bluuebunny/crossref_metadata_2025 huggingface dataset:
The radius distribution of M dwarf-hosted planets and its evolution
Authors: Gaidos Eric , Ali Aleezah , Kraus Adam L , Rowe Jason F
Published: September 2024

M dwarf stars are the most promising hosts for detection and characterization of small and potentially habitable planets, and provide leverage relative to solar-type stars to test models of planet formation and evolution. Using Gaia astrometry, adaptive optics imaging, and calibrated gyrochronologic relations to estimate stellar properties and filter binaries, we refined the radii of 117 Kepler objects of interest (confirmed or candidate planets) transiting 74 single late K-type and early M-type stars, and assigned stellar rotation-based ages to 113 of these. We constructed the radius distribution of 115 small (${\lt} 4\, {\rm R}_{\rm{\oplus}}$) planets and assessed their evolution. As for solar-type stars, the inferred distribution contains distinct populations of ‘super-Earths’ (at ${\sim} 1.3 \, {\rm R}_{\rm{\oplus}}$) and ‘sub-Neptunes’ (at ${\sim} 2.2 \, {\rm R}_{\rm{\oplus}}$) separated by a gap or ‘valley’ at ${\approx} 1.7 \, {\rm R}_{\rm{\oplus}}$ that has a period dependence that is significantly weaker (power-law index of −0.03$^{+0.01}_{-0.03}$) than for solar-type stars. Sub-Neptunes are largely absent at short periods (${\lt} 2 \, {\rm d}$) and high irradiance, a feature analogous to the ‘Neptune desert’ observed around solar-type stars. The relative number of sub-Neptunes to super-Earths declines between the younger and older halves of the sample (median age 3.86 Gyr), although the formal significance is low ($p = 0.08$) because of the small sample size. The decline in sub-Neptunes appears to be more pronounced on wider orbits and low stellar irradiance. This is not due to detection bias and suggests a role for H2O as steam in inflating the radii of sub-Neptunes and/or regulating the escape of H/He from them.
A transcription-independent role for HIF-1α in modulating microprocessor assembly
Authors: Li Jie-Ning , Wang Ming-Yang , Ruan Jhen-Wei , Lyu Yu-Jhen , Weng Yi-Hsiu , Brindangnanam Pownraj , Coumar Mohane Selvaraj , Chen Pai-Sheng
Published: September 2024

Microprocessor is an essential nuclear complex responsible for the initial RNase-mediated cleavage of primary miRNA, which is a tightly controlled maturation process that requires the proper assembly of Drosha and DGCR8. Unlike previously identified mechanisms directly targeting the enzymatic subunit Drosha, current knowledge about the biological ways of controlling miRNA nuclear maturation through DGCR8 is less addressed. In this study, we unveiled that the microprocessor assembly is governed by a master gene regulator HIF-1α irrespective of its canonical transcriptional activity. First, a widespread protein binding of HIF-1α with DGCR8 instead of Drosha was observed in response to biological stimulations. Similar protein interactions between their corresponding orthologues in model organisms were also observed. After dissecting the essential protein domains, we noticed that HIF-1α suppresses microprocessor assembly via binding to DGCR8. Furthermore, our results showed that HIF-1α hijacks monomeric DGCR8 thus reducing its dimer formation prior to microprocessor assembly, and consequently, the suppressed microprocessor formation and nuclear processing of primary miRNA were demonstrated. In conclusion, here we unveiled the mechanism of how microprocessor assembly is regulated by HIF-1α, which not only demonstrates a non-transcriptional function of nuclear HIF-1α but also provides new molecular insights into the regulation of microprocessor assembly through DGCR8.
Health-related quality of life in patients with progressive glioblastoma treated with combined bevacizumab and lomustine versus lomustine only: Secondary outcome of the randomized phase III EORTC 26101 study
Authors: Dirven Linda , Machingura Abigirl , van den Bent Martin J , Coens Corneel , Bottomley Andrew , Brandes Alba A , Domont Julien , Idbaih Ahmed , Koekkoek Johan A F , Reijneveld Jaap C , Platten Michael , Wick Wolfgang , Taphoorn Martin J B
Published: September 2024

Background

Progression-free survival, but not overall survival, was prolonged with bevacizumab and lomustine compared to lomustine only in the randomized phase 3 European Organization for Research and Treatment of Cancer (EORTC) 26101 study.

Objective

To evaluate the impact of treatment on health-related quality of life (HRQoL) in progressive glioblastoma patients participating in the EORTC 26101 study.

Methods

Patients with progressive glioblastoma, after standard radio-chemotherapy, were 2:1 randomized to either BEV/LOM or LOM. HRQoL was a secondary trial outcome and assessed using the EORTC QLQ-C30 and QLQ-BN20 questionnaires at baseline, and subsequently every 12 weeks. Predefined scales for analysis were global health status (GH), physical functioning, social functioning (SF), motor dysfunction, and communication deficit. The primary endpoint was HRQoL during the last assessment up to week 36. Moreover, time to HRQoL deterioration (TTD) and HRQoL deterioration-free survival (DFS) were calculated.

Results

Out of 437 patients, 402 (92%) patients had a baseline HRQoL assessment, which dropped to 66% at week 36. During the last assessment up to week 36, no differences were observed for predefined scales, apart from SF being clinically relevant lower in the combination arm (mean 66.0 versus 81.0, p = .001). Of note, the baseline SF score was 66.4 for patients in the combination arm, showing stable SF. Median DFS was significantly longer in the combination arm (12.4 weeks) compared to lomustine alone (6.7 weeks), reflecting the difference in time to progression between arms. TTD, not including progression as an event, was not different between treatment arms (median 13.0 versus 12.9 weeks).

Conclusion

The addition of bevacizumab to lomustine did not negatively affect HRQoL during the progression-free period.
Membrane protein provision controls prothylakoid biogenesis in tobacco etioplasts
Authors: Li Bingqi , Armarego-Marriott Tegan , Kowalewska Łucja , Thiele Wolfram , Erban Alexander , Ruf Stephanie , Kopka Joachim , Schöttler Mark Aurel , Bock Ralph
Published: September 2024

The cytochrome b559 heterodimer is a conserved component of photosystem II whose physiological role in photosynthetic electron transfer is enigmatic. A particularly puzzling aspect of cytochrome b559 has been its presence in etiolated seedlings, where photosystem II is absent. Whether or not the cytochrome has a specific function in etioplasts is unknown. Here, we have attempted to address the function of cytochrome b559 by generating transplastomic tobacco (Nicotiana tabacum) plants that overexpress psbE and psbF, the plastid genes encoding the 2 cytochrome b559 apoproteins. We show that strong overaccumulation of the PsbE apoprotein can be achieved in etioplasts by suitable manipulations of the promoter and the translation signals, while the cytochrome b559 level is only moderately elevated. The surplus PsbE protein causes striking ultrastructural alterations in etioplasts; most notably, it causes a condensed prolamellar body and a massive proliferation of prothylakoids, with multiple membrane layers coiled into spiral-like structures. Analysis of plastid lipids revealed that increased PsbE biosynthesis strongly stimulated plastid lipid biosynthesis, suggesting that membrane protein abundance controls prothylakoid membrane biogenesis. Our data provide evidence for a structural role of PsbE in prolamellar body formation and prothylakoid biogenesis and indicate that thylakoid membrane protein abundance regulates lipid biosynthesis in etioplasts.
The transcription factor CAMTA2 interacts with the histone acetyltransferase GCN5 and regulates grain weight in wheat
Authors: Zhang Ruijie , An Kexin , Gao Yujiao , Zhang Zhaoheng , Zhang Xiaobang , Zhang Xue , Rossi Vincenzo , Cao Yuan , Xiao Jun , Xin Mingming , Du Jinkun , Hu Zhaorong , Liu Jie , Peng Huiru , Ni Zhongfu , Sun Qixin , Yao Yingyin
Published: September 2024

Grain weight and size are major traits targeted in breeding to improve wheat (Triticum aestivum L.) yield. Here, we find that the histone acetyltransferase GENERAL CONTROL NONDEREPRESSIBLE 5 (GCN5) physically interacts with the calmodulin-binding transcription factor CAMTA2 and regulates wheat grain size and weight. gcn5 mutant grains were smaller and contained less starch. GCN5 promoted the expression of the starch biosynthesis genes SUCROSE SYNTHASE 2 (Sus2) and STARCH-BRANCHING ENZYME Ic (SBEIc) by regulating H3K9ac and H3K14ac levels in their promoters. Moreover, immunoprecipitation coupled to mass spectrometry (IP–MS) revealed that CAMTA2 physically interacts with GCN5. The CAMTA2–GCN5 complex activated Sus2 and SBEIc by directly binding to their promoters and depositing H3K9ac and H3K14ac marks during wheat endosperm development. camta2 knockout mutants exhibited similar phenotypes to gcn5 mutants, including smaller grains that contained less starch. In gcn5 mutants, transcripts of high-molecular-weight (HMW) Glutenin (Glu) genes were downregulated, leading to reduced HMW glutenin protein levels, gluten content, and sodium dodecyl sulfate (SDS) sedimentation volume. However, the association of GCN5 with Glu genes was independent of CAMTA2, since GCN5 enrichment on Glu promoters was unchanged in camta2 knockouts. Finally, we identified a CAMTA2-AH3 elite allele that corresponded with enhanced grain size and weight, serving as a candidate gene for breeding wheat varieties with improved grain weight.
The transcription factor RppA regulates chlorophyll and carotenoid biosynthesis to improve photoprotection in cyanobacteria
Authors: Yu Chen , Xu Hai-Feng , Liu Yan-Ru , Yan Wei-Wei , Kong Xin-Ling , Zhang Zhong-Chun , Dai Guo-Zheng , Qiu Bao-Sheng
Published: September 2024

Chlorophyll is an essential photosynthetic pigment but also a strong photosensitizer. Excessive free chlorophyll and its precursors can cause oxidative damage to photosynthetic organisms. Cyanobacteria are the oldest oxygenic photosynthetic organisms and the ancestors of the chloroplast. Owing to their complex habitats, cyanobacteria require precise regulation of chlorophyll synthesis to respond to environmental factors, especially changes in light. Chlorophyll synthase, encoded by chlG, is the enzyme catalyzing the final step of chlorophyll biosynthesis, which is closely related to photosynthesis biogenesis. However, the transcriptional regulation on chlG remains unclear. Here, the transcription factor, regulator of photosynthesis and photopigment-related gene expression A (RppA), was identified to bind to the chlG promoter by screening a yeast 1-hybrid library in the cyanobacterium Synechocystis sp. PCC 6803. The rppA knockout mutant showed a phenotype of slow growth and severe oxidative damage under dark–light transition conditions. The upregulated transcriptional expression of chlG was significantly higher and more chlorophyll and its precursors accumulated in the rppA knockout mutant than those in the wild-type strain during the transition from darkness to light, indicating that RppA represses the expression of chlG in Synechocystis. Meanwhile, RppA could synchronously promote the transcription of carotenoids biosynthesis-related genes to enhance carotenoids synthesis during the dark–light transition. These results reveal synergistic regulation of chlorophyll and carotenoids biosynthesis in cyanobacteria in response to frequent dark–light transitions, which slows down chlorophyll biosynthesis while promoting carotenoids biosynthesis to avoid oxidative damage caused by excessive reactive oxygen species accumulation.
Impact of Segmental Lordosis Restoration During Degenerative Spinal Fusion on Two-Year Adjacent Segment Disease and Revision Rates
Authors: Singh Manjot , Kuharski Michael J. , Abdel-Megid Hazem , Balmaceno-Criss Mariah , Knebel Ashley , Daher Mohammad , Nassar Joseph E. , Basques Bryce , Kuris Eren O. , Diebo Bassel G. , Daniels Alan H.
Published: September 2024

Study Design:

Retrospective cohort study.

Objective:

Assess the impact of inadequate correction of L4-S1 lordosis during transforaminal lumber interbody fusion (TLIF) on adjacent segment disease and revision rates.

Background:

Restoring alignment is an important consideration in spinal fusions. Failure to correct to level-specific alignment goals could promote the development of adjacent segment disease. As such, it is crucial to investigate the role of sagittal segmental alignment on clinical outcomes following short segment lumbar fusion.

Methods:

Patients who underwent 1- to 3-level transforaminal lumbar interbody fusion (TLIF) and had two-year outcomes data were included in this retrospective cohort study. Segmental lumbar lordosis was assessed in all patients with L3-L4, L4-L5, and L5-S1 constructs. Demographics, radiographic spinopelvic alignment, and complications were compared in a sub-group of patients fused at L4-S1 with adequate (i.e., within 35-45°) and inadequate (i.e., <35°) L4-S1 lordosis.

Results:

Among the 168 included patients, mean age was 61.7 years, 56.0% were female, and mean follow-up was 32.3 months. Segmental lumbar lordosis did not change significantly after TLIF of L3-L4, L4-L5, or L5-S1 (P>0.05). Two-year postoperatively, 32.7% developed adjacent segment disease and 19.6% underwent revisions. After stratification by adequate (N=15) or inadequate (N=54) restoration of L4-S1 lordosis following initial TLIF surgery, adequately-restored patients had higher preoperative L4-S1 lordosis (Adequately-Restored=39.3° vs Inadequately-Restored=29.5°, P<0.001) and lower two-year postoperative adjacent segment disease (6.7% vs. 33.3%, P=0.032) and revision (5.7% vs. 25.9%, P=0.l33) rates. Adjacent segment disease patients had higher implant-related complications (Adjacent Segment Disease=36.8% vs No Adjacent Segment Disease=8.0%, P=0.008) and subsequent revisions (61.1% vs. 8.7%, P<0.001).

Conclusions:

Adjacent segment disease and revisions after degenerative lumbar spinal fusion are common. In this cohort, suboptimal restoration of L4-S1 lordosis was associated with higher rates of adjacent segment disease and subsequent revisions, thus highlighting the importance of restoring sagittal alignment in degenerative spine surgery.

Level of Evidence:

III
A rare case of Pancreatic lesion: Pancreatic mass and chronic pancreatitis caused by parasitic infection
Authors: Yuan Xuetao , Li Wei , Duan Wanxing , Wang Zheng , Li Xuqi , Yang Xue
Published: September 2024

A middle-age male patient was hospitalized for six-months upper abdominal pain. The patient had experienced 3 episodes of acute pancreatitis in the past 6 years. All the examination pointed to chronic pancreatitis and tumor, which, however, covering up the truth that the patient was in infection with Clonorchis sinensis in his pancreas. As the condition met the surgical indications, we performed pancreaticoduodenectomy and found the infection of Clonorchis sinensis in the postoperative pathological report. The patient maintain healthy during subsequent follow-up. Pancreatic mass with Clonorchis sinensis infected were rarely seen clinically, here we report the case which indicate us that further study on parasite and pancreatic lesion should be implemented. This case report is in accordance with Strengthening the reporting of Clinical Case Report and Helsinki Declaration.
Cariprazine as a maintenance treatment in dual schizophrenia: a 6-month observational study in patients with schizophrenia and cannabis use disorder
Authors: Szerman Nestor , Vega Pablo , Roncero Carlos , Peris Lola , Grau-López Lara , Basurte-Villamor Ignacio
Published: September 2024

Schizophrenia is often associated with substance use disorders, particularly cannabis use disorder (CUD). However, treatments frequently fail to address both conditions simultaneously. This study aimed to evaluate the antipsychotic effectiveness of cariprazine in patients with both schizophrenia and CUD in a real-world setting. A 6-month observational study was conducted on 58 patients diagnosed with schizophrenia and CUD, treated with cariprazine. Antipsychotic effectiveness was measured using the Positive and Negative Syndrome Scale and the Clinical Global Impression-Schizophrenia Scale, along with the Improvement and Severity scales. Cannabis consumption and addiction severity were assessed using the Cannabis Abuse Screening Test and the Severity of Dependence Scale, while functioning was evaluated with the Sheehan Disability Inventory. Cariprazine treatment resulted in significant improvements in schizophrenia symptoms (Positive and Negative Syndrome Scale change: −47.88 points, P < 0.0001; Clinical Global Impression-Schizophrenia Scale change: −8.26 points, P < 0.0001). Cannabis use and dependence also decreased (Cannabis Abuse Screening Test change: −7.0 points, P < 0.0001; Severity of Dependence Scale change: −7.88 points, P < 0.0001), alongside improvements in functioning (Sheehan Disability Inventory change: −9.48 points, P < 0.0001). These results suggest that cariprazine is effective for both schizophrenia and CUD, though further research is needed to confirm these findings.
The roles of TAF1 in neuroscience and beyond
Authors: Crombie Elisa M. , Cleverley Karen , Timmers H. T. Marc , Fisher Elizabeth M. C.
Published: September 2024

The transcriptional machinery is essential for gene expression and regulation; dysregulation of transcription can result in a range of pathologies, including neurodegeneration, cancer, developmental disorders and cardiovascular disease. A key component of RNA polymerase II-mediated transcription is the basal transcription factor IID, which is formed of the TATA box-binding protein (TBP) and 14 TBP-associated factors (TAFs), the largest of which is the TAF1 protein, encoded on the X chromosome (Xq13.1).
TAF1
is dysregulated in X-linked dystonia–parkinsonism and congenital mutations in the gene are causative for neurodevelopmental phenotypes; TAF1 dysfunction is also associated with cardiac anomalies and cancer. However, how TAF1 contributes to pathology is unclear. Here, we highlight the key aspects of the
TAF1
gene and protein function that may link transcriptional regulation with disorders of development, growth and adult-onset disorders of motor impairment. We highlight the need to experimentally investigate the full range of TAF1 messenger RNA variants and protein isoforms in human and mouse to aid our understanding of TAF1 biology. Furthermore, the X-linked nature of
TAF1
-related diseases adds complexity to understanding phenotypes. Overall, we shed light on the aspects of TAF1 biology that may contribute to disease and areas that could be addressed for future research and targeted therapeutics.
The impact of high-fat, obesogenic diets on brain volume in a commercially available mouse model of fatty liver disease
Authors: Jiang Li , Elsaid Salaheldeen , Zhan Cindy , Li Xin , Xu Su , Tee Sui Seng
Published: September 2024

The obesity pandemic poses significant health challenges, despite recent advancements in weight loss medications. Mouse models fed obesogenic diets serve as invaluable tools for dissecting the pleiotropic mechanisms underlying weight gain. Here, we utilize these models to analyze brain morphometrics using MRI techniques, inspired by similar findings in human studies linking obesity to brain volume changes. We hypothesize that the mouse model of obesity will exhibit brain volume alterations akin to those observed in obese humans, potentially shedding light on the neurological implications of obesity. To test our hypothesis, mice were provided free access to either regular chow or a diet consisting of high fat and high sugar and MRI scans for total brain volumes as well as volumes of specific brain regions were estimated and compared between obese and control mice. We found that obesogenic diets resulted in ∼13% greater weight gain compared to control chow diets. MRI brain scans revealed reduced total brain volume in obese mice that trended towards significance. In contrast, analysis of specific brain volumes showed an increase in neocortical regions of obese mice, that were significant when compared to controls. In conclusion, diet-induced obesity mouse models are a readily available avatar for studying the obesity epidemic, with significant increases in body weight within a reasonable timeframe. While weight gain among individual mice fed obesogenic diets showed some variability, MRI brain scans were able to reveal significant differences, especially within different anatomical regions of the brain.
Clinical Utility and Outcomes of Targeted Next-Generation Sequencing in Pediatric Respiratory Tract Infections: A Nine-Month Retrospective Study at a North Chinese Hospital
Authors: Wang Lixiang , Zhong Hui , Yang Lexia , Yang Xue
Published: September 2024

Background/Objectives

Children are at increased risk for respiratory tract infections (RTIs) due to their developing pulmonary functions and immune systems, highlighting the necessity of accurate and rapid pathogen diagnostic methods.

Methods

In this study, 940 pediatric hospitalized patients with RTIs were included to evaluate the clinical utility and outcomes of 107-pathogen targeted next-generation sequencing (tNGS) panel by comparing it with CMTs.

Results

Our study demonstrated that tNGS exhibited significantly higher sensitivity in pathogen detection compared to CMTs, with a detection rate of 91.38%. tNGS was capable of identifying a broader range of pathogens, including low-abundance and RNA viruses frequently missed by CMTs, and it was able to detect mixed infections, whereas CMTs typically identified only a single pathogen. Treatment adjustments based on tNGS results led to clinical improvements in the majority of patients, with 35.32% experiencing escalated treatment plans and 29.04% experiencing de-escalated treatment plans. Additionally, the analysis revealed significant variations in pathogen prevalence across different age groups and seasons, highlighting the need for tailored diagnostic, treatment, and prevention strategies.

Conclusions

The findings highlight the potential of tNGS to improve clinical outcomes in pediatric RTIs by providing more accurate and comprehensive pathogen detection.
Improved precision oncology question-answering using agentic LLM
Authors: Das Rangan , Maheswari K , Siddiqui Shaheen , Arora Nikita , Paul Ankush , Nanshi Jeet , Udbalkar Varun , Sarvade Apoorva , Chaturvedi Harsha , Shvartsman Tammy , Masih Shet , Thippeswamy R , Patil Shekar , Nirni S S , Garsson Brian , Bandyopadhyay Sanghamitra , Maulik Ujjwal , Farooq Mohammed , Sengupta Debarka
Published: September 2024

The clinical adoption of Large Language Models (LLMs) in biomedical research has been limited by concerns regarding the quality, accuracy, and reliability of their outputs, particularly in precision oncology, where clinical decision-making demands high precision. Current models, often based on fine-tuned foundational LLMs, are prone to issues such as hallucinations, incoherent reasoning, and loss of context. In this work, we present GeneSilico Copilot, an advanced agent-based architecture that transforms LLMs from simple response synthesizers to clinical reasoning systems. Our approach is centred around a bespoke ReAct agent that orchestrates a suite of specialized tools for asynchronous information retrieval and synthesis. These tools access curated document vector stores containing clinical treatment guidelines, genomic insights, drug information, clinical trials, and breast cancer-specific literature. To leverage large context windows of current LLMs, we implement a hybrid search strategy that prioritizes key information and dynamically integrates summarized content, reducing context fragmentation. Incorporating additional metadata further allows for precise, transparent and evidence-backed reasoning at each step of the thought process. The system ensures that at every stage, the agent can synthesize meaningful, context-aware observations that contribute to a coherent and comprehensive final response that aligns with clinical standards. Evaluations on real-world breast cancer cases show that GeneSilico Copilot significantly improves response accuracy and personalization. This system represents a critical advancement toward making LLMs clinically deployable in precision oncology and has potential applications in broader medical domains requiring complex, data-driven decision-making.
Drinking motives and alcohol sensitivity mediate multi-dimensional genetic influences on alcohol use behaviors
Authors: Savage Jeanne E. ,   Spit for Science Working Group, Dick Danielle M. , Posthuma Danielle
Published: September 2024

Background

Genetic influences account for a substantial proportion of individual differences in alcohol use behaviors (AUBs). However, multiple distinct sets of genes are linked to different AUBs, which may explain their dramatic variability in risk factors and manifestations. In this study, we explore whether intermediate neurobiological traits and alcohol-related cognitions mediate the relationship between polygenic scores (PGS) and multiple AUBs, with the aim to better understand processes captured by different genetic profiles.

Methods

Using results from prior genome-wide association studies, we derived PGS for 6 AUBs in participants from Spit for Science, a longitudinal study of college students in the U.S. (n=4,549). Self-report measures included personality traits, alcohol expectancies, drinking motivations, and alcohol sensitivity measures as well as drinking frequency, drinking quantity, alcohol use disorder (AUD) symptoms, and maximum drinks in 24 hours. Using linear regression and multiple mediation models, we investigated the direct and indirect effects of PGS on AUBs.

Results

In univariable regression results, PGSs indexing broad AUB dimensions such as drinks per week (DPW) and AUD predicted higher levels of sensation-seeking and multiple drinking motives, whileBeerPrefPGSs (indexing a variable pattern of alcohol problems associated with a preference for beer) predicted higher negative urgency and lower alcohol sensitivity. Mediational models indicated strong direct and indirect effects of DPW PGSs on multiple AUBs via social/enhancement drinking motives and alcohol sensitivity, indirect effects of AUD PGSs on AUD symptoms via coping motives, and indirect effects ofBeerPrefPGS on all AUBs via the joint effect of mediators including alcohol sensitivity.

Conclusions

These findings provide initial evidence that the genetic influences on different AUBs are associated with and partially mediated by intermediate neurobiological and cognitive factors, which may be more amenable to intervention. Greater focus on drinking motives and alcohol sensitivity is warranted in genetic research, as well as attention to the heterogeneous pathways linking genes to alcohol use outcomes.
Improving ALS Detection and Cognitive Impairment Stratification with Attention-Enhanced Deep Learning Models
Authors: Xia Yuqing , Gregory Jenna M , Waldron Fergal M , Spence Holly , Vallejo Marta
Published: September 2024

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease marked by motor deterioration and cognitive decline. Early diagnosis is challenging due to the complexity of sporadic ALS and the lack of a defined risk population. In this study, we developed Miniset-DenseSENet, a convolutional neural network combining DenseNet121 with a Squeeze-and-Excitation attention mechanism, using 190 autopsy brain images from the Gregory Laboratory at the University of Aberdeen. The model distinguishes ALS patients from controls with 97.37% accuracy and detects cognitive impairments, a critical but underdiagnosed feature of ALS. Miniset-DenseSENet outperformed other transfer learning models, achieving a sensitivity of 1 and specificity of 0.95. These findings suggest that integrating transfer learning and attention mechanisms into neuroimaging can enhance diagnostic accuracy, enabling earlier ALS detection and improving patient stratification. This model has the potential to guide clinical decisions and support personalized therapeutic strategies.
Personal Involvement with Celiac Disease as a Motive for Research among Celiac Disease Researchers
Authors: Banegas Marcela , Sprague Rebecca , Vigna Carolina , González Jose Emmanuel , Flores-Marín David , Palacios Cesar , Silvester Jocelyn , Therrien Amelie
Published: September 2024

Introduction

We investigated the frequency of personal involvement with celiac disease (CeD) among CeD researchers and their motive to pursue CeD research, compared to researchers in inflammatory bowel disease (IBD) or type 1 diabetes (T1D) research.

Methods

An online survey was sent to CeD, IBD and T1D researchers.

Results

42% of CeD researchers had an involvement with their research interest, which was similar to T1D (51%) and significantly higher than the IBD respondents (27%, p<0.02).

Discussion

Personal involvement is common among the CeD researchers. Personal involvement with the disease may be beneficial when conducting patient-oriented research.
Relationship between Retinal Vessels and OCT-Derived Retinal Neural Parameters
Authors: Yusufu Mayinuer , Weinreb Robert N. , Kang Mengtian , Vingrys Algis J. , Shang Xianwen , Zhang Lei , Shi Danli , He Mingguang
Published: September 2024

Objective

To investigate structural relationships between retinal vasculometry derived from color fundus photography (CFP) and neural parameters obtained from Optical Coherence Tomography (OCT) scans and validate their causal relationships.

Design

Cross-sectional study

Participants

Participants with fundus photographs data and OCT data in the UK Biobank cohort study

Methods

We used the Retina-based Microvascular Health Assessment System (RMHAS) to extract retinal vascular measurements in the 6*6mm area centered on the macular region. OCT parameters were available from the UK Biobank. First, pairwise correlations between individual retinal layers and vascular parameters were investigated. Canonical correlation analysis (CCA) was then used to examine associations between sets of variables. Lastly, bidirectional two-sample Mendelian randomization was employed to investigate potential causal relationships.

Main Outcome Measures

Measurements of retinal vascular network and neural layers

Results

Data from 67,918 eyes of 43,029 participants were included. The Ganglion Cell-Inner Plexiform Layer (GC-IPL) thickness showed the strongest correlations with vascular Density and Complexity (r=0.199 for arterial Vessel Area Density and r=0.175 for Number of Segments). The Inner Nuclear Layer (INL) thickness showed positive correlations with Width (r=0.122) and Vessel Area Density (artery) (r=0.127). Mendelian randomization analysis indicated bidirectional causal relationships between retinal vascular features and layer thicknesses. Genetically predicted higher Vessel Density was associated with increased thickness across various retinal layers, with the strongest effect on Inner Segment/Outer Segment + Photoreceptor Segment thickness (standardized effect size 1.50, p<0.001). Genetically predicted increases in retinal layer thicknesses, particularly the Outer Plexiform Layer, were linked to higher Vessel Density (standardized effect size 0.45, p=0.002) and Fractal Dimension (standardized effect size 0.48, p<0.001).

Conclusions

The positive associations of macular thickness with vascular Density and Caliber measurements were mainly attributable to their associations with GC-IPL and INL. Multidimensional relationships revealed by CCA revealed a complementary nature between the two sets of parameters, highlighting their value as a composite biomarker. Mendelian Randomization uncovered a bidirectional causal relationship that should provide insights into novel therapeutic approaches targeting both vascular and neuronal components.
Engineered antibodies targeted to bacterial surface integrate effector functions with toxin neutralization to provide superior efficacy against bacterial infections
Authors: Adhikari Rajan P. , Alem Farhang , Kemboi Daniel , Kanipakala Tulasikumari , Sherchand Shardulendra P. , Kailasan Shweta , Purcell Bret K. , Heine Henry S. , Russell-Lodrigue Kasi , Etobayeva Irina , Howell Katie A. , Vu Hong , Shulenin Sergey , Holtsberg Frederick W. , Roy Chad J. , Hakami Ramin M. , Nelson Daniel C. , Aman M. Javad
Published: September 2024

Anti-bacterial monoclonal antibody (mAb) therapies either rely on toxin neutralization or opsonophagocytic killing (OPK). Toxin neutralization protects the host from toxin-induced damage, while leaving the organism intact. OPK inducing antibodies clear the bacteria but leave the released toxins unencountered. Infection site targeted anti-toxin antibodies (ISTAbs) that we report here addresses this binary paradigm by combining both functionalities into a single molecule. ISTAbs consist of cell wall targeting (CWT) domains of bacteriophage endolysins fused to toxin neutralizing mAbs (IgG). CWT governs specific binding to the surface of bacteria while the IgG variable domain neutralizes the toxins as they are released. The complex is then cleared by phagocytic cells. As proof of concept, we generated several ISTAb prototypes targeting major toxins from two Gram-positive spore forming pathogens that have a high clinical significance;Clostridium difficile, causative agent of the most common hospital-acquired infection, andBacillus anthracis, a Category A select agent pathogen. Both groups of ISTAbs exhibited potent toxin neutralization, binding to their respective bacterial cells, and induction of opsonophagocytosis. In mice infected withB. anthracis, ISTAbs exhibit significantly higher efficacy than parental IgG in both pre- and post-challenge models. Furthermore, ISTAbs fully protected againstB. anthracisinfection in a nonhuman primate (NHP) aerosol challenge model. These findings establish that as a platform technology, ISTAbs are broadly applicable for therapeutic intervention against several toxigenic bacterial pathogens.
Sport Specialization, Injury and Illness: A Prospective Study of Elite Female Adolescent Soccer Players
Authors: Watson Andrew , Haraldsdottir Kristin
Published: September 2024

Context

Although considerable cross-sectional evidence exists regarding the association between sport specialization and injury, sport-specific, prospective research is lacking. Similarly, sport specialization is associated with impairments in sleep and subjective well-being in youth athletes, but it is unknown whether this increases the risk of illness.

Objective

To determine the relationship between sport specialization status and in-season injury and illness risk in elite female adolescent soccer players.

Design

Prospective Cohort Study

Setting

Pre-season evaluation of maximal aerobic capacity (VO2max) and sport specialization, and in-season self-reporting of daily training load (session-rating of perceived exertion), injury and illness resulting in lost sport participation time.

Participants

80 female youth soccer players (ages 13-18) from a local youth soccer organization.

Main outcome measures

Sport specialization status, injury and illness incidence during two 4-month competitive soccer seasons. Athletes were considered specialized if they participated in soccer exclusively versus multiple sports during the year. Mixed effects logistic regression models were used to individual injury and illness (yes/no) during the study period, using sport specialization, age, and training load as fixed effects and individual athlete as a random effect.

Results

Specialized (n=46) athletes did not differ from non-specialized (n=34) athletes with respect to age, preseason physical activity, VO2maxor in-season training load (all p>0.05). No difference was seen in the proportion of individuals from each group that reported an in-season injury (specialized = 19% v 17%, p=0.83) or illness (40% v 38%, p=0.82). After adjusting for age and training load, the individual injuries (OR= 0.86 [0.26, 2.8], p=0.81) and illnesses were not significantly predicted by specialization (OR= 1.06 [0.45, 2.5], p=0.89).

Conclusions

After adjusting for age and training load, sport specialization status was not associated with in-season injury or illness risk in elite female soccer players.

Key points

Prior research regarding the associations between sport specialization and health outcomes has been primarily cross-sectional and failed to account for the confounding role of training load.

Among elite adolescent female soccer players with similar pre-season physical activity levels in-season training loads, sport specialization was not associated with injury or illness incidence across two competitive seasons.
The Brain-Lung Immunotherapy Prognostic (BLIP) Score: A Novel Robust Tool for Prognostication in Non-Small Cell Lung Cancer Patients with Brain Metastases
Authors: Skribek Marcus , Livanou Maria-Effrosyni , Vathiotis Ioannis , Strandman Viktor , Thorell Axel , Koulouris Andreas , Syrigos Konstantinos , Ekman Simon , Tsakonas Georgios
Published: September 2024

Background

Lung cancer remains the leading cause of cancer-related mortality, with brain metastases (BMs) significantly worsening prognosis and quality of life. The advent of immune checkpoint inhibitors (ICIs) has revolutionized the treatment landscape for non-small cell lung cancer (NSCLC). However, precise prognostic tools are essential to optimize clinical decision-making in this context.

Methods

The Brain-Lung Immunotherapy Prognostic (BLIP) score was developed based on a retrospective cohort of NSCLC patients treated with ICIs at Karolinska University Hospital, Sweden. Prognostic factors were identified using both univariate and multivariate Cox regression analyses. Internal validation was conducted using bootstrap resampling, penalized Cox regression, k-fold cross-validation, and receiver operating characteristics (ROC) analysis. External validation was performed using an independent cohort from Sotiria Thoracic Diseases Hospital of Athens, Greece.

Results

From a total cohort of 1844 patients screened across both study sites, 152 patients from Karolinska University Hospital and 116 from Sotiria Thoracic Diseases Hospital of Athens, Greece, were included in the final analysis. Key prognostic factors influencing outcomes included histology, actionable mutations, age at BM diagnosis, and the number of BMs. The BLIP score effectively stratified patients into two prognostic groups: “Good” and “Poor”, with a median overall survival (OS) of 15 and 7 months, respectively (hazard ratio [HR]: 0.4;p< 0.0001). External validation confirmed these findings, showing a significantly lower risk of death for the “Good” group compared to the “Poor” group (HR: 0.49;p= 0.0063). The model’s robust prognostic performance was confirmed with an area under the ROC curve of 0.87, highlighting its accuracy in predicting survival outcomes.

Conclusion

The BLIP score provides a reliable, validated prognostic tool for NSCLC patients with BMs undergoing ICI therapy. By integrating both molecular and clinical variables, it offers significant improvements over existing models. Prospective validation could further support its use in personalized treatment strategies, improving clinical outcomes and patient management.

Highlights

The BLIP score is a new prognostic tool for NSCLC.

It focuses on patients with brain metastases undergoing immunotherapy.

The score integrates clinical and molecular factors.

Internal validation showed strong prognostic power and reliability.

External validation confirmed effectiveness across diverse patient populations.

Key factors include histology, actionable mutations, age, and brain metastases count.

The score stratifies patients into “Good” and “Poor” groups.

The BLIP score aids in personalized treatment decision-making.
DrugOn: A Comprehensive Drug Ontology for Precision Oncology
Authors: Kornrumpf Kevin , Gnaß Vera , Holm Myrine , Beißbarth Tim , Koch Raphael , Dönitz Jürgen
Published: September 2024

Introduction

Precision oncology and biomedical cancer research increasingly rely on tools to select optimal drugs targeting specific genetic alterations in cancer. A major challenge for bioinformatic tools supporting drug selection is to standardize different annotations (substance, drug name, drug class) to a common level, typically the drug class. While manual classification is time-consuming and potentially biased, existing resources often lack completeness, granularity, or mix up drug classes and drug targets. A structured, automatically built drug ontology such as DrugOn fills these gaps, improving decision support and data-driven research.

Methods

DrugOn integrates information from multiple sources to create a comprehensive drug ontology. It includes categories, molecular targets and additional annotations from DrugBank, ATC, MesH, KEGG and ClueIO. The combination of this data enables accurate identification of drug categories for each drug.

Results

DrugOn’s effectiveness was demonstrated by classifying 336 drugs from CIViC. It agreed with manually curated database-derived classifications for 268 out of 282 drugs assessed in translational lymphoma research. In 54 cases, classification was not possible due to data gaps. DrugOn provides a REST API and a front-end application for ontology exploration and automated drug queries.

Conclusion

DrugOn, a unified drug ontology, is derived from public datasets and refined by precise processing rules to ensure a reliable, updatable resource for drug information, in precision medicine. It uniquely categorizes drug classes and target proteins, and its structured format, complemented by an accessible API, allows for easy integration into data driven pipelines. Initially tailored for lymphoma research, DrugOn’s adaptable nature supports broader cancer research applications and potential data source expansions. DrugOn is accessible athttps://mtb.bioinf.med.uni-goettingen.de/drugon-web.
Prognostic Value of CD8+ T-Cells at the Invasive Margin is Comparable to Immune Score in Non-Metastatic Colorectal Cancer: Prospective Multicenter Cohort Study
Authors: Wankhede Durgesh , Halama Niels , Kloor Matthias , Edelmann Dominic , Brenner Hermann , Hoffmeister Michael
Published: September 2024

Background

The Immunoscore® is a validated tool for predicting colorectal cancer (CRC) prognosis, yet its adoption is impeded by complex commercial software and patient reimbursement challenges. Utilizing open-source methods, this study aimed to explore whether an immune cell score can be facilitated by focusing on single T-cell markers, to provide a simplified prognostic model in non-metastatic CRC.

Methods

A multicentric prospective cohort study was conducted in non-metastatic CRC patients who underwent curative surgical resection. CD3+ and CD8+ tumor infiltrating lymphocytes (TILs) were quantified in both invasive margin (IM) and tumor core (TC) using QuPath. A composite score, termed immune cell score, mirroring the methods employed for the Immunoscore®, was calculated based on the TIL densities (CD3-IM, CD8-IM, CD3-TC, CD8-TC]. We used a split sample approach (70:30) to estimate adjusted hazard ratios of cancer-specific survival (CSS) in a training and a validation set. Classification and regression tree analysis (CART) was performed to select the most prognostic TIL. The model incorporating the CART-selected TIL was compared to a two-tiered immune cell score model for overall performance (Brier score) and discrimination (concordance probability estimate, CPE).

Results

During a median follow-up time of 9.0 years, among 1260 patients, there were 203 CRC specific deaths. CART-selected CD8-IM was the most prognostic TIL at a cut-off of 231 cells/mm2. Patients with CD8-IMHihad better CSS than CD8-IMLowin both training (HR 0.58, 95% CI 0.40-0.84) and validation sets (HR 0.35, 95% CI 0.21-0.60). Brier scores of CD-8IM and immune cell score survival models were comparable in both training and validation cohort, whereas the survival discrimination of CD8-IM slightly outperformed the immune cell score in the validation set (CPE: CD8-IM 0.748, IS 0.730).

Conclusion

A single TIL marker, specifically CD8-IM, provided prognostic information comparable to the immune cell score. Simplified and cost-effective TIL assessments could enhance their bench to bedside translation and may guide adjuvant therapy in early-stage CRC.
Characterizing Highly Fermentable Carbohydrate Foods in the Diets of Children with Disorders of Gut-Brain Interaction and Healthy Children
Authors: Narayana Vishnu , Chang Jocelyn , McMeans Ann R. , Levy Rona L. , Shulman Robert J. , Chumpitazi Bruno P.
Published: September 2024

Objectives

Restricting fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) intake can alleviate symptoms in children with gut-brain interaction disorders (DGBI). Due to the restrictive nature of the low FODMAP diet (LFD), the less restrictive FODMAP Gentle diet (FGD) has been suggested. However, the types of high FODMAP foods and carbohydrates commonly consumed by US children are unknown, as is the impact of the FGD on a typical diet. This project aimed to identify the high FODMAP foods and proportions of FODMAP carbohydrates consumed by children with DGBI and healthy children (HC), and to determine which usually ingested FODMAPs would be restricted on the FGD.

Methods

Three-day diet records from both HC and children with DGBI were analyzed to assess the type of high FODMAP foods and carbohydrates ingested. Results were compared between the groups. The ingested FODMAPs that would be restricted on the FGD was determined.

Results

The number of foods ingested daily was similar between children with DGBI and HC (12.3 ± 4.2 vs 12.9 ± 3.4, respectively); high FODMAP foods comprised most foods eaten in both groups. Children with DGBI (vs HC) ate less high FODMAP foods per day (6.5 ± 2.3 vs 8.7 ± 2.4, P<0.0001, respectively). Fructans were the most consumed FODMAP carbohydrate in both groups and children with DGBI (vs HC) consumed fewer fructans, lactose, fructose, and polyols (all P<0.0001). The top 3 food categories consumed in both groups were wheat-containing foods, dairy, and fruits and 100% fruit juices. In children with DGBI, 80.9% of the high FODMAP foods consumed would be limited on the FGD.

Discussion

Children with DGBI consume significantly fewer high FODMAP foods and carbohydrates than HC. In both groups, the top consumed FODMAP carbohydrates are fructans, lactose, and fructose. A FODMAP Gentle diet would restrict a large majority of high FODMAP foods consumed by children with DGBI.