Thompson Frank , Dunbar Paul , LaMothe Robert A. , Garrett Tracy E. , Colletti Nick , Hohmann Anja F. , Tubo Noah , Bullock Caroline , Le Mercier Isabelle , Sofjan Katri , Merkin Jason J. , Keegan Sean , Kryukov Gregory V. , Dugopolski Caroline , Stegmeier Frank , Wong Karrie , Sharp Fiona A. , Cadzow Louise , Benson Micah J. 
Published: September 2023

AbstractCell therapies such as Tumor Infiltrating Lymphocyte (TIL) therapy have shown promise in the treatment of patients with refractory solid tumors, with improvement in response rates and durability of responses nevertheless sought. To identify targets capable of enhancing the anti-tumor activity of T cell therapies, large-scale in vitro and in vivo CRISPR/Cas9 screens were performed, with the suppressor of cytokine signaling 1 (SOCS1) gene identified as a top T cell-enhancing target. In murine CD8 T cell therapy models, SOCS1 served as a critical checkpoint in restraining the accumulation of T central memory cells in lymphoid organs as well as intermediate (Texint) and effector (Texeff) exhausted T cell subsets derived from progenitor exhausted T cell (Texprog) cells in tumors. A comprehensive CRISPR tiling screen of theSOCS1coding region identified sgRNAs targeting the SH2 domain of SOCS1 as the most potent, with a sgRNA with minimal off-target cut sites used to manufacture KSQ-001, an engineered TIL therapy with SOCS1 inactivated by CRISPR/Cas9. KSQ-001 possessed increased responsiveness to cytokine signals and enhanced in vivo anti-tumor function in mouse models. These data demonstrate the use of CRISPR/Cas9 screens in the rational design of T cell therapies.
Investigating Task-Free Functional Connectivity Patterns in Newborns Using functional Near-Infrared Spectroscopy
Authors: Vahidi Homa , Kowalczyk Alexandra , Stubbs Kevin , Musabi Melab , Roychaudhuri Sriya , Kent Michaela , Bhattacharya Soume , de Ribaupierre Sandrine , Lawrence Keith St. , Mohsenzadeh Yalda , Duerden Emma 
Published: September 2023

AbstractSignificanceResting-state networks (RSN), particularly the sensorimotor network, begin to develop in the third trimester of pregnancy and mature extensively by term age. The integrity and structure of these networks have been linked to neurological health outcomes in neonates, highlighting the significance of monitoring RSN development. To this end, functional near-infrared spectroscopy (fNIRS) has emerged as a neuroimaging technique that utilizes near-infrared light to indirectly measure neural activity by detecting changes in oxygenated (HbO) and deoxygenated (HbR) hemoglobin concentrations. Compared to other imaging methods, fNIRS is non-invasive and allows for naturalistic monitoring of neural activity at the bedside, particularly in awake infants.AimUse fNIRS to expand on previous findings regarding the development of functional networks in awake neonates.ApproachfNIRS was acquired in 41 term-born neonates (17 females, gestational age range=36+0 to 42+1 weeks) within the first 48 hours after birth.ResultsGroup level analysis of functional connectivity showed strong positive connectivity in most channel-pairs over the sensorimotor network, especially the left hemisphere (q < 0.05). Next, we examined the relationship between functional connectivity, gestational age and postnatal age, while controlling for sex and subject effects. Both gestational and postnatal age were found to be positively associated with an increase in functional connectivity in the sensorimotor RSN, especially in channels covering the posterior portion.ConclusionsOur findings emphasize the importance of considering developmental changes in functional networks in awake infants. Moreover, our study demonstrates the potential of fNIRS as a valuable tool for studying neural activity in naturalistic settings in neonates.
Trials and tribulations of Neotropical plant taxonomy: pace of tree species description
Authors: Luján Manuel , Lemos Rosalinda Medina , Lucas Eve , Michelangeli Fabián A. , Prance Ghillean , Pennington Terry D. , Rzedowski Jerzy , Santamaría-Aguilar Daniel , Serpell Ella , Sothers Cynthia , Zuntini Alexandre R. 
Published: September 2023

SummaryOne of the main aspects of taxonomic research is the description of new species. Identifying how to describe new species more efficiently is key to completing the inventory of the Neotropical flora in an era of massive biodiversity loss.Here we calculate the interval between first specimen collection and new species publication for a group of 2126 Neotropical trees, and discuss the historical context surrounding specimen collection and new species publication events.Our results reveal that on average, it takes almost 16 years from specimen collection to publication of a new Neotropical tree species, which is considerably shorter than previous estimates for other tropical groups. The central Andes is the region that had the longest average time lags, while the Choco had the shortest. Peru had the longest average time lags by country, while Haiti had the shortest. The average time lags increased until the early 1900s, when a decrease was observed, with the shortest lags between 1941 to 1960.We found that the majority of the species described more rapidly are from plants collected and described by the same researcher. We demonstrate how political instability and conflict can delay or impede the completion of research initiatives in the region. We argue that enhancing international collaboration and training opportunities in Latin American countries, as well as ensuring safe plant collection campaigns, are critical to complete the inventory of the Neotropical flora.Societal Impact StatementThis study aims to answer the question of how long it takes to describe a new species of tree in the Neotropics by calculating the time elapsed from collection of the first specimen to the publication of a new species. Given the current unprecedented concerns for global biodiversity loss, it is critical to identify best practices for describing new species more efficiently so we can complete the inventory of the Neotropical flora and implement appropriate conservation strategies in a timely manner.
Salinity plays a limited role in determining rates of size evolution in fishes globally across multiple scales
Authors: Clarke John T. , Davis Robert B. 
Published: September 2023

ABSTRACTSubstantial progress has been made to map biodiversity and its drivers across the planet at multiple scales, yet studies that quantify the evolutionary processes that underpin this biodiversity, and test their drivers at multiple scales, are comparatively rare. Studying most fish species, we quantify rates of body size evolution to test the role of fundamental salinity habitats in shaping rates of evolution at multiple scales. We also determine how four additional factors shape evolutionary rates.In up to 1710 comparisons studying over 27,000 ray-finned fish species, we compare rates of body size evolution between five salinity habits using 12 metrics. The comparisons span a molecular tree, supertrees, and ten scales of observation to test for robust patterns and reveal how patterns change with scale. Then, three approaches assess the role of three non-salinity factors on rates, and an alternative habitat scheme tests if lakes influence evolutionary rates.Rates of size evolution rarely differ consistently between salinity habitats; rate patterns are highly clade- and scale-dependent. One exception is freshwater-brackish fishes, which possess among the highest size rates of any salinity, and show higher rates than euryhaline fishes in most groupings studied at most scales, and verses marine, freshwater, and marine-brackish habitats at specific scales. Additionally, species richness had the greatest potential to predict phenotypic rates, followed by branch duration and absolute values of body size. Lacustrine environments were consistently associated with high rates of size evolution.We reveal the rate patterns that underpin global body size diversity for fishes, identifying factors that play a limited role in shaping rates of size evolution, such as salinity, and those such as species richness, age, and lake environments that consistently shape evolutionary rates across half of vertebrate diversity.
Distinct adrenal gland macrophages regulate corticosteroid production
Authors: O’Brien Conan JO , Sidarta-Oliveira Davi , Stawiarski Aleksander , Ratti Giorgio , Loyher Pierre-Louis , Makhlouf Mélanie , AbouMoussa Eman H , Haberman Emma , Sweeney Charles , Mizuno Yusuke , Ishii Tomohiro , Hasegawa Tomonobu , Gomez-Sanchez Elise P , Gomez-Sanchez Celso E , Gordon Siamon , Greaves David R , Saraiva Luis R , Geissmann Frederic , Domingos Ana I 
Published: September 2023

SummaryThe adrenal glands are hormone secreting glands that sit on top of the kidneys. Adrenal glands produce glucocorticoids, mineralocorticoids, and catecholamines, and are therefore critical regulators of the stress response, the immune response, metabolism, and blood pressure. Despite being identified for more that 30 years, our understanding of adrenal macrophages remains incomplete. In numerous other tissues, macrophages carry out a plethora of physiological and homeostatic roles in addition to their classical immune functions. The aim of this study was to characterise the macrophage compartment of the adrenal gland and assess its contribution to adrenal function. Using anin vivoapproach, we herein describe two morphologically and spatially distinct subsets of adrenal macrophages – dendritic-like macrophages that are present throughout the gland in young and old mice, and “foamy” lipid-laden macrophages that accumulate in the murine adrenal cortex in an age and diet-dependent manner. Furthermore, we present data showing that these foamy-like macrophages accumulate cholesterol and thereby regulate adrenal hormonal output, at steady state and in the context of obesity. We hereby provide novel insights into the physiological roles of macrophages in the adrenal gland and the mechanisms by which adrenal hormone production is regulated.
Chromosome-level genome assembly for the angiospermSilene conica
Authors: Fields Peter D. , Weber Melody M. , Waneka Gus , Broz Amanda K. , Sloan Daniel B. 
Published: September 2023

AbstractThe angiosperm genusSilenehas been the subject of extensive study in the field of ecology and evolution, but the availability of high-quality reference genome sequences has been limited for this group. Here, we report a chromosome-level assembly for the genome ofSilene conicabased on PacBio HiFi, Hi-C and Bionano technologies. The assembly produced 10 scaffolds (one per chromosome) with a total length of 862 Mb and only ∼1% gap content. These results confirm previous observations thatS. conicaand its relatives have a reduced base chromosome number relative to the genus’s ancestral state of 12.Silene conicahas an exceptionally large mitochondrial genome (>11 Mb), predominantly consisting of sequence of unknown origins. Analysis of shared sequence content suggests that it is unlikely that transfer of nuclear DNA is the primary driver of this mitochondrial genome expansion. More generally, this assembly should provide a valuable resource for future genomic studies inSilene, including comparative analyses with related species that recently evolved sex chromosomes.SignificanceWhole-genome sequences have been largely lacking for species in the genusSileneeven though these flowering plants have been used for studying ecology, evolution, and genetics for over a century. Here, we address this gap by providing a high-quality nuclear genome assembly forS. conica, a species known to have greatly accelerated rates of sequence and structural divergence in its mitochondrial and plastid genomes. This resource will be valuable in understanding the coevolutionary interactions between nuclear and cytoplasmic genomes and in comparative analyses across this highly diverse genus.
Cross-tolerance evolution is driven by selection on heat tolerance inDrosophila subobscura
Authors: Castañeda Luis E. 
Published: September 2023

ABSTRACTThe evolution of heat tolerance is a crucial mechanism for the adaptive response to global warming, but it depends on the genetic variance carried by populations and on the intensity of thermal stress in nature. Experimental selection studies have greatly benefited research into heat tolerance, providing valuable insights into its evolutionary process. However, the impact of varying levels of heat stress intensity on the associated changes in resistance traits has not yet been explored. Here, the correlated evolution of increasing knockdown temperature inDrosophila subobscurawas evaluated on the knockdown time at different stress temperatures (35, 36, 37, and 38 °C), thermal death time (TDT) curves, and desiccation and starvation resistance. The selection of heat tolerance was performed using different ramping temperatures to compare the impact of heat intensity selection on resistance traits. Correlated evolution was found for these four resistance traits inD. subobscura, indicating that the evolutionary response to tolerance of higher temperatures also confers the ability to tolerate other stresses such as desiccation and starvation. However, these correlated responses depended on the intensity of thermal selection and sex, which may limit our ability to generalize these results to natural scenarios. Nevertheless, this study confirms the value of the experimental evolutionary approach for exploring and understanding the adaptive responses of natural populations to global warming.
Regulatory Transposable Elements in the Encyclopedia of DNA Elements
Authors: Du Alan Y. , Chobirko Jason D. , Zhuo Xiaoyu , Feschotte Cédric , Wang Ting 
Published: September 2023

AbstractTransposable elements (TEs) make up about half of the human genome and many have the biochemical hallmarks of tissue- or cell type-specificcis-regulatory elements. While some TEs have been rigorously documented to contribute directly to host gene regulation, we still have a very partial view of their regulatory landscape. Leveraging Phase 4 ENCODE data, we carried out the most comprehensive study to date of TE contributions to the regulatory genome. Here we investigated the sequence origins of candidatecis-regulatory elements (cCREs), showing that ∼25% of human cCREs comprising 236,181 elements are derived from TEs. Human-mouse comparisons indicate that over 90% of TE-derived cCREs are lineage-specific, accounting for 8-36% of lineage-specific cCREs across cCRE types. Next, we found that cCRE-associated transcription factor (TF) binding motifs in TEs originated from TE ancestral sequences significantly more than expected in all TE classes except for SINEs. Using both cCRE and TF binding data, we discovered that TEs providing cCREs and TF binding sites are closer in genomic distance to non-TE sites compared to other TEs, suggesting that TE integration site influences their later co-option as regulatory elements. We show that TEs have promoted TF binding site turnover events since human-mouse divergence, accounting for 3-56% of turnover events across 30 TFs examined. Finally, we demonstrate that TE-derived cCREs share similar features with non-TE cCREs, including massively parallel reporter assay activity and GWAS variant enrichment. Overall, our results substantiate the notion that TEs have played an important role in shaping the human regulatory genome.