bluuebunny/crossref_metadata_2025 huggingface dataset:
Hyperbaric Oxygen Therapy Inhibits Neuronal Ferroptosis After Spinal Cord Injury in Mice
Authors: Yao Ruizhang , Liu Mo , Liang Fang , Sun Zhencheng , Yang Jing , Zhou Junlin , Su Qingjun , Liu Xuehua
Published: September 2023

Study Design.

Basic science study investigating the potential molecular mechanisms of hyperbaric oxygen (HBO) therapy in mice with spinal cord injury (SCI).

Objective.

We aimed to explore the intrinsic mechanisms of HBO for SCI through the lens of ferroptosis in the subacute phase.

Summary of Background Data.

HBO has been observed to facilitate the restoration of neurological function subsequent to SCI. Ferroptosis is a distinct cellular death mechanism that can be distinguished from apoptosis, necrosis, and autophagy. However, the precise relationship between these two phenomena remains poorly understood.

Methods.

We established an SCI model and employed a range of techniques, including behavioral assessments, electron microscopy, immunofluorescence, RT-qPCR, Western blotting (WB), Glutathione (GSH) measurement, and iron assay, to investigate various aspects of HBO therapy on SCI in mice. These included analyzing mitochondrial morphology, neuronal count, GSH levels, iron levels, and the expression of genes (Acyl-CoA synthetase family member-2, Iron-responsive element-binding protein-2) and proteins (Glutathione peroxidase 4; system Xc-light chain) associated with ferroptosis. The study included three groups: Sham-operated, SCI, and HBO. Group comparisons were performed using one-way analysis of variance and one-way repeated measures analysis of variance, followed by Tukey’s post hoc test. Statistical significance was set at a P < 0.05.

Results.

Our findings revealed that HBO therapy significantly enhanced the recovery of lower limb motor function in mice following SCI in the subacute phase. This was accompanied by upregulated expression of GPX4 and system Xc-light chain proteins, elevated GSH levels, increased number of NeuN+ cells, decreased expression of the iron-responsive element-binding protein-2 gene, and reduced iron concentration.

Conclusions.

Our research suggests that HBO therapy has the potential to be an effective treatment for SCI in the subacute phase by mitigating ferroptosis.
Molecular classification of small cell lung cancer subtypes: Characteristics, prognostic factors, and clinical translation
Authors: Guo Hanfei , Li Wenqian , Guo Ye , Chen Naifei , Cui Jiuwei
Published: September 2023

Small cell lung cancer (SCLC) is a highly malignant tumor with a very poor prognosis; therefore, more effective treatments are urgently needed for patients afflicted with the disease. In recent years, emerging molecular classifications based on key transcription factors of SCLC have provided more information on the tumor pathophysiology, metastasis, immune microenvironment, and acquired therapeutic resistance and reflected the intertumoral heterogeneity of the various SCLC phenotypes. Additionally, advances in genomics and single-cell sequencing analysis have further revealed the high intratumoral heterogeneity and plasticity of the disease. Herein, we review and summarize these recent lines of evidence and discuss the possible pathogenesis of SCLC.
Outcome Analysis of Combined Surgical Approaches in Advanced-stage Upper Extremity Breast Cancer-related Lymphedema
Authors: Myung Yujin , Park Joseph Kyu-hyung , Beom Jaewon , Lim Jae-Young , Park Young Suk , Ahn Sang-Hoon , Kang Eunyoung , Shin Hee-Chul , Kim Eun-Kyu , Nam Sun-Young , Heo Chan Yeong , Jeong Jae Hoon
Published: September 2023

Background:

This study aimed to discuss several surgical approaches for advanced-stage breast cancer-related lymphedema and compared their treatment outcomes.

Methods:

The patients who underwent surgery with International Society of Lymphology stage III lymphedema were included in this study. The three surgical methods used here were (1) suction-assisted lipectomy with lymphovenous anastomosis, (2) autologous breast reconstruction with muscle-sparing transverse rectus abdominis muscle flap combined with inguinal lymph node transfer, and (3) vascularized lymph node transfer with free omental flap. Analysis of the postoperative outcomes in the patients was based on the difference in volume between patients pre- and postoperatively, LYMPH-Q questionnaire, and bioelectrical impedance analysis.

Results:

Eighty-seven patients with stage IIb or higher disease underwent surgery. 38 patients underwent suction-assisted lipectomy + lymphovenous anastomosis, 23 underwent autologous breast reconstruction with vascularized lymph node transfer + lymphovenous anastomosis, and 26 underwent right gastroepiploic omental vascularized lymph node transfer with lymphovenous anastomosis. The LYMPH-Q questionnaire, which evaluates patients’ subjective satisfaction, showed that the autologous breast reconstruction group showed the greatest improvement, whereas in bioimpedance analysis, the omental flap group demonstrated the greatest postoperative improvement compared with preoperative values. However, suction-assisted lipectomy was considered the most effective surgical method for reducing limb volume in patients with high-stage lymphedema accompanied by fibrosis and volume increase.

Conclusions:

We observed slightly different clinical effects for each surgical method; however, all surgical methods demonstrated a reduction in the degree of edema and an increase in patient satisfaction.
Modified L-shaped incision technique for supracardiac total anomalous pulmonary venous connection as an alternative to sutureless technique
Authors: Feng Zicong , He Qiyu , Yuan Jianhui , Dou Zheng , Wu Dongdong , Liu Yuze , Rui Lu , He Fengpu , Wu Zhongkai , Li Shoujun
Published: September 2023

Background:

Modified L-shaped incision technique (MLIT) was successfully applied to the repair of supracardiac total anomalous pulmonary venous connection (TAPVC) with promising mid-term outcomes. It is, however, unclear whether or not MLIT could be an alternative to sutureless technique (ST).

Methods:

All patients (n=141) who underwent MLIT or ST repair for supracardiac TAPVC between June 2009 to June 2022 were included and a propensity score-matched analysis was performed to reduce the heterogeneity.

Results:

MLIT was performed in 80.9% (114/141), whereas ST was performed in 19.1% (27/141). Patients who underwent MLIT repair had a lower incidence of pulmonary veinous obstruction (PVO)-related reintervention (1.8% vs. 18.5%, P=0.002), and late mortality (2.6% vs. 18.2%, P=0.006). Overall survival at 10 years was 92.5% (87.7%-97.7%) for MLIT and 66.8% (44.4%-100%) for ST (P=0.012). Freedom from postoperative PVO at 10 years was 89.1% (83.2%-95.5%) for MLIT and 79.9% (65.6%-97.4%) for ST (P=0.12). Cox proportional hazards regression identified prolonged mechanical ventilation duration, postoperative PVO, respiratory dysfunction and low cardiac output syndrome were associated with postoperative death and PVO-related reintervention.

Conclusions:

The MLIT strategy is a safe, technologically feasible, and effective approach for supracardiac TAPVC, which is associated with more favourable and promising freedom from death and PVO-related reintervention.
Is Positive Communication Sufficient to Modulate Procedural Pain and Anxiety in the Emergency Department? A Randomized Controlled Trial
Authors: Berna Chantal , Favre-Bulle Anne , Bonzon Adélaïde , Gross Nathan , Gonthier Ariane , Gerhard-Donnet Hélène , Taffé Patrick , Hugli Olivier
Published: September 2023

Objective

Research suggests that therapeutic communication could enhance patient comfort during medical procedures. Few studies have been conducted in clinical settings, with adequate blinding. Our hypothesis was that a positive message could lead to analgesia and anxiolysis, and that this effect would be enhanced by an empathetic interaction with the nurse performing the procedure, compared with an audio-taped message. This study aimed to modulate the contents and delivery vector of a message regarding peripheral intravenous catheter (PIC) placement in the emergency department (ED).

Methods

This study was a 2 + 2 randomized controlled trial registered on ClinicalTrials.gov (NCT03502655). A positive versus standard message was delivered through audio tape (double-blind) in the first phase (N = 131) and through the nurse placing the catheter (single-blind) in the second phase (N = 120).

Results

By design, low practitioner empathic behavior was observed in the first phase (median, 1 of 5 points). In the second phase, higher empathic behavior was observed in the positive than in the standard message (median, 2 versus 3, p < .001). Contrary to our hypothesis, the intervention did not affect pain or anxiety reports due to PIC placement in either phase (all p values > .2).

Conclusions

The positive communication intervention did not impact pain or anxiety reports after PIC. There might have been a floor effect, with low PIC pain ratings in a context of moderate pain due to the presenting condition. Hence, such a therapeutic communication intervention might not be sufficient to modulate a mild procedural pain in the ED.
Penicillium rhizophilum, a novel species in the section Exilicaulis isolated from the rhizosphere of sugarcane in Southwest Iran
Authors: Ansari Laleh , Asgari Bita , Zare Rasoul , Zamanizadeh Hamid Reza
Published: September 2023

During a survey of species diversity of Penicillium and Talaromyces in sugarcane (Saccharum officinarum) rhizosphere in the Khuzestan province of Iran [], 195 strains were examined, from which 187 belonged to Penicillium (11 species) and eight to Talaromyces (one species). In the present study, three strains of Penicillium belonging to section Exilicaulis series Restricta, identified as P. restrictum by Ansari et al. [], were subjected to a phylogenetic study. The multilocus phylogeny of partial β-tubulin, calmodulin and RNA polymerase II second largest subunit genes enabled the recognition of one new phylogenetic species that is here formally described as Penicillium rhizophilum sp. nov. This species is phylogenetically distinct in series Restricta, but it does not show significant morphological differences from other species previously classified in the series. Therefore, we here placed bias on the phylogenetic species concept. The holotype of Penicillium rhizophilum sp. nov. is IRAN 18169F and the ex-type culture is LA30T (=IRAN 4042CT=CBS 149737T).
Field study to determine the reliability of HIV viral load results shows minimal impact of delayed testing
Authors: Hardie Diana , Newman Howard , Ried Joanna , Hsiao Nei-Yuan , van Zyl Gert , Hans Lucia , Odayar Jasantha , Korsman Stephen
Published: September 2023

Understanding factors that impact on the accuracy of HIV viral load (VL) results is key to quality improvements of VL programmes, particularly in resource limited settings. In this study we evaluated whether testing delay and room temperature storage (between 25-30°C) prior to testing affected results. 249 individuals who were on antiretroviral therapy, or with newly diagnosed HIV, were recruited and three PPT samples were collected from each patient. One sample was tested within 24 hours, while the others were stored un-centrifuged at ambient temperature prior to testing.

Centrifugation and testing of matched samples were performed on days 4 and 7 after collection. In samples with initial VL >2 log copies/mL, time delay and ambient temperature storage had minimal impact. When grouped according to day 1 VL range, 96-100% of samples at day 4 and 93-100% at day 7 had a VL within 0.5 log copies/mL of the first result. Greatest variability was observed at day 4 and 7 when the day 1 VL was <2 log copies/mL, however, there was no trend of increasing difference with time. Of day 1 samples with undetectable VL or VL <50copies/mL, 80% and 78% had concordant results at days 4 and 7, respectively. Detection in later samples appeared to be stochastic, rather than showing a worsening trend. These results provide further evidence that VL is stable in PPT tubes for up to 7 days when stored at room temperature. It shows that there is significant variability in samples with VL close to the limit of detection, not affected by testing delay. Stochastic variation or technical factors that may increase the chance of false positive results could possibly account for this.
Integrated antigenic and nucleic acid detection in single virions and virion-infected host-derived extracellular vesicles
Authors: Nguyen Kim Truc , Rima Xilal Y. , Nguyen Luong T. H. , Wang Xinyu , Kwak Kwang Joo , Yoon Min Jin , Li Hong , Chiang Chi-Ling , Doon-Ralls Jacob , Scherler Kelsey , Fallen Shannon , Godfrey Stephanie L. , Wallick Julie A. , Magaña Setty M. , Palmer Andre F. , Lee Inyoul , Nunn Christopher C. , Reeves Kimberly M. , Kaplan Henry G. , Goldman Jason D. , Heath James R. , Wang Kai , Pancholi Preeti , Lee L. James , Reátegui Eduardo
Published: September 2023

Virion-mediated outbreaks are imminent and despite rapid responses, they continue to cause adverse symptoms and death. Therefore, tunable, sensitive, high-throughput assays are needed to control future virion-mediated outbreaks. Herein, we developed a tunablein situassay to selectively sort virions and infected host-derived extracellular vesicles (IHD-EVs) and simultaneously detect antigens and nucleic acids at a single-particle resolution. The Biochip Antigen and RNA Assay (BARA) enhanced sensitivities, enabling the detection of virions in asymptomatic patients, genetic mutations in single virions, and the continued long-term expression of virion-RNA in the IHD-EVs of post-acute sequelae of COVID-19 patients. The BARA revealed highly accurate diagnoses by simultaneously detecting the spike glycoprotein and nucleocapsid-encoding RNA on single SARS-CoV-2 virions in saliva and nasopharyngeal swab samples. Altogether, the single-particle detection of antigens and virion-RNA provides a tunable framework for the diagnosis, monitoring, and mutation screening of current and future outbreaks.

Teaser

The BARA enables antigenic and nucleic acid testing in single virions for unprecedented perspectives on viral diseases
Gender and Socio-Economic Status as moderators in the associations between Social Support Sources and Adolescents’ Mental and Behavioral Health Indicators
Authors: Bermejo-Martins E. , Torres-Sahli M. , Madsen K. Rich , Tabs-Damgraads M. , Nielsen L. , Meilstrup C.B. , Toftager M. , Santini Z. I.
Published: September 2023

Background

Extensive research has established the intricate links between diverse social support sources and vital adolescent health indicators, such as mental wellbeing (MWB), problematic social media use (PSMU), and physical activity (PA). However, existing studies have not explored these interrelationships within a unified model or examined the moderating effects of gender and socio-economic status (SES).

Methods

This cross-sectional study employed a representative Danish sample of 2.034 adolescents, aged 13 and 15 years. A Multi-group Structural Equation Model (SEM) and covariance-based comparisons analysis utilized items from Multidimensional Scales of Perceived Social Support, The Warwick–Edinburgh Mental Well-being Scale, Social Media Disorder Scale, and measures of PA duration and frequency.

Results

The associations between MWB-Teacher Support and MWB-Classmate Support were stronger in low SES adolescents than those with mid-high SES. Notably, the PSMU-Family Support negative association was more pronounced among girls, while PSMU-Friend Support’s negative relationship was stronger among boys. The PA-Family Support positive relationship was more robust in boys, while the PA-Teacher Support positive association was stronger among low-mid SES adolescents than those in high SES. The positive correlation between PA and MWB was stronger among boys and mid-low SES adolescents.

Conclusions

Strategies designed to enhance family and school support, considering gender and SES, could effectively promote MWB and deter behavioural issues like PSMU and sedentary behaviours in adolescents.
A Longitudinal Study of Executive Function in Daily Life in Male Fragile X Premutation Carriers and Association with FXTAS Conversion
Authors: Hessl David , Rojas Karina Mandujano , Ferrer Emilio , Espinal Glenda , Famula Jessica , Schneider Andrea , Hagerman Randi , Tassone Flora , Rivera Susan M.
Published: September 2023

Background

Men with fragile X-associated tremor/ataxia syndrome (FXTAS) often develop executive dysfunction, characterized by disinhibition, frontal dyscontrol of movement, and working memory and attention changes. Although cross-sectional studies have suggested that earlier executive function changes may precede FXTAS, the lack of longitudinal studies have made it difficult to address this hypothesis.

Methods

This study included 66 FMR1 premutation carriers (PC) ranging from 40-78 years (Mean=59.5) and 31 well-matched healthy controls (HC) ages 40-75 (Mean 57.7) at baseline. Eighty-four participants returned for 2-5 follow up visits over a duration of 1 to 9 years (Mean=4.6); 28 of the PC developed FXTAS. The Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) was completed by participants and their spouses/partners at each visit.

Results

Longitudinal mixed model regression analyses showed a greater decline with age in PC compared to HC on the Metacognition Index (MI; self-initiation, working memory, organization, task monitoring). Conversion to FXTAS was associated with worsening MI and Behavioral Regulation Index (BRI; inhibition, flexibility, emotion modulation). For spouse/partner report, FXTAS conversion was associated with worsening MI. Finally, BRIEF-A executive function problems at baseline significantly predicted later development of FXTAS.

Conclusions

These findings suggest that executive function changes represent a prodrome of the later movement disorder.
Upregulation of ARHGAP9 is correlated with poor prognosis and immune infiltration in clear cell renal cell carcinoma
Authors: Xiong Yu-ling , Peng Chao , Tian Yue
Published: September 2023

Background

Rho GTPase Activating Protein (ARHGAP) family genes play critical roles in the onset and progression of human cancer. Rho GTPase Activating Protein 9 (ARHGAP9) is upregulated in various tumors. However, far too little attention has been paid to the prognostic value of ARHGAP9 and correlation with immune infiltration in clear cell renal cell carcinoma. Our aim is to evaluate the prognostic significance of ARHGAP9 expression and its correlation with immune infiltration in clear cell renal cell carcinoma.

Methods

Transcriptional expression profiles of ARHGAP9 between clear cell renal cell carcinoma tissues and normal tissues were downloaded from the Cancer Genome Atlas (TCGA). The ARHGAP9 protein expression was assessed by the Clinical Proteomic Tumor Analysis Consortium (CPTAC). Receiver operating characteristic (ROC) curve was used to differentiate clear cell renal cell carcinoma from adjacent normal tissues. The Kaplan-Meier method was conducted to assess the effect of ARHGAP9 on survival. Protein-protein interaction (PPI) networks were constructed by the STRING. Functional enrichment analyses were performed using the "ClusterProfiler" package. The immune infiltration patterns were evaluated via the tumor immune estimation resource 2.0 (TIMER 2.0) and TISIDB database.

Results

ARHGAP9 expression was substantially higher in clear cell renal cell carcinoma tissues than in adjacent normal tissues. Increased ARHGAP9 mRNA expression was shown to be linked to high TNM stage and lymph node metastases. The diagnostic value of ARHGAP9 gene expression data was assessed using ROC curve analysis. The survival analysis module of GEPIA2 and the Kaplan-Meier plotter both showed clear cell renal cell carcinoma patients with high-ARHGAP9 had a worse prognosis than those with low-ARHGAP9. Correlation analysis indicated ARHGAP9 mRNA expression was significantly correlated with tumor purity and immune infiltrates.

Conclusion

These findings demonstrate that up-regulated ARHGAP9 indicates poor prognosis and immune infiltration in clear cell renal cell carcinoma. The current findings suggest that ARHGAP9 can be an effective biomarker and potential therapeutic strategy for ccRCC.
Application of MALDI-MS and Machine Learning to Detection of SARS-CoV-2 and non-SARS-CoV-2 Respiratory Infections
Authors: Yegorov Sergey , Kadyrova Irina , Korshukov Ilya , Sultanbekova Aidana , Barkhanskaya Valentina , Bashirova Tatiana , Zhunusov Yerzhan , Li Yevgeniya , Parakhina Viktoriya , Kolesnichenko Svetlana , Baiken Yeldar , Matkarimov Bakhyt , Vazenmiller Dmitriy , Miller Matthew S. , Hortelano Gonzalo H. , Turmuhambetova Anar , Chesca Antonella E. , Babenko Dmitriy
Published: September 2023

Background

Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) could aid the diagnosis of acute respiratory infections (ARI) owing to its affordability and high-throughput capacity. MALDI-MS has been proposed for use on commonly available respiratory samples, without specialized sample preparation, making this technology especially attractive for implementation in low-resource regions. Here, we assessed the utility of MALDI-MS in differentiating SARS-CoV-2 versus non-COVID acute respiratory infections (NCARI) in a clinical lab setting of Kazakhstan.

Methods

Nasopharyngeal swabs were collected from in- and outpatients with respiratory symptoms and from asymptomatic controls (AC) in 2020-2022. PCR was used to differentiate SARS-CoV-2+ and NCARI cases. MALDI-MS spectra were obtained for a total of 252 samples (115 SARS-CoV-2+, 98 NCARI and 39 AC) without specialized sample preparation. In our first sub-analysis, we followed a published protocol for peak preprocessing and Machine Learning (ML), trained on publicly available spectra from South American SARS-CoV-2+ and NCARI samples. In our second sub-analysis, we trained ML models on a peak intensity matrix representative of both South American (SA) and Kazakhstan (Kaz) samples.

Results

Applying the established MALDI-MS pipeline ”as is” resulted in a high detection rate for SARS-CoV-2+ samples (91.0%), but low accuracy for NCARI (48.0%) and AC (67.0%) by the top-performing random forest model. After re-training of the ML algorithms on the SA-Kaz peak intensity matrix, the accuracy of detection by the top-performing Support Vector Machine with radial basis function kernel model was at 88.0, 95.0 and 78% for the Kazakhstan SARS-CoV-2+, NCARI, and AC subjects, respectively with a SARS-CoV-2 vs. rest ROC AUC of 0.983 [0.958, 0.987]; a high differentiation accuracy was maintained for the South American SARS-CoV-2 and NCARI.

Conclusions

MALDI-MS/ML is a feasible approach for the differentiation of ARI without a specialized sample preparation. The implementation of MALDI-MS/ML in a real clinical lab setting will necessitate continuous optimization to keep up with the rapidly evolving landscape of ARI.
Characterizing human postprandial metabolic response using multiway data analysis
Authors: Yan Shi , Li Lu , Horner David , Ebrahimi Parvaneh , Chawes Bo , Dragsted Lars O. , Rasmussen Morten A. , Smilde Age K. , Acar Evrim
Published: September 2023

Analysis of time-resolved postprandial metabolomics data can enhance our knowledge about human metabolism by providing a better understanding of similarities and differences in postprandial responses of individuals, with the potential to advance precision nutrition and medicine. Traditional data analysis methods focus on clustering methods relying on summaries of data across individuals or use univariate methods analyzing one metabolite at a time. However, they fail to provide a compact summary revealing the underlying patterns, i.e., groups of subjects, clusters of metabolites, and their temporal profiles. In this study, we analyze NMR (Nuclear Magnetic Resonance) spectroscopy measurements of plasma samples collected at multiple time points during a meal challenge test from 299 individuals from the COPSAC2000cohort. We arrange the data as a three-way array:subjectsbymetabolitesbytime, and use the CAN-DECOMP/PARAFAC (CP) tensor factorization model to capture the underlying patterns. We analyze thefasting statedata to reveal static patterns of subject group differences, and thefasting state-corrected postprandial data to reveal dynamic markers of group differences. Our analysis demonstrates that the CP model reveals replicable and biologically meaningful patterns capturing certain metabolite groups and their temporal profiles, and showing differences among males according to their body mass index (BMI). Furthermore, we observe that certain lipoproteins relate to the group difference differently in the fasting vs. dynamic state in males. While similar dynamic patterns are observed in response to the challenge test in males and females, the BMI-related group difference is only observed in males in the dynamic state.
Comparison of dental topography of marmosets and tamarins (Callitrichidae) to other platyrrhine primates using a novel freeware pipeline
Authors: de Vries Dorien , Janiak Mareike C. , Batista Romina , Boubli Jean P. , Goodhead Ian B. , Ridgway Emma , Boyer Doug M. , St. Clair Elizabeth , Beck Robin M.D.
Published: September 2023

Dental topographic metrics (DTMs), which quantify different aspects of the shape of teeth, are powerful tools for studying dietary adaptation and evolution in mammals. However, comparative samples of scanned mammal teeth suitable for analysis with DTMs remain limited in size and scope, with little or no representation of some major lineages, even within well-studied clades such as primates. In addition, current DTM protocols usually rely on proprietary software, which may be unavailable to many researchers for reasons of cost. We address these issues in the context of a DTM analysis of the primate clade Platyrrhini (“New World monkeys”) by: 1) presenting a large comparative sample of scanned second lower molars (m2s) of callitrichids (marmosets and tamarins), which were previously underrepresented in publicly available platyrrhine datasets; and 2) giving full details of an entirely freeware pipeline for DTM analysis. We also present an updated discrete dietary classification scheme for extant platyrrhines, based on cluster analysis of dietary data extracted from 98 primary studies. Our freeware pipeline performs equally well in dietary classification accuracy of an existing sample of platyrrhine m2s (excluding callitrichids) as a published protocol that uses proprietary software, at least when multiple DTMs are combined. Individual DTMs however, sometimes showed very different results in classification accuracies between that of our freeware pipeline and that of the proprietary protocol, most likely due to the differences in the smoothing functions used. The addition of callitrichids still resulted in high classification accuracy in predicting diet with combined DTMs, although accuracy was considerably higher when molar size was included (90%) than excluded (73%). We conclude that our new freeware DTM pipeline is capable of accurately predicting diet in platyrrhines based on tooth shape and size, and so is suitable for inferring probable diet of taxa for which direct dietary information is unavailable, such as fossil species.
Dysregulation of γδ intraepithelial lymphocytes precedes Crohn’s disease-like ileitis
Authors: Xu Weili , Golovchenko Natasha B. , Fong Andrew , Achi Sajan , Bucar Edie B. , Vidmar Kaylynn J. , Zhang Lanjing , Frey Mark R. , Prinz Immo , Pizarro Theresa T. , Kollias George , Edelblum Karen L.
Published: September 2023

Intraepithelial lymphocytes expressing the γδ T cell receptor (γδ IELs) provide immunosurveillance of the intestinal barrier. Interestingly, γδ IEL number is reduced in patients with active Crohn’s disease (CD). Here, we report an underappreciated role for γδ IELs in maintaining mucosal tolerance during the onset and progression of CD-like ileitis using the TNFΔARE/+mouse model. Decreased epithelial HNF4G/BTNL expression is followed by a loss of ileal γδ IELs and impaired barrier surveillance prior to the histological onset of disease. A reduction of immunoregulatory CD39+γδ IELs coincides with the influx of immature, peripheral CD39-γδ T cells into the epithelium leading to an expansion of induced IELs, while an earlier depletion of γδ IELs correlates with accelerated onset of ileal inflammation. Our findings identify multiple layers of γδ IEL dysregulation prior to ileitis development indicating that the loss of tissue-resident immunoregulatory γδ IELs may contribute to the initiation of ileal CD.
Human gut metagenomic mining reveals an untapped source of peptide antibiotics
Authors: Torres Marcelo D. T. , Brooks Erin , Cesaro Angela , Sberro Hila , Nicolaou Cosmos , Bhatt Ami S. , de la Fuente-Nunez Cesar
Published: September 2023

Drug-resistant bacteria are outpacing traditional antibiotic discovery efforts. Here, we computationally mined 444,054 families of putative small proteins from 1,773 human gut metagenomes, identifying 323 peptide antibiotics encoded in small open reading frames (smORFs). To test our computational predictions, 78 peptides were synthesized and screened for antimicrobial activityin vitro, with 59% displaying activity against either pathogens or commensals. Since these peptides were unique compared to previously reported antimicrobial peptides, we termed themsmORF-encoded peptides (SEPs). SEPs killed bacteria by targeting their membrane, synergized with each other, and modulated gut commensals, indicating that they may play a role in reconfiguring microbiome communities in addition to counteracting pathogens. The lead candidates were anti-infective in both murine skin abscess and deep thigh infection models. Notably, prevotellin-2 fromPrevotella copripresented activity comparable to the commonly used antibiotic polymyxin B. We report the discovery of hundreds of peptide sequences in the human gut.
Melanin-concentrating hormone receptor antagonism differentially attenuates nicotine experience-dependent locomotor behavior in female and male rats
Authors: Kuebler Isabel R.K. , Liu Youxi , Bueno Álvarez Bárbara S. , Huber Noah M. , Jolton Joshua A. , Dasari Raaga , Wakabayashi Ken T.
Published: September 2023

Nicotine is a significant public health concern because it is the primary pharmacological agent in tobacco use disorder. One neural system that has been implicated in the symptoms of several substance use disorders is the melanin-concentrating hormone (MCH) system. MCH regulates various motivated behaviors depending on sex, yet little is known of how this interaction affects experience with drugs of abuse, particularly nicotine. The goal of this study was to determine the effect of MCH receptor antagonism on experience-dependent nicotine-induced locomotion after chronic exposure, particularly on the expression of locomotor sensitization. Adult female and male Wistar rats were given saline then cumulative doses of nicotine (0.1, 0.32, 0.56, and 1.0 mg/kg) intraperitoneally to determine the acute effects of nicotine (day 1). Next, rats were treated with 1.0 mg/kg nicotine for 6 days, given an identical series of cumulative doses (day 8), and then kept in a drug-free state for 6 days. On day 15, rats were pretreated with vehicle or the MCH receptor antagonist GW803430 (10 or 30 mg/kg) before another series of cumulative doses to assess response to chronic nicotine. After vehicle, male rats increased nicotine locomotor activation from day 1 to day 15, and both sexes showed a sensitized response when normalized to saline. The lower dose of GW803430 decreased locomotion compared to vehicle in females, while the higher dose decreased locomotion in males. Both sexes showed nicotine dose-dependent effects of GW803430, strongest at lower doses of nicotine. Controlling for sex-based locomotor differences revealed that females are more sensitive to GW803430. The high dose of GW803430 also decreased saline locomotion in males. Together, the results of our study suggest that MCH is involved in the expression of nicotine locomotor sensitization, and that MCH regulates these nicotine behavioral symptoms differently across sex.
Flexible neural representations of abstract structural knowledge in the human Entorhinal Cortex
Authors: Mark S. , Schwartenbeck P. , Hahamy A , Samborska V , Baram AB. , Behrens TEJ
Published: September 2023

Humans’ ability for generalisation is outstanding. It is flexible enough to identify cases where knowledge from prior tasks is relevant, even when many features of the current task are different, such as the sensory stimuli or the size of the task state space. We have previously shown that in abstract tasks, humans can generalise knowledge in cases where the only cross-task shared feature is the statistical rules that govern the task’s state-state relationships. Here, we hypothesized that this capacity is associated with generalisable representations in the entorhinal cortex (EC). This hypothesis was based on the EC’s generalisable representations in spatial tasks and recent discoveries about its role in the representation of abstract tasks. We first develop an analysis method capable of testing for such representations in fMRI data, explain why other common methods would have failed for our task, and validate our method through a combination of electrophysiological data analysis, simulations and fMRI sanity checks. We then show with fMRI that EC representations generalise across complex non-spatial tasks that share a hexagonal grid structural form but differ in their size and sensory stimuli, i.e. their only shared feature is the rules governing their statistical structure. There was no clear evidence for such generalisation in EC for non-spatial tasks with clustered, as opposed to planar, structure.
Genome report: Whole genome sequence and annotation ofPenstemon davidsonii
Authors: Ostevik Kate L. , Alabady Magdy , Zhang Mengrui , Rausher Mark D.
Published: September 2023

Penstemonis the most speciose flowering plant genus endemic to North America.Penstemonspecies’ diverse morphology and adaptation to various environments have made them a valuable model system for studying evolution, but the absence of publicly available reference genomes limits possible research directions. Here we report the first reference genome assembly and annotation forPenstemon davidsonii. Using PacBio long-read sequencing and Hi-C scaffolding technology, we constructed a de novo reference genome of 437,568,744 bases, with a contig N50 of 40 Mb and L50 of 5. The annotation includes 18,199 gene models, and both the genome and transcriptome assembly contain over 95% complete eudicot BUSCOs. This genome assembly will serve as a valuable reference for studying the evolutionary history and genetic diversity of thePenstemongenus.
Illuminating the Terminal Nerve: Uncovering the Link between GnRH-1 and Olfactory Development
Authors: Amato Enrico , Taroc Ed Zandro M , Forni Paolo E.
Published: September 2023

During embryonic development, the olfactory placode (OP) generates migratory neurons, including olfactory pioneer neurons, cells of the terminal nerve (TN), Gonadotropin-releasing hormone-1 (GnRH-1) neurons, and other uncharacterized neurons. Pioneer neurons from the olfactory placode induce olfactory bulb morphogenesis.

In mice, GnRH-1 neurons appear in the olfactory system around mid-gestation and migrate via the terminal nerve axons to different brain regions. The GnRH-1 neurons are crucial in controlling the hypothalamic-pituitary-gonadal (HPG) axis. Kallmann syndrome is characterized by impaired olfactory system development, defective olfactory bulbs, defective secretion of GnRH-1, and infertility. The precise mechanistic link between the olfactory system and GnRH-1 development remains unclear. Studies in humans and mice highlight the importance of the Prokineticin-2/Prokineticin-Receptor-2 (Prokr2) signaling pathway in olfactory bulb morphogenesis and GnRH-1 neuronal migration.Prokr2loss-of-function mutations can cause Kallmann syndrome, and hence the Prokr2 signaling pathway represents a unique model to decipher the olfactory/GnRH-1 connection. We discovered that Prokr2 is expressed in the TN neurons during the critical period of GnRH-1 neuron formation, migration, and induction of olfactory bulb morphogenesis. Single-cell RNA sequencing identified that the TN is formed by neurons that are distinct from the olfactory neurons. The TN neurons express multiple genes associated with KS. Our study suggests that the aberrant development of pioneer/TN neurons might cause the KS spectrum.

Key Points

1) Pioneer or terminal nerve neurons play a crucial role in initiating the development of the olfactory bulbs. We found that the Prokineticin Receptor-2 gene, associated with Kallmann syndrome, is expressed by the olfactory pioneer/terminal nerve neurons.

2) We genetically traced, isolated, and conducted Single-cell RNA sequencing on terminal nerve neurons of rodents. This analysis revealed a significant enrichment of gene expression related to Kallmann syndrome.

3) Our study indicates that the investigation of Pioneer/terminal nerve neurons should be a pivotal focal point for comprehending developmental defects affecting olfactory and GnRH-1 systems.
Losartan rewires ovarian cancer tumor-immune microenvironment and suppresses IGF-1 to amplify chemo-immunotherapy sensitivity
Authors: Sun Yao , Yin Zhenzhen , Wu Limeng , Yue Changli , Zhang Yanling , Subudhi Sonu , Lei Pinji , Muzikansky Alona , Zhang Luo , Rueda Bo R. , Jain Rakesh K. , Xu Lei
Published: September 2023

Ovarian cancer (OvCa) is the most lethal of the gynecologic malignancies. Immune checkpoint inhibitors, which have revolutionized the treatment of multiple malignancies, have had limited efficacy in OvCa patients. Here, using syngeneic OvCa models and genetic and pharmacologic perturbations, we discovered that losartan – a widely prescribed anti-hypertensive drug – exhibits dual effects on both the tumor microenvironment and cancer cells to sensitize OvCa to chemo-immunotherapy. Specifically, losartan treatment i) reprograms the tumor microenvironment leading to increased vascular perfusion, and thus enhances drug delivery and immune effector cell intratumoral infiltration and function; and ii) rewires the OvCa cells by suppressing the IGF-1 signaling, resulting in enhanced chemosensitivity. As a result of the combined tumor and stromal effects, losartan treatment enhances the efficacy of chemo-immunotherapy in OvCa models. The safety and low cost (less than $1-2/day) of losartan warrant rapid translation of our findings to patients with OvCa.
Tick hemocytes have pleiotropic roles in microbial infection and arthropod fitness
Authors: Rolandelli Agustin , Laukaitis-Yousey Hanna J. , Bogale Haikel N. , Singh Nisha , Samaddar Sourabh , O’Neal Anya J. , Ferraz Camila R. , Butnaru Matthew , Mameli Enzo , Xia Baolong , Mendes M. Tays , Butler L. Rainer , Marnin Liron , Cabrera Paz Francy E. , Valencia Luisa M. , Rana Vipin S. , Skerry Ciaran , Pal Utpal , Mohr Stephanie E. , Perrimon Norbert , Serre David , Pedra Joao H.F.
Published: September 2023

Uncovering the complexity of systems in non-model organisms is critical for understanding arthropod immunology. Prior efforts have mostly focused on Dipteran insects, which only account for a subset of existing arthropod species in nature. Here, we describe immune cells or hemocytes from the clinically relevant tickIxodes scapularisusing bulk and single cell RNA sequencing combined with depletion via clodronate liposomes, RNA interference, Clustered Regularly Interspaced Short Palindromic Repeats activation (CRISPRa) and RNA-fluorescencein situhybridization (FISH). We observe molecular alterations in hemocytes upon tick infestation of mammals and infection with either the Lyme disease spirocheteBorrelia burgdorferior the rickettsial agentAnaplasma phagocytophilum. We predict distinct hemocyte lineages and reveal clusters exhibiting defined signatures for immunity, metabolism, and proliferation during hematophagy. Furthermore, we perform a mechanistic characterization of twoI. scapularishemocyte markers:hemocytinandastakine. Depletion of phagocytic hemocytes affectshemocytinandastakinelevels, which impacts blood feeding and molting behavior of ticks. Hemocytin specifically affects the c-Jun N-terminal kinase (JNK) signaling pathway, whereas astakine alters hemocyte proliferation inI. scapularis. Altogether, we uncover the heterogeneity and pleiotropic roles of hemocytes in ticks and provide a valuable resource for comparative biology in arthropods.
A Linkable, Polycarbonate Gut Microbiome-Distal Tumor Chip Platform for Interrogating Cancer Promoting Mechanisms
Authors: Brasino Danielle S.K. , Speese Sean D. , Schilling Kevin , Schutt Carolyn E. , Barton Michelle C.
Published: September 2023

Gut microbiome composition has been tied to diseases ranging from arthritis to cancer to depression. However, mechanisms of action are poorly understood, limiting development of relevant therapeutics. Organ-on-chip platforms, which model minimal functional units of tissues and can tightly control communication between them, are ideal platforms to study these relationships. Many gut microbiome models have been published to date but devices are typically fabricated using oxygen permeable PDMS, requiring interventions to support anaerobic bacteria. To address this challenge, a novel platform was developed where the chips were fabricated entirely from gas-impermeable polycarbonate without tapes or gaskets. These chips replicated polarized villus-like structures of the native tissue. Further, they enabled co-cultures of commensal anaerobic bacteriaBlautia coccoideson the surface of gut epithelia for two days within a standard incubator. Another complication of PDMS devices is high ad-/absorption, limiting applications in high-resolution microscopy and biomolecule interaction studies. For future communication studies between gut microbiota and distal tumors, an additional polycarbonate chip design was developed to support hydrogel-embedded tissue culture. These chips enable high-resolution microscopy with all relevant processing done on-chip. Designed forfacilelinking, this platform will make a variety of mechanistic studies possible.
Pulmonary function and survival one year after dupilumab treatment of acute moderate to severe COVID-19: A follow up study from a Phase IIa trial
Authors: Hendrick Jennifer , Ma Jennie Z. , Haughey Heather M. , Coleman Rachael , Nayak Uma , Kadl Alexandra , Sturek Jeffrey M. , Jackson Patrick , Young Mary K. , Allen Judith E. , Petri William A.
Published: September 2023

Background

We previously conducted a Phase IIa randomized placebo-controlled trial of 40 subjects to assess the efficacy and safety of dupilumab use in those hospitalized with COVID-19 (NCT04920916). Based on our pre-clinical data suggesting downstream pulmonary dysfunction with COVID-19 induced type 2 inflammation, we contacted patients from our Phase IIa study at 1 year for assessment of Post Covid-19 Conditions (PCC).

Methods

Subjects at 1 year after treatment underwent pulmonary function testing (PFTs), high resolution computed tomography (HRCT) imaging, symptom questionnaires, neurocognitive assessments, and serum immune biomarker analysis, with subject survival also monitored. The primary outcome was the proportion of abnormal PFTs, defined as an abnormal diffusion capacity for carbon monoxide (DLCO) or 6-minute walk testing (6MWT) at the 1-year visit.

Results

Sixteen of the 29 one-year survivors consented to the follow up visit. We found that subjects who had originally received dupilumab were less likely to have abnormal PFTs compared to those who received placebo (Fisher’s exact p=0.011, adjusted p=0.058). We additionally found that 3 out of 19 subjects (16%) in the dupilumab group died by 1 year compared to 8 out of 21 subjects (38%) in the placebo group (log rank p=0.12). We did not find significant differences in neurocognitive testing, symptoms or CT chest imaging between treatment groups but observed evidence of reduced type 2 inflammation in those who received dupilumab.

Conclusions

We observed evidence of reduced long-term morbidity and mortality from COVID-19 with dupilumab treatment during acute hospitalization when added to standard of care regimens.
The mediating role of mammographic density in the protective effect of early-life adiposity on breast cancer risk: a multivariable Mendelian randomization study
Authors: Vabistsevits Marina , Smith George Davey , Richardson Tom G. , Richmond Rebecca C. , Sieh Weiva , Rothstein Joseph H. , Habel Laurel A. , Alexeeff Stacey E. , Lloyd-Lewis Bethan , Sanderson Eleanor
Published: September 2023

Observational studies suggest that mammographic density (MD) may have a role in the unexplained protective effect of childhood adiposity on breast cancer risk. Here, we investigated a complex and interlinked relationship between puberty onset, adiposity, MD, and their effects on breast cancer using Mendelian randomization (MR).

We estimated the effects of childhood and adulthood adiposity, and age at menarche on MD phenotypes (dense area (DA), non-dense area (NDA), percent density (PD)) using MR and multivariable MR (MVMR), allowing us to disentangle their total and direct effects. Next, we examined the effect of MD on breast cancer risk, including risk of molecular subtypes, and accounting for genetic pleiotropy. Finally, we used MVMR to evaluate whether the protective effect of childhood adiposity on breast cancer was mediated by MD.

Childhood adiposity had a strong inverse effect on mammographic DA, while adulthood adiposity increased NDA. Later menarche had an effect of increasing DA and PD, but when accounting for childhood adiposity, this effect attenuated to the null. DA and PD had a risk-increasing effect on breast cancer across all subtypes. The MD single-nucleotide polymorphism (SNP) estimates were extremely heterogeneous, and examination of the SNPs suggested different mechanisms may be linking MD and breast cancer. Finally, MR mediation analysis estimated that 56% (95% CIs [32% - 79%]) of the childhood adiposity effect on breast cancer risk was mediated via DA.

In this work, we sought to disentangle the relationship between factors affecting MD and breast cancer. We showed that higher childhood adiposity decreases mammographic DA, which subsequently leads to reduced breast cancer risk. Understanding this mechanism is of great importance for identifying potential targets of intervention, since advocating weight gain in childhood would not be recommended.
A mathematical model for multiple COVID-19 waves applied to Kenya
Authors: Ogana Wandera , Juma Victor Ogesa , Bulimo Wallace D. , Chiteri Vincent Nandwa
Published: September 2023

The COVID-19 pandemic, which began in December 2019, prompted governments to implement non-pharmaceutical interventions (NPIs) to curb its spread. Despite these efforts and the discovery of vaccines and treatments, the disease continued to circulate globally, evolving into multiple waves, largely driven by emerging COVID-19 variants. Mathematical models have been very useful in understanding the dynamics of the pandemic. Mainly, their focus has been limited to individual waves without easy adaptability to multiple waves. In this study, we propose a compartmental model that can accommodate multiple waves, built on three fundamental concepts. Firstly, we consider the collective impact of all factors affecting COVID-19 and express their influence on the transmission rate through piecewise exponential-cum-constant functions of time. Secondly, we introduce techniques to model the fore sections of observed waves, that change infection curves with negative gradients to those with positive gradients, hence, generating new waves. Lastly, we implement a jump mechanism in the susceptible fraction, enabling further adjustments to align the model with observed infection curve. By applying this model to the Kenyan context, we successfully replicate all COVID-19 waves from March 2020 to January 2023. The identified change points align closely with the emergence of dominant COVID-19 variants, affirming their pivotal role in driving the waves. Furthermore, this adaptable approach can be extended to investigate any new COVID-19 variant or any other periodic infectious diseases, including influenza.