bluuebunny/crossref_metadata_2025_split huggingface dataset:
Simultaneous Pancreas-Kidney Transplant Outcomes Stratified by Autoantibodies Status and Pretransplant Fasting C-peptide
Authors: Parajuli Sandesh , Tamburrini Riccardo , Aziz Fahad , Dodin Ban , Astor Brad C. , Mandelbrot Didier , Kaufman Dixon , Odorico Jon 
Published: October 2024

Backgrounds.
Pancreatic beta cell function and islet autoantibodies classically distinguish types of diabetes (type 1 diabetes mellitus [DM] or type 2 DM). Here, we sought to evaluate simultaneous pancreas-kidney (SPK) transplant outcomes stratified by the presence or absence of beta cell function and autoantibodies.

Methods.
SPK recipients were eligible if pretransplant autoantibodies were measured against insulin, islet cell, or glutamic acid decarboxylase 65-kD isoform. Recipients were categorized as A+ or A– based on the detection of ≥1 autoantibodies. Recipients were similarly categorized on the basis of detectable pretransplant fasting C-peptide of ≥2 ng/mL (β+) or <2 ng/mL (β–). Thus, recipients were categorized into 4 groups: A+β–, A–β–, A–β+, and A+β+. Outcomes of interest were overall pancreas graft failure (non–death-censored), death-censored pancreas, or kidney graft failure (death-censored pancreas graft failure [DCGF]; kidney DCGF), composite outcomes with any of the 3 outcomes as pancreas DCGF, use of an antidiabetic agent, or hemoglobin A1c >6.5.

Results.
One hundred eighty-three SPK recipients were included: A+β– (n = 72), A–β– (n = 42), A–β+ (n = 49), and A+β+ (n = 20). We did not detect a statistical difference in non–death-censored pancreas graft failure for A+β– recipients compared with other groups: A–β– (adjusted hazard ratio [aHR]: 0.44; 95% confidence interval [CI], 0.14-1.42), A–β+ (aHR: 1.02; 95% CI, 0.37-2.85), and A+β+ (aHR: 0.67; 95% CI, 0.13-3.33) in adjusted analyses. Similar outcomes were observed for other outcomes.

Conclusions.
In SPK recipients, outcomes were similar among recipients with classic features of type 1 DM and various other types of DM.
The mineralization of osteonal cement line depends on where the osteon is formed
Authors: Cantamessa A. , Blouin S. , Rummler M. , Berzlanovich A. , Weinkamer R. , Hartmann M.A. , Ruffoni D. 
Published: October 2024

AbstractThe cement line (CL) is a thin layer separating secondary osteons from interstitial bone and other osteons. It is assumed to play a significant role in bone fracture resistance, owing to its ability to deflect or arrest microcracks. Despite the possible role for bone quality, the CL is still one of the least understood microstructural features of bones, with unknowns on CL composition, mineralization, and mechanical properties. This study, focusing on CL mineralization, aims to elucidate the interplay between the mineral content of the CL and of adjacent bone tissue. Using quantitative backscattered electron imaging, osteons with different degrees of mineralization coming from human femoral samples were analyzed. We implemented a spatially resolved analysis of the mineral content in layers along the CL, considering both regions inside the osteon (i.e., formed soon after CL deposition) and outside (i.e., already present at the time of CL deposition). We found that the mineral content of the CL correlates strongly with the mineral content outside of the osteon, but not inside. Assuming the mineral content of the osteon as a proxy of its age, we demonstrate that not only the osteon, but also the CL increases its mineral content with time. However, the rate of increase is lower in the CL. Importantly, the specific value of the high initial mineral content of the CL depends on the mineral content of the local surrounding, in which the osteon was formed. Our findings highlight the central role of the local degree of mineralization of the bone around the osteon for building the CL.
A novel approach to digital characterisation of Tertiary Lymphoid Structures in colorectal cancer
Authors: Munoz-Erazo Luis , Park Saem Mul , Lin Shelly , Chen Chun-Jen J. , Zhou Lisa Y.Y. , Rhodes Janet L , Jeon Taesung , Fenton Sonya , McCall John L. , Kemp Roslyn A. , Dunbar P. Rod 
Published: October 2024

AbstractTertiary Lymphoid Structures (TLS) in cancer tissue are potential sites for the organisation of immune responses to cancer, and correlate positively with improved clinical outcomes for patients including in colorectal cancer (CRC). However it has proven challenging to standardise assessment of TLS due to the highly variable appearances of circumscribed domains of TLS within tissue sections. A recent three-dimensional reconstruction of TLS in CRC tissue showed that TLS are often large, multi-lobular structures, suggesting that assessing TLS across whole sections may be necessary to provide an accurate view of TLS activity in a patient’s tumour. In a pilot study we therefore used whole slide scans of multiplexed immunofluorescence images to characterise TLS from 22 subjects with CRC. Multiplexed staining for CD20, CD3, CD8, FoxP3 and Ki-67 enabled us to identify B-cells, CD8+ T cells, FoxP3– CD4 T-cells, and Foxp3+ CD4 T cells in all sections, and quantify both the presence of these cell subsets in lymphocytic clusters and their degree of proliferation within those clusters. In total we identified 524 lymphocytic clusters with morphology consistent with TLS. The count of TLS domains varied substantially between samples (from 4 to 100, mean 24) as did the proportion of total section area occupied by TLS (0.2%-7.8%) as well as size, morphology and cellular constituents; reflecting the intersection of the section plane with complex 3-dimensional structures. We quantified proliferation of B-cells and T-cell subsets within TLS domains across entire sections and compared to the canonical approach of counting and phenotyping individual TLS domains. The whole-slide approach proved far simpler than the canonical approach, generating digital summaries across our sample set clearly identifying patients with strikingly different levels of immune activity within their TLS. It also allowed us to demonstrate strong correlations between the proliferation of B-cells within CRC TLS and that of T-cell subsets. In summary we find that whole-section digital quantification of immune cell activity within TLS has major advantages over canonical approaches. Such whole-section approaches should accelerate research into correlations between TLS status and clinical outcomes, and ultimately enable standardised clinical tests based on automated analysis of multiplexed images.
IgG autoantibodies in bullous pemphigoid directly induce a pathogenic MyD88-dependent pro-inflammatory response in keratinocytes
Authors: Bao Lei , Juarez Christian F. Guerrero , Li Jing , Pigors Manuela , Emtenani Shirin , Liu Yingzi , Ahmed Aadil , Ishii N , Hashimoto T , White Bethany E. Perez , Green Stefan , Kunstman Kevin , Nowak Nicole C , Cole Connor , Macias Virgilia , Sverdlov Maria , McAlexander M. Allen , McCrae Christopher , Nazaroff Christopher D. , Schmidt Enno , Amber Kyle T. 
Published: October 2024

AbstractWhile autoantibodies in bullous pemphigoid (BP) are known to activate the innate immune response, their direct effect on keratinocytes, and the contribution of BP-IgG autoantibody-dependent keratinocyte responses to BP pathology is largely unknown. Herein, we performed multiplex immunoassays and bulk RNA-seq on primary keratinocytes treated with IgG from BP patients or controls. We identified a pro-inflammatory and proteolytic response with release of several cytokines (IL-6, IL-24, TGF-β1), chemokines (CXCL16, CTACK, MIP-3β, RANTES), C1s, DPP4, and MMP-9. We further validated this response using spatial transcriptomics and scRNA-seq of diseased and control skin. Blistering itself appeared to be major driver of this inflammatory response, with attached BP skin and spongiotic dermatitis revealing highly similar transcriptomes. Based on elevated levels of MyD88 and MyD88-dependent cytokines, we studied the impact of MyD88 deficiency in keratinocytes and demonstrated that MyD88 regulates BP-IgG-induced expression of IL-8, IL-24, and MMP-9. Induction of experimental BP in mice withKrt14-specificMyd88knockout revealed significantly decreased disease severity with decreased serum levels of IL-1β, IL-4, and IL-9 indicating the contributory role of keratinocyte-derived skin inflammation towards systemic response. Our work demonstrates the key contributions of keratinocyte and MyD88 dependent signaling in response to autoantibodies in BP.Key Messages-IgG antibodies from bullous pemphigoid (BP) patients induce significant upregulation of several inflammatory markers in keratinocytes including cytokines (IL-6, IL-24, TGF-β1), chemokines (CXCL16, CTACK, MIP-3β, RANTES), C1s, DPP4, and MMP9. Several of these markers, including IL-8, IL-24, and MMP9 are regulated by MyD88.-Spatial transcriptomics reveals that BP patient blistered skin demonstrated similar transcriptomic profiles to BP-IgG-treated keratinocytes. With attached skin demonstrating a comparable transcriptome to that seen in spongiotic dermatitis.-In a mouse BP model, keratinocyte-specific MyD88 deficiency results in decreased disease severity with a subsequent decrease in serum IL-1β, IL-4, and IL-9 levels.Capsule summaryIgG from patients with bullous pemphigoid (BP) induces a pro-inflammatory response in keratinocytes, indicating their direct role in driving the inflammatory response in BP.
Spatial variations in sap flow rates in mature tree stems before and after drilling treatment
Authors: Umebayashi Toshihiro , Saitoh Taku M. , Tsuruta Kenji , Otieno Dennis 
Published: October 2024

AbstractThe dye uptake and heat transfer methods are used to understand sap movement in mature tree stems, but correlation of results between both methods is weak. The circumferential variation of sap movement is detected generally in the heated transfer method. On the other hand, the tangential movement such as helical ascent is tracked in dye uptake method. It is still unclear whether the circumferential and the tangential movements in both methods mean same and/or related phenomenon. In this study, we monitored sap flux density (Fd) on the east and west sides in intact stems ofBetula ermaniiCham. using the thermal-dissipation method to identifyFdresponse to the creation of artificial flows through severed vessels by drill treatments. We then tracked sap flow by injecting dye solution. TheFdvalues in east side tended to be higher than that in west side before drilling treatment. SimilarFdvalues in both sides were detected after drilling treatments, and dye heights were similar toFdvalues after drilling in any sides. Simple comparison of water ascent using both methods can lead to errors, because water ascent from severed vessels may differ from water ascent via roots.
In vivotwo-photon FLIM resolves photosynthetic properties of maize bundle sheath cells
Authors: Chen Zhufeng , Li Jing , Wang Baichen , Tian Lijin 
Published: October 2024

AbstractMaize (Zea maysL.) performs highly efficient C4photosynthesis by dividing photosynthetic metabolism between mesophyll and bundle sheath cells.In vivophysiological measurements are indispensable for C4photosynthesis research as any isolated cells or sectioned leaf often show interrupted and abnormal photosynthetic activities. Yet, directin vivoobservation regarding bundle sheath cells in the delicate anatomy of the C4leaf is still challenging. In the current work, we used two-photon fluorescence-lifetime imaging microscopy (two-photon-FLIM) to access the photosynthetic properties of bundle sheath cells on intact maize leaves. The results provide spectroscopic evidence for the diminished total PSII activity in bundle sheath cells at its physiological level and show that the single PSIIs could undergo charge separation as causal. We also report an acetic acid-induced chlorophyll fluorescence quenching on intact maize leaves, which might be a physiological state related to the nonphotochemical quenching mechanism.
Opioid receptors reveal a discrete cellular mechanism of endosomal G protein activation
Authors: Fisher Nicole M. , von Zastrow Mark 
Published: October 2024

AbstractMany GPCRs initiate a second phase of G protein-mediated signaling from endosomes, which inherently requires an increase in G protein activity on the endosome surface. Gs-coupled GPCRs are thought to achieve this by internalizing and allosterically activating cognate G proteins again on the endosome membrane. Here we demonstrate that the μ-opioid receptor (MOR), a Gi-coupled GPCR, increases endosomal G protein activity in a different way. Leveraging conformational biosensors, we resolve the subcellular activation dynamics of endogenously expressed MOR and Gi/o-subclass G proteins. We show that MOR activation triggers a transient increase of active-state Gi/oon the plasma membrane that is followed by a prolonged increase on endosomes. Contrary to the Gs-coupled GPCR paradigm, however, we show that the MOR-induced increase of active-state Gi/oon endosomes requires neither internalization of MOR nor activation of MOR in the endosome membrane. We propose a distinct and additional cellular mechanism for GPCR-triggered elevation of G protein activity on endosomes that is mediated by regulated trafficking of the activated G protein rather than its activating GPCR.
The effects of conditional loss of myosin binding protein H-like on cardiac function
Authors: Burnham Hope V. , Peña Alex , Gandhi Shreeya , Fritzmann Geena , Barefield David Y 
Published: October 2024

ABSTRACTMutations in the myosin-binding protein H-like (MyBP-HL) gene,MYBPHL, are linked to hereditary dilated cardiomyopathy (DCM), atrial fibrillation, and atrioventricular arrhythmias. MyBP-HL is a sarcomeric protein that is highly expressed in the atria with only scarce, distinct clusters of MyBP-HL positive cells within and surrounding the ventricular conduction system. Constitutive knock-out of MyBP-HL in mice causes atrial dilation, arrhythmia, and DCM. Whether MyBP-HL plays a developmental role, or if knock-down in adulthood will recapitulate a similar phenotype has yet to be examined. Moreover, the significance of the MyBP-HL expressing ventricular cells, or the functional need for differential thick filament regulation is currently unknown.We used a conditional floxedMybphlmouse to further elucidate the role of MyBP-HL. We crossed this mouse with a ROSA26-Cre(ERT2) LoxP mouse to conditionally knock-downMybphlafter tamoxifen treatment. We also crossed theMybphlflox mouse with a Contactin-2-Cre mouse that deletesMybphlsolely in the cardiac conduction system from birth. Echocardiography was used to measure contractile function, and conscious telemetry allowed for monitoring of heart rhythm and electrical signal conduction changes.We demonstrate that mice with conditional decrease of MyBP-HL in adulthood develop a hypertrophic phenotype with atrial contractile changes, increased total heart weight to body weight, and increased heart rate variability. Deletion ofMybphlsolely within the cardiac conduction system trends toward mild hypercontractility, lower heart rates, and interventricular septal thickening. These data show that MyBP-HL is essential for proper cardiac function, and even minor alteration in protein levels cause a diseased cardiac phenotype.
Mesoscale regulation of MTOCs by the E3 ligase TRIM37
Authors: Yeow Zhong Y. , Sarju Sonia , Breugel Mark v. , Holland Andrew J. 
Published: October 2024

AbstractCentrosomes ensure accurate chromosome segregation during cell division. Although the regulation of centrosome number is well-established, less is known about the suppression of non-centrosomal MTOCs (ncMTOCs). The E3 ligase TRIM37, implicated in Mulibrey nanism and 17q23-amplified cancers, has emerged as a key regulator of both centrosomes and ncMTOCs. Yet, the mechanism by which TRIM37 achieves enzymatic activation to target these mesoscale structures had remained unknown. Here, we elucidate TRIM37’s activation process, beginning with TRAF domain-directed substrate recognition, progressing through B-box domain-mediated oligomerization, and culminating in RING domain dimerization. Using optogenetics, we demonstrate that TRIM37’s E3 activity is directly coupled to the assembly state of its substrates, activating only when centrosomal proteins cluster into higher-order assemblies resembling MTOCs. This regulatory framework provides a mechanistic basis for understanding TRIM37-driven pathologies and, by echoing TRIM5’s restriction of the HIV capsid, unveils a conserved activation blueprint among TRIM proteins for controlling mesoscale assembly turnover.
Evaluating the risk of mosquito-borne diseases in non-endemic regions: A dynamic modeling approach
Authors: Stollenwerk Nico , Mateus Luís , Steindorf Vanessa , Guerrero Bruno V. , Blasco-Aguado Rubén , Cevidanes Aitor , Bidaurrazaga Van-Dierdonck Joseba , Aguiar Maíra 
Published: October 2024

AbstractMosquito-borne diseases are spreading into temperate zones, raising concerns about local outbreaks driven by imported cases. Using stochastic methods, we developed a vector-host model to estimate the risk of import-driven autochthonous outbreaks in non-endemic regions. The model explores key factors such as imported cases and vector abundance. Our analysis shows that mosquito population abundance significantly affects the probability and timing of outbreaks. Even with moderate mosquito populations, isolated or clustered outbreaks can be triggered, highlighting the importance of monitoring vector abundance for effective public health planning and interventions.
Effects of oral contraceptive pills on brain networks: A replication and extension
Authors: Haase Gino , Liu Jason , Jordan Timothy , Rapkin Andrea , London Edythe D. , Petersen Nicole 
Published: October 2024

AbstractNeuroimaging research has identified significant effects of oral contraceptive pills (OCPs) on brain networks. A wide variety of approaches have been employed, largely in observational samples, with few converging results. This study therefore was designed to test for replication and extend this previous work using a randomized, double-blind, placebo-controlled crossover trial of the effects of OCPs on brain networks. Using functional MRI, we focused on brain regions identified in prior studies. Our analyses did not strictly replicate previously reported effects of OCPs on functional connectivity. Exploratory analyses suggested that traditional seed-based approaches may miss broader, network-level effects of OCPs on brain circuits. We applied data-driven, multivariate techniques to assess these network-level changes, A deeper understanding of neural effects of OCPs can be important in helping patients make informed decisions regarding contraception, mitigating unwanted side effects. Such information can also identify potentially confounding effects of OCPs in other neuroimaging investigations.
Tumor suppressor miR-317 and lncRNA Peony are expressed from a polycistronic non-coding RNA locus that regulates germline differentiation and testis morphology
Authors: Carney Travis D. , Shcherbata Halyna R. 
Published: October 2024

AbstractThis research focuses on investigating the impact of non-coding RNAs on stem cell biology and differentiation processes. We found thatmiR-317plays a role in germline stem cell progeny differentiation.miR-317and its neighbor, the lncRNAPeony,originate and are co-expressed from a singular polycistronic non-coding RNA locus. Alternative polyadenylation is implicated in regulation of their differential expression. While the increased expression of the lncRNAPeonyresults in the disruption of the muscle sheath covering the testis, the absence ofmiR-317leads to the emergence of germline tumors in young flies. The deficiency ofmiR-317increases Notch signaling activity in the somatic cyst cells, which drives germline tumorigenesis. Germline tumors also arise from upregulation of several predicted targets ofmiR-317, among which are regulators of the Notch pathway. This implicatesmiR-317as a novel tumor suppressor that modulates Notch signaling strength.
Sanfetrinem, an oral β-lactam antibiotic repurposed for the treatment of tuberculosis
Authors: Ramón-García Santiago , González del Río Rubén , Arenaz-Callao María Pilar , Boshoff Helena , Rullás Joaquín , Anca Sara , Izquierdo Mónica Cacho , Porras de Francisco Esther , Herrán Esther Pérez , Santos-Villarejo Angel , Mendoza-Losana Alfonso , Ferrer-Bazaga Santiago , Thompson Charles J. , Aguirre David Barros , Bates Robert H. 
Published: October 2024

ABSTRACTTuberculosis (TB) is historically the world’s deadliest infectious disease. New TB drugs that can avoid pre-existing resistance are desperately needed. The β-lactams are the oldest and most widely used class of antibiotics to treat bacterial infections but, for a variety of reasons, they were largely ignored until recently as a potential treatment option for TB. Recently, a growing body of evidence indicates that later-generation carbapenems in the presence of β-lactamase inhibitors could play a role in TB treatment. However, most of these drugs can only be administered intravenously in the clinic.We performed a screening of β-lactams against intracellularMycobacterium tuberculosis (Mtb)and identified sanfetrinem cilexetil as a promising oral β-lactam candidate. Preclinicalin vitroandin vivostudies demonstrated that: (i) media composition impacts the activity of sanfetrinem againstMtb, being more potent in the presence of physiologically relevant cholesterol as the only carbon source, compared to the standard broth media; (ii) sanfetrinem shows broad spectrum activity againstMtbclinical isolates, including MDR/XDR strains; (iii) sanfetrinem is rapidly bactericidalin vitroagainstMtbdespite being poorly stable in the assay media; (iv) there are strongin vitrosynergistic interactions with amoxicillin, ethambutol, rifampicin and rifapentine and, (v) sanfetrinem cilexetil is active in anin vivomodel of infection. These data, together with robust pre-clinical and clinical studies of broad-spectrum carbapenem antibiotics carried out in the 1990s by GSK, identified sanfetrinem as having potential for treating TB and catalyzed a repurposing proof-of-concept Phase 2a clinical study (NCT05388448) currently underway in South Africa.
Plasma Exosomes in Insulin Resistant Obesity Exacerbate Progression of Triple Negative Breast Cancer
Authors: Llevenes Pablo , Chen Andrew , Lawton Matthew , Qiu Yuhan , Seen Michael , Monti Stefano , Denis Gerald V. 
Published: October 2024

AbstractBreast cancer, the most common cancer among women worldwide, continues to pose significant public health challenges. Among the subtypes of breast cancer, triple-negative breast cancer (TNBC) is particularly aggressive and difficult to treat due to the absence of receptors for estrogen, progesterone, or human epidermal growth factor receptor 2, rendering TNBC refractory to conventional targeted therapies. Emerging research underscores the exacerbating role of metabolic disorders, such as type 2 diabetes and obesity, on TNBC aggressiveness. Here, we investigate the critical cellular and molecular factors underlying this link. We explore the pivotal role of circulating plasma exosomes in modulating the tumor microenvironment and enhancing TNBC aggressiveness. We find that plasma exosomes from diet-induced obesity mice induce epithelial- mesenchymal transition features in TNBC cells, leading to increased migrationin vitroand enhanced metastasisin vivo. We build on our previous reports demonstrating that plasma exosomes from obese, diabetic patients, and exosomes from insulin-resistant 3T3-L1 adipocytes, upregulate key transcriptional signatures of epithelial- mesenchymal transition in breast cancer. Bioinformatic analysis reveals that TNBC cells exhibit higher expression and activation of proteins related to the Rho-GTPase cascade, particularly the small Ras-related protein Rac1. Our approach suggests novel therapeutic targets and exosomal biomarkers, ultimately to improve prognosis for TNBC patients with co-morbid metabolic disorders.