bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical and Histopathological Findings in HIV-positive to HIV-positive Kidney Transplant Recipients
Authors: Wearne Nicola , Botha Francois , Manning Kathryn , Price Brendon , Barday Zunaid , Post Frank A. , Freercks Robert , Bertels Laurie , Mtingi-Nkonzombi Lungiswa , Muller Elmi 
Published: November 2024

Background.
The spectrum of histological findings in transplanted kidneys from HIV-positive donors to HIV-positive recipients is relatively unexplored. This study describes the type and timing of histological diagnoses observed in this unique cohort.

Methods.
Adequate biopsies were analyzed at implantation and posttransplant between September 2008 and May 2022. Histological disease spectrum, distributions over time, and relevant clinical characteristics and management were reported for both for-cause and protocol biopsies.

Results.
Twenty-four implantation biopsies from 31 deceased donors and 179 allograft biopsies (100 for-cause, 79 protocol) from 50 recipients were analyzed. Most rejection episodes occurred in the first year posttransplant. Eighteen recipients (36%) had at least 1 episode of biopsy-confirmed acute/chronic T cell–mediated rejection (TCMR) or active antibody-mediated rejection (AMR). Protocol biopsies showed no active AMR or acute/chronic TCMR. However, 9 of 79 biopsies identified borderline/suspicious TCMR. Common nonrejection diagnoses were interstitial fibrosis and tubular atrophy, ascending pyelonephritis, and calcineurin inhibitor toxicity. Classic and suspected HIV-associated nephropathy (HIVAN) were identified in 3 and 6 patients, respectively. Protocol biopsies diagnosed 1 case of classic HIVAN and 6 cases of suspected HIVAN. AMR most adversely affected kidney function and significantly contributed to graft failure.

Conclusions.
The histological findings in this cohort of HIV-positive kidney transplant recipients who received grafts from unmatched HIV-positive donors revealed a spectrum of abnormalities. Protocol biopsies added to surveillance on borderline rejection and assisted in the recognition of HIVAN. Confirmed rejection occurred in 18 recipients (36%). Understanding the factors contributing to this may assist in the optimization of immunosuppressive protocols in the future.
Increased Systemic Immune-Inflammatory Index and Association with Occult Nodal Disease in Non-Small Cell Lung Cancer
Authors: Khan Arsalan A , Shah Savan K , Basu Sanjib , Alex Gillian C , Liptay Michael J , Geissen Nicole M , Seder Christopher W 
Published: November 2024

Background:
It has been proposed that more aggressive tumors trigger a stronger inflammatory response than less aggressive types. We hypothesize that systemic immune inflammatory index (SII) is associated with occult nodal disease (OND) in clinically node negative (cN0) patients undergoing lung resection for non-small cell lung cancer (NSCLC).

Study Design:
The study included patients who underwent lung resection with nodal dissection, according to current guidelines, at a single center between 2010-2021 for NSCLC. Pre-operative SII within three weeks of surgery, was calculated. OND was defined as a clinically node-negative patient found to be pathologically node-positive. Cut-point analysis for SII was performed to identify the level most strongly associated with OND. Univariable and multivariable logistic regressions were used to examine the association between SII, clinical factors, and OND.

Results:
A total of 199 patients met inclusion criteria, of which 51% (102/199) were female. The median number of nodes and nodal stations examined was 13 (IQR 9-17) and 6 (IQR 5-6), respectively. The cut-point was determined to be SII ≥112. On univariable analysis, high SII was associated with OND (OR 15.75, CI 2.09-118.73, p=0.007). On multivariable analysis, after controlling for age, BMI, approach, gender, pack years, FEV1, performance status, comorbidities, histology, lymphovascular invasion, tumor differentiation and tumor size, high SII was associated with OND (OR 34.59, CI 2.69-444.88, p=0.007).

Conclusion:
Increased SII is associated with OND in patients undergoing lung resection for NSCLC.
Uninterpretable graphs at a scientific conference
Authors: Faulkes Zen 
Published: November 2024

AbstractComparing averages requires knowing sample variation, which can be shown visually using a bar graph with error bars or a box plot. Because error bars and box plots can show different measures, they must be labelled to be interpretable. Of graphs of averages shown at a scientific conference in 2020, 87.5% of graphs did not contain enough information on the slide to interpret them. The only graphs that were fully interpretable (12.5%) were bar graphs. By comparison, 92% of graphs of averages published in a journal in the same field contained enough information to interpret them. While conferences are not and should not be as stringent about data presentation as journals, that a statistical value as simple as an average are not clearly presented suggests graphs are created by rote.
Rapid and precise quantification of lymphocyte iron content by single cell inductively coupled plasma mass spectrometry
Authors: Holdship Philip , Teh Megan R. , Mazurczyk Michalina , Chuang Huei-Wen , Pironaci Giulia , Hilton Robert G. , Price David , Wade Jon , Drakesmith Hal 
Published: November 2024

AbstractMetals facilitate catalysis during cellular metabolism, but heterogeneity of metal content at single-cell level within and between cell populations is poorly characterized. This is important because deficiencies of biometals, for example iron, are enormously prevalent worldwide. Here we quantify metal content of single-cells using inductively-coupled plasma mass spectrometry. To develop the method, we used rhodium and iridium-intercalated Jurkat cells, obtaining >0.96% r2cross-analytical correlation with mass cytometry. We quantified iron and calcium mass/cell for murine T-lymphocytes with 3% and 8% 2-sigma intra-precision, respectively, when assessing thousands of cells/minute. T-lymphocytes exposed to a 625-fold difference in extracellular iron concentrations maintained close iron homeostatic control, varying ∼20% in iron content. Nevertheless, this relatively small variation strongly correlated with changes in cellular activation characteristics measured by flow cytometry. We also assessed human B-cell iron content, which was ∼10-fold higher than murine T-lymphocytes. Overall, we demonstrate rapid iron quantification at single-cell level in different cell types and relate cellular iron content to cell function.TeaserPrecise and rapid iron metallomics of lymphocytes by single cell ICP-MS is a powerful approach for accessing signatures of immunological status.
Communication subspaces align with training in ANNs
Authors: Poggi Peter G. , Mihalas Stefan , Mastrovito Dana 
Published: November 2024

AbstractCommunication subspaces have recently been identified as a promising mechanism for selectively routing information between brain areas. In this study, we explored whether communication sub-spaces develop with training in artificial neural networks (ANNs) and explored differences across connection types. Specifically, we analyzed the subspace angles between activations and weights in ResNet-50 before and after training. We found that activations were more aligned to the weight layers after training, although this effect decreased in deeper layers. We also analyzed the angles between pairs of weight layers. We found that for all branching, direct, and skip connections, weight layer pairs were more geometrically aligned in trained versus untrained models throughout the entire network. These findings indicate that such alignment is essential for the proper functioning of deep networks and highlights the potential to enhance training efficiency through pre-alignment. In biological data, our results motivate further exploration into whether learning induces similar subspace alignment.
Proteome-wide reverse molecular docking reveals folic acid receptor as a mediator of PFAS-induced neurodevelopmental toxicity
Authors: Kong Ally Xinyi , Johnson Maja , Eno Aiden F , Pham Khoa , Zhang Ping , Geng Yijie 
Published: November 2024

ABSTRACTPer- and polyfluoroalkyl substances (PFAS) are a class of long-lasting chemicals with widespread use and environmental persistence that have been increasingly studied for their detrimental impacts to human and animal health. Several major PFAS species are linked to neurodevelopmental toxicity. For example, epidemiological studies have associated prenatal exposure to perfluorooctanoate (PFOA) and perfluorononanoate (PFNA) with autism risk. However, the neurodevelopmental toxicities of major PFAS species have not been systematically evaluated in an animal model, and the molecular mechanisms underlying these toxicities have remained elusive. Using a high-throughput zebrafish social behavioral model, we screened six major PFAS species currently under regulation by the Environmental Protection Agency (EPA), including PFOA, PFNA, perfluorooctane sulfonate (PFOS), perfluorohexanesulfonic acid (PFHxS), perfluorobutane sulfonate (PFBS), and hexafluoropropylene oxide dimer acid ammonium salt (GenX). We found that embryonic exposure to PFNA, PFOA, and PFOS induced social deficits in zebrafish, recapitulating one of the hallmark behavioral deficits in autistic individuals. To uncover protein targets of the six EPA-regulated PFAS, we screened a virtual library containing predicted binding pockets of over 80% of the 3D human proteome through reverse molecular docking. We found that folate receptor beta (FR-β, encoded by the geneFOLR2) interacts strongly with PFNA, PFOA, and PFOS but to a lesser degree with PFHxS, PFBS, and GenX, correlating positively with theirin vivotoxicity. Embryonic co-exposure to folic acid rescued social deficits induced by PFAS. The folic acid pathway has been implicated in autism, indicating a novel molecular mechanism for PFAS in autism etiology.
ENTPD3-specific CAR Regulatory T cells for Local Immune Control in T1D
Authors: Pieper Tom , Riet Tobias , Saetzler Valerie , Bergerhoff Katharina , McGovern Jenny , Delsing Louise , Atkinson Mark , Lodie Tracey , Jermutus Lutz , Noyan Fatih , Hust Michael , Kusmartseva Irina , Hagedorn Maike , Lieber Maren , Henschel Pierre , Glaser Viktor , Geffers Robert , Yang Mingxing , Polansky-Biskup Julia , Eiz-Vesper Britta , Bonifacius Agnes , Martinez Llordella Marc , Henry Luke , Penston Daniela , Gavriil Artemis , Grothier Thomas , Nikolopoulou Evanthia , Demertzis Nikolaos , Koullourou Victoria , Cox Phillipa , Zarrouki Bader , Sini Marcella , Pfeiff Janice , Matthiesen Isabelle , Hardtke-Wolenski Matthias , Jaeckel Elmar 
Published: November 2024

AbstractDespite advances in Type 1 Diabetes (T1D) management such a hybrid closed loop systems, patients still face significant morbidity, reduced life expectancy, and impaired glucose regulation compared to healthy individuals or those with pancreas transplants.Here we developed beta cell-specific Chimeric Antigen Receptors (CAR) targeting the antigen ectonucleoside triphosphate diphosphohydrolase 3 (ENTPD3) using a novel cell-based phage display methodology. ENTPD3 is highly expressed on beta cells of both early and progressed T1D patients. ENTPD3 CAR regulatory T cells (Tregs) homed, expanded and persisted in pancreatic islets in a T1D mouse model (NOD) and completely prevented disease progression. Human ENTPD3 CAR Tregs displayed a stable regulatory phenotype, strong activation, and suppression. Importantly, ENTPD3 CAR T cells recognised and were fully activated by human islets.This approach holds great promise as a durable treatment option for patients with prediabetes, new-onset diabetes, or those undergoing beta cell replacement therapy.
Vertical sleeve gastrectomy in rodents: impact on metabolic, cardiovascular and hepatic functions of mothers and perinatal consequences
Authors: Payen Cyrielle , Guillot Abigaëlle , Chaigneau Julien , Bichot Lucile , Testa Eugénie , Bourreau Jennifer , Gascoin Géraldine , Vessières Emilie , Proux Carolyne , Moal Valérie , Loufrani Laurent , Schmitt Françoise , Fassot Céline 
Published: November 2024

AbstractBackgroundMaternal obesity is a well-known risk factor for obstetrical complications during pregnancy, and cardiovascular and metabolic pathologies in the offspring. In the last two decades, bariatric surgery has emerged as the most effective treatment for severe obesity, and is known to improve fertility, leading to a rise in procedures among women of childbearing age.ObjectivesThis study investigates the impact of pre-conceptional sleeve gastrectomy (SG) on metabolic, cardiovascular and hepatic functions of mothers at short and middle terms after surgery, and its perinatal consequences.MethodsSprague-Dawley female control rats (CM) received a standard diet, while others were fed a high-fat, high-sugar diet (HFHS). HFHS rats were divided into obese mothers (OM) and sleeve gastrectomy mothers (SM). One month after surgery, all groups underwent gestation and subsequent lactation Metabolic function was assessed at 1 and 4 months after surgery; cardiovascular and hepatic functions were evaluated only 4 months after SG.ResultsFrom 1 month post-surgery, SM showed normalized leptin and insulin levels compared to OM. Moreover, SG normalized body weight associated with a decreased white adipose tissue weight and adipocyte size at 4 months post-surgery. Interestingly, although steatosis has been detected in HFHS rats, SM exhibited only hepatic fibrosis at 4 months post-surgery. Moreover, SM showed a hypertrophic remodeling of thoracic aorta without effect on its vasoreactivity but along with endothelial dysfunction of mesenteric artery, associated with a stronger involvement of COX/PGI2 pathway. In the offspring, obesity in mothers was associated to a decreased liter size, reversed by sleeve gastrectomy without any effect on the birth weight of pups.ConclusionWhile this study reports an improvement of metabolic function at short- and medium-terms after bariatric surgery, our results highlight an alteration of hepatic and vascular functions by sleeve gastrectomy, with minimal effect on the offspring in the perinatal period.
Unveiling epigenetic regulatory elements associated with breast cancer development
Authors: Jardanowska-Kotuniak Marta , Dramiński Michał , Własnowolski Michał , Łapiński Marcin , Sengupta Kaustav , Agarwal Abhishek , Filip Adam , Ghosh Nimisha , Pancaldi Vera , Grynberg Marcin , Saha Indrajit , Plewczynski Dariusz , Dąbrowski Michał J. 
Published: November 2024

AbstractBreast cancer is the most common cancer in women and the 2nd most common cancer worldwide, yearly impacting over 2 million females and causing 650 thousand deaths. It has been widely studied, but its epigenetic variation is not entirely unveiled. We aimed to identify epigenetic mechanisms impacting the expression of breast cancer related genes to detect new potential biomarkers and therapeutic targets. We considered The Cancer Genome Atlas database with over 800 samples and several omics datasets such as mRNA, miRNA, DNA methylation, which we used to select 2701 features that were statistically significant to differ between cancer and control samples using the Monte Carlo Feature Selection and Interdependency Discovery algorithm, from an initial total of 417,486. Their biological impact on cancerogenesis was confirmed using: statistical analysis, natural language processing, linear and machine learning models as well as: transcription factors identification, drugs and 3D chromatin structure analyses. Classification of cancer vs control samples on the selected features returned high classification weighted Accuracy from 0.91 to 0.98 depending on feature-type: mRNA, miRNA, DNA methylation, and classification algorithm. In general, cancer samples showed lower expression of differentially expressed genes and increasedβ-values of differentially methylated sites. We identified mRNAs whose expression is well explained by miRNA expression and differentially methylated sitesβ-values. We recognized differentially methylated sites possibly affecting NRF1 and MXI1 transcription factors binding, causing a disturbance inNKAPLandPITX1expression, respectively. Our 3D models showed more loosely packed chromatin in cancer. This study successfully points out numerous possible regulatory dependencies.
Boosting GPT Models for Genomics Analysis: Generating Trusted Genetic Variant Annotations and Interpretations through RAG and fine-tuning
Authors: Lu Shuangjia , Cosgun Erdal 
Published: November 2024

AbstractLarge language models (LLMs) have acquired a remarkable level of knowledge through their initial training. However, they lack expertise in particular domains such as genomics. Variant annotation data, an important component of genomics, is crucial for interpreting and prioritizing disease-related variants among millions of variants identified by genetic sequencing. In our project, we aimed to improve LLM performance in genomics by adding variant annotation data to LLMs by retrieval-augmented generation (RAG) and fine-tuning techniques. Using RAG, we successfully integrated 190 million highly accurate variant annotations, curated from 5 major annotation datasets and tools, into GPT-4o. This integration empowers users to query specific variants and receive accurate variant annotations and interpretations supported by advanced reasoning and language understanding capabilities of LLMs. Additionally, fine-tuning GPT-4 on variant annotation data also improved model performance in some annotation fields, although the accuracy across more fields remains suboptimal. Our model significantly improved the accessibility and efficiency of the variant interpretation process by leveraging LLM capabilities. Our project also revealed that RAG outperforms fine-tuning in factual knowledge injection in terms of data volume, accuracy, and cost-effectiveness. As a pioneering study for adding genomics knowledge to LLMs, our work paves the way for developing more comprehensive and informative genomics AI systems to support clinical diagnosis and research projects, and it demonstrates the potential of LLMs in specialized domains.
Pleistocene sea-level fluctuation shapes archipelago-wide population structure in the Endangered Lord Howe Island cockroachPanesthia lata
Authors: Adams Maxim W.D. , Ewart Kyle M. , Carlile Nicholas , Rose Harley A. , Walker James A. , Hutton Ian , Ho Simon Y.W. , Lo Nathan 
Published: November 2024

AbstractStudies of biogeographic processes have often centred islands as model systems, yet questions remain about the role of Pleistocene sea-level fluctuations in shaping islands’ biodiversity. One novel, potentially informative model system is the Lord Howe Island Group of Australia. Despite the World Heritage status of this archipelago, almost nothing is known of the biogeographic origins, evolutionary distinctiveness or genetic diversity of the ecological communities across its 28 islands. In this study, we focused on the cockroachPanesthia lata, an ecologically specialized invertebrate with one of the broadest recorded distributions of any LHIG species. To investigate the influence of Pleistocene sea-level fluctuations on LHIG fauna, we explored the phylogeography ofP. latausing single-nucleotide polymorphisms and complete mitochondrial genomes. Our analyses reveal that the lineage on the permanently isolated islet Ball’s Pyramid is highly divergent from the remaining populations, while those on the episodically connected Lord Howe, Roach and Blackburn Islands experienced gene flow during the last glacial period. These results offer the first evidence that Pleistocene land bridges allowed for overland migration across the archipelago. Further, althoughP. latawas believed to have been locally extirpated by rodents on Lord Howe Island, we discovered two surviving, relict populations. We also detected high levels of inbreeding in all populations, emphasizing the need for ongoing conservation management. Finally, the combination of shallow genetic structure and low diversity suggests that genetic rescue from another island may be a viable strategy to conserve the Lord Howe Island population ofP. lata, as well as other species that have been similarly impacted by rodents.
Restoring Synaptic Balance in Schizophrenia: Insights from a thalamo-cortical conductance-based model
Authors: S Berndt Lioba C , Singh Krish D , Shaw Alexander D 
Published: November 2024

AbstractThe dysconnectivity hypothesis of schizophrenia suggests that atypical, aberrant neural communication underlies the disorder’s diverse symptoms. Building on this framework, our study introduces a novel approach to understanding schizophrenia and exploring potential ways to adjust neural activity through synaptic restoration. Using a combination of magnetoencephalography data and dynamic causal modeling, we identified specific synaptic disturbances in schizophrenia patients, including increased NMDA receptor-mediated excitation in superficial pyramidal neurons and reduced GABA-B receptor-mediated inhibition between interneurons and pyramidal cells. These findings reveal a critical imbalance in excitation and inhibition within thalamo-cortical circuits, manifesting as altered gamma and alpha oscillations. The cornerstone of our research is an in silico synaptic restoration analysis, which demonstrates that targeted modifications to AMPA, NMDA, GABA-A, and GABA-B receptor-mediated connections can recalibrate altered neural activity in schizophrenia, aligning it with healthy control patterns. This restoration approach not only highlights the complex nature of synaptic dysfunction in the disorder but also identifies specific pathways as potential therapeutic targets, offering new avenues for investigating schizophrenia’s diverse symptomatology.
Whisker stimulation with different frequencies reveals non-uniform modulation of functional magnetic resonance imaging signal across sensory systems in awake rats
Authors: Paasonen Jaakko , Valjakka Juha S. , Salo Raimo A. , Paasonen Ekaterina , Tanila Heikki , Michaeli Shalom , Mangia Silvia , Gröhn Olli 
Published: November 2024

AbstractPrimary sensory systems are classically considered to be separate units, however there is current evidence that there are notable interactions between them. We examined the cross-sensory interplay by applying a quiet and motion-tolerant zero echo time functional magnetic resonance imaging (fMRI) technique to elucidate the evoked brain-wide responses to whisker pad stimulation in awake and anesthetized rats. Specifically, characterized the brain-wide responses in core and non-core regions to whisker pad stimulation by the varying stimulation-frequency, and determined whether isoflurane-medetomidine anesthesia, traditionally used in preclinical imaging, confounded investigations related to sensory integration. We demonstrated that unilateral whisker pad stimulation not only elicited robust activity along the whisker-mediated tactile system, but also in auditory, visual, high-order, and cerebellar regions, indicative of brain-wide cross-sensory and associative activity. By inspecting the response profiles to different stimulation frequencies and temporal signal characteristics, we observed that the non-core regions responded to stimulation in a very different way compared to the primary sensory system, likely reflecting different encoding modes between the primary sensory, cross-sensory, and integrative processing. Lastly, while the activity evoked in low-order sensory structures could be reliably detected under anesthesia, the activity in high-order processing and the complex differences between primary, cross-sensory, and associative systems were visible only in the awake state. We conclude that our study reveals novel aspects of the cross-sensory interplay of whisker-mediated tactile system, and importantly, that these would be difficult to observe in anesthetized rats.