bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficient axonal trafficking of endolysosomes depends on the balanced ratio of microtubule tyrosination and detyrosination
Authors: Konietzny Anja , Peris Leticia , Han Yuhao , Popp Yannes , Bommel Bas van , Sharma Aditi , Delagrange Philippe , Arbez Nicolas , Moutin Marie-Jo , Mikhaylova Marina
Published: October 2023

In neurons, the microtubule (MT) cytoskeleton forms the basis for long-distance protein transport from the cell body into and out of dendrites and axon. To maintain neuronal polarity, the axon initial segment (AIS) serves as a physical barrier, separating the axon from the somatodendritic compartment and acting as a filter for axonal cargo. Selective trafficking is further instructed by axonal enrichment of MT post-translational modifications, which affect MT dynamics and the activity of motor proteins. Here, we compared two knockout mouse lines lacking the respective enzymes for MT tyrosination and detyrosination and we found that both knockouts led to a shortening of the AIS. Neurons from both lines also showed an increased immobile fraction of endolysosomes present in the axon, whereas mobile organelles displayed shortened run distances in the retrograde direction. Overall, our results highlight the importance of maintaining the balance of tyrosinated/detyrosinated MT for proper AIS length and axonal transport processes.

Summary Statement

Despite opposite effects on microtubule dynamics, shifting the balance of microtubule tyrosination/detyrosination in either direction resulted in surprisingly similar defects in axonal organelle transport.
Di- and tri-methylation of histone H3K36 play distinct roles in DNA double-strand break repair
Authors: Chen Runfa , Zhao Meng-Jie , Li Yu-Min , Liu Ao-Hui , Wang Ru-Xin , Mei Yu-Chao , Chen Xuefeng , Du Hai-Ning
Published: October 2023

Histone H3 Lys36 (H3K36) methylation and its associated modifiers are crucial for DNA double-strand break (DSB) repair, but the mechanism governing whether and how different H3K36 methylation forms impact repair pathways is unclear. Here, we unveil the distinct roles of H3K36 dimethylation (H3K36me2) and H3K36 trimethylation (H3K36me3) in DSB repair via non-homologous end joining (NHEJ) or homologous recombination (HR). Yeast cells lacking H3K36me2 or H3K36me3 exhibit reduced NHEJ or HR efficiency. yKu70 and Rfa1 bind H3K36me2- or H3K36me3-modified peptides and chromatin, respectively. Disrupting these interactions impairs yKu70 and Rfa1 recruitment to damaged H3K36me2- or H3K36me3-rich loci, increasing DNA damage sensitivity and decreasing repair efficiency. Conversely, H3K36me2-enriched intergenic regions and H3K36me3-enriched gene bodies independently recruit yKu70 or Rfa1 under DSB stress. Importantly, human KU70 and RPA1, the homologs of yKu70 and Rfa1, exclusively associate with H3K36me2 and H3K36me3 in a conserved manner. These findings provide valuable insights into how H3K36me2 and H3K36me3 regulate distinct DSB repair pathways, highlighting H3K36 methylation as a critical element in the choice of DSB repair pathway.
Frataxin Deficiency Drives a Shift from Mitochondrial Metabolism to Glucose Catabolism, Triggering an Inflammatory Phenotype in Microglia
Authors: Sciarretta Francesca , Zaccaria Fabio , Ninni Andrea , Ceci Veronica , Turchi Riccardo , Apolloni Savina , Milani Martina , Valle Ilaria Della , Tiberi Marta , Chiurchiù Valerio , D’Ambrosi Nadia , Pedretti Silvia , Mitro Nico , Aquilano Katia , Lettieri-Barbato Daniele
Published: October 2023

Immunometabolism investigates the complex interplay between the immune system and cellular metabolism. This study highlights the effects of mitochondrial frataxin (FXN) depletion, which causes Friedreich’s ataxia (FRDA), a neurodegenerative condition characterized by coordination and muscle control deficiencies. Using single-cell RNA sequencing, we identified specific cell groups in the cerebellum of a FRDA mouse model, emphasizing a notable inflammatory microglial response. These FXN-deficient microglia cells exhibited enhanced inflammatory reactions. Furthermore, our metabolomic analyses revealed increased glycolysis and itaconate production in these cells, possibly driving the inflammation. Remarkably, butyrate treatment counteracted these immunometabolic changes, triggered an antioxidant response via the itaconate-Nrf2-GSH pathways, and dampened inflammation. The study also pinpointed Hcar2 (GPR109A) as a potential agent for butyrate anti-inflammatory impact on microglia. Tests on FRDA mice highlighted the neuroprotective attributes of butyrate intake, bolstering neuromotor performance. In essence, our findings shed light on how cerebellar microglia activation contributes to FRDA and highlight butyrate potential to alleviate neuroinflammation, rectify metabolic imbalances, and boost neuromotor capabilities in FRDA and similar conditions.
A precise balance of TETRASPANIN1/TORNADO2 activity is required for vascular proliferation and ground tissue patterning in Arabidopsis
Authors: Konstantinova Nataliia , Mor Eliana , Verhelst Eline , Nolf Jonah , Vereecken Kenzo , Wang Feng , Van Damme Daniel , De Rybel Bert , Glanc Matouš
Published: October 2023

The molecular mechanisms guiding oriented cell divisions in the root vascular tissues ofArabidopsis thalianaare still poorly characterized. By overlapping bulk and single-cell transcriptomic datasets, we unveiledTETRASPANIN1 (TET1)as a putative regulator in this process.TET1is expressed in root vascular cells and loss-of-function mutants contain fewer vascular cells files. We further generated and characterized a CRISPR deletion mutant and show, unlike previously described mutants, that the full knock out is additionally missing endodermal cells in a stochastic way. Finally, we show that HA-tagged versions of TET1 are functional in contrast to fluorescent TET1 translational fusions. Immunostaining using HA-TET1 lines complementing the mutant phenotype revealed a dual plasma membrane and intracellular localization in the root vasculature and a polar membrane localization in young cortex, endodermal and initial cells. Taken together, we show that TET1 is involved in both vascular proliferation and ground tissue patterning. Our initial results pave the way for future work into deciphering its precise mode of action.

Summary statement

This study reveals a novel role of tetraspanin TET1/TRN2 in root vascular development and ground tissue patterning in the model plantArabidopsis thaliana.
Electrosensory and metabolic responses of weakly electric fish to changing water conductivity
Authors: Wiser Shannon D. , Markham Michael R.
Published: October 2023

Weakly electric Gymnotiform fishes use self-generated electric organ discharges (EODs) to navigate and communicate. The electrosensory range for these processes is a function of EOD amplitude, determined by the fish’s electric organ (EO) output and the electrical conductivity of the surrounding water. Anthropogenic activity, such as deforestation, dams, and industrial/agricultural runoff, are known to increase water conductivity in neotropical habitats, likely reducing the electrosensory range of these fish. We investigated whether fish modulate EO output as means of re-expanding electrosensory range after a rapid increase in water conductivity in the pulse-typeBrachyhypopomus gauderioand the wave-typeEigenmannia virescens. Furthermore, because EOD production incurs significant metabolic costs, we assessed whether such compensation is associated with an increase in metabolic rate. Following the conductivity increaseB. gauderioincreased EOD amplitude by 20.2 ± 4.3% over six days but with no associated increase in metabolic rate, whereas the EOD amplitude ofE. virescensremained constant, accompanied by an unexpected decrease in metabolic rate. Our results suggest thatB. gauderiouses a compensation mechanism that requires no metabolic investment, such as impedance matching, or a physiological tradeoff wherein energy is diverted from other physiological processes to increase EO output. These divergent responses between species could be the result of differences in reproductive life history or evolutionary adaptations to different aquatic habitats. Continued investigation of electrosensory responses to changing water conditions will be essential for understanding the effects of anthropogenic disturbances on gymnotiforms, and potential physiological mechanisms for adapting to a rapidly changing aquatic environment.
Daylong Acoustic Recordings of Grazing and Rumination Activities in Dairy Cows
Authors: Martinez-Rau Luciano S. , Chelotti José O. , Ferrero Mariano , Utsumi Santiago A. , Planisich Alejandra M. , Vignolo Leandro D. , Giovanini Leonardo L. , Rufiner H. Leonardo , Galli Julio R.
Published: October 2023

Monitoring livestock feeding behavior may help assess animal welfare and nutritional status, and to optimize pasture management. The need for continuous and sustained monitoring requires the use of automatic techniques based on the acquisition and analysis of sensor data. This work describes an open dataset of acoustic recordings of the foraging behavior of dairy cows. The dataset includes 662 h of daily records obtained using unobtrusive and non-invasive instrumentation mounted on five lactating multiparous Holstein cows continuously monitored for six non-consecutive days in pasture and barn. Labeled recordings precisely delimiting grazing and rumination bouts are provided for a total of 400 h and for over 6,200 ingestive and rumination jaw movements. Companion information on the audio recording quality and expert-generated labels is also provided to facilitate data interpretation and analysis. This comprehensive dataset is a useful resource for studies aimed at exploring new tools and solutions for precision livestock farming.
Listeriaadhesion protein orchestrates caveolae-mediated apical junctional remodeling of epithelial barrier forL. monocytogenestranslocation
Authors: Drolia Rishi , Tenguria Shivendra , Bryant Donald B. , Thind Jessie , Amelunke Breanna , Liu Dongqi , Gallina Nicholas L.F. , Mishra Krishna K. , Samaddar Manalee , Sawale Manoj R. , Mishra Dharmendra K. , Cox Abigail , Bhunia Arun K
Published: October 2023

The cellular junctional architecture remodeling by LAP-Hsp60 interaction forL. monocytogenes(Lm) passage through the epithelial barrier is incompletely understood. Here, using the gerbil model, permissive to internalin (Inl) A/B-mediated pathways like in humans, we demonstrate thatLmcrosses the intestinal villi at 48 h post-infection. In contrast, the single isogenic (lap─or ΔinlA) or double (lap─ΔinlA) mutant strains show significant defects. LAP promotesLmtranslocation via endocytosis of cell-cell junctional complex in enterocytes that do not display luminal E-cadherin. In comparison, InlA-mediated transcytosis occurs in enterocytes displaying apical E-cadherin during cell extrusion and mucus expulsion from goblet cells. LAP hijacks caveolar endocytosis to traffic integral junctional proteins to the early and recycling endosomes. Pharmacological inhibition in a cell line and genetic knock-out of caveolin-1 in mice prevents LAP-induced intestinal permeability, junctional endocytosis, andLmtranslocation. Furthermore, LAP-Hsp60-dependent tight junction remodeling is also necessary for InlA access to E-cadherin forLmintestinal barrier crossing in InlA-permissive hosts.
Th2 and Th17-Associated Immunopathology Following SARS-CoV-2 Breakthrough Infection in Spike-Vaccinated ACE2-humanized Mice
Authors: Zhang Tianyi , Magazine Nicholas , McGee Michael C. , Carossino Mariano , Veggiani Gianluca , Kousoulas Konstantin G. , August Avery , Huang Weishan
Published: October 2023

Vaccines have demonstrated remarkable effectiveness in protecting against COVID-19; however, concerns regarding vaccine-associated enhanced respiratory diseases (VAERD) following breakthrough infections have emerged. Spike protein subunit vaccines for SARS-CoV-2 induce VAERD in hamsters, where aluminum adjuvants promote a Th2-biased immune response, leading to increased type 2 pulmonary inflammation in animals with breakthrough infections. To gain a deeper understanding of the potential risks and the underlying mechanisms of VAERD, we immunized ACE2-humanized mice with SARS-CoV-2 Spike protein adjuvanted with aluminum and CpG-ODN. Subsequently, we exposed them to increasing doses of SARS-CoV-2 to establish a breakthrough infection. The vaccine elicited robust neutralizing antibody responses, reduced viral titers, and enhanced host survival. However, following a breakthrough infection, vaccinated animals exhibited severe pulmonary immunopathology, characterized by a significant perivascular infiltration of eosinophils and CD4+T cells, along with increased expression of Th2/Th17 cytokines. Intracellular flow cytometric analysis revealed a systemic Th17 inflammatory response, particularly pronounced in the lungs. Our data demonstrate that aluminum/CpG adjuvants induce strong antibody and Th1-associated immunity against COVID-19 but also prime a robust Th2/Th17 inflammatory response, which may contribute to the rapid onset of T cell-mediated pulmonary immunopathology following a breakthrough infection. These findings underscore the necessity for further research to unravel the complexities of VAERD in COVID-19 and to enhance vaccine formulations for broad protection and maximum safety.

Significance statement

This research investigates the safety and efficacy of a Spike protein subunit vaccine adjuvanted with Alum and CpG in an ACE2-humanized mouse model, simulating SARS-CoV-2 breakthrough infections. The study reveals that despite robust protection against severe COVID-19, vaccinated mice exhibit substantial pulmonary immunopathology, including eosinophilia and enhanced Th2 effector immunity, following breakthrough infections. Surprisingly, the study also uncovers a significant systemic Th17 inflammatory response in vaccinated mice. This research sheds light on the potential risks associated with COVID-19 vaccine breakthrough infections and the need for a comprehensive understanding of vaccine-induced immune responses, emphasizing the importance of ongoing research, surveillance, and careful vaccine development for both protection and safety in the fight against the COVID-19 pandemic.
Caveolin-1 mediates neuroinflammation and cognitive impairment in SARS-CoV-2 infection
Authors: Trevino Troy N. , Fogel Avital B. , Minshall Richard , Richner Justin M. , Lutz Sarah E.
Published: October 2023

Leukocyte infiltration of the CNS can contribute to neuroinflammation and cognitive impairment. Brain endothelial cells regulate adhesion, activation, and diapedesis of T cells across the blood-brain barrier (BBB) in inflammatory diseases. The integral membrane protein Caveolin-1 (Cav-1) critically regulates BBB permeability, but its influence on T cell CNS infiltration in respiratory viral infections is unknown. In this study, we sought to determine the role of Cav-1 at the BBB in neuroinflammation in a COVID-19 mouse model. We used mice genetically deficient in Cav-1 to test the role of this protein in T cell infiltration and cognitive impairment. We found that SARS-CoV-2 infection upregulated brain endothelial Cav-1. Moreover, SARS-CoV-2 infection increased brain endothelial cell vascular cell adhesion molecule-1 (VCAM-1) and CD3+ T cell infiltration of the hippocampus, a region important for short term learning and memory. Concordantly, we observed learning and memory deficits. Importantly, genetic deficiency in Cav-1 attenuated brain endothelial VCAM-1 expression and T cell infiltration in the hippocampus of mice with SARS-CoV-2 infection. Moreover, Cav-1 KO mice were protected from the learning and memory deficits caused by SARS-CoV-2 infection. These results indicate the importance of BBB permeability in COVID-19 neuroinflammation and suggest potential therapeutic value of targeting Cav-1 to improve disease outcomes.
Exploring archaeogenetic studies of dental calculus to shed light on past human migrations in Oceania
Authors: Velsko Irina M. , Fagernäs Zandra , Tromp Monica , Bedford Stuart , Buckley Hallie R. , Clark Geoffrey , Dudgeon John , Flexner James , Leal-Tamarii Anatauarii , Lewis Cecil M. , Matisoo-Smith Elizabeth , Nägele Kathrin , Ozga Andrew T. , Rohrlach Adam B. , Posth Cosimo , Shing Richard , Spriggs Matthew , Willie Edson , Valentin Frédérique , Warinner Christina
Published: October 2023

The Pacific islands have experienced multiple waves of human migrations, providing a case study for exploring the potential of using the microbiome to study human migration. We performed a metagenomic study of archaeological dental calculus from 103 ancient individuals, originating from 12 Pacific islands and spanning a time range of ∼3000 years. Oral microbiome DNA preservation in calculus is far higher than that of human DNA in archaeological bone from the Pacific, and comparable to that seen in calculus from temperate regions. Variation in the microbial community composition was minimally driven by time period and geography within the Pacific, while comparison with samples from Europe, Africa, and Asia reveal the microbial communities of Pacific calculus samples to be distinctive. Phylogenies of individual bacterial species in Pacific calculus reflect geography. Archaeological dental calculus shows potential to yield information about past human migrations, complementing studies of the human genome.
Jet Lag Does Not Impact Football Performance: Using Randomization Inference to Handle Complexity
Authors: Tenan Matthew S. , Rezai Ali R. , Vigotsky Andrew D.
Published: October 2023

Introduction

It is commonly accepted that traveling across time zones affects sport performance (i.e., via jet lag). This belief is based on poor quality evidence for team sports and simplistic analyses, such ast-tests and linear regression, to explore complex phenomena. For instance, Roy & Forest used such analyses to examine win percentages for the NFL, NBA, and NHL, concluding that East Coast teams were disadvantaged. Similarly, Smith et al. primarily usedt-tests to show that West Coast NFL teams were more likely than East Coast teams to beat the Vegas spread in evening games (non-coastal teams were omitted). Neither analysis considered time zone change or game time as continuous constructs nor did they account for important contextual information. We used modern causal inference methods and a decade of collegiate football games to determine if jet lag and kickoff time have any causal effect on beating the Vegas spread. This required fitting nonlinear splines for both data re-weighting and analysis; however, using weights in a generalized additive model (GAM) presents challenges for standard frequentist inferences. Thus, non-parametric simulations were developed to obtain valid causal inferences via randomization inference (RI).

Methods

Pro Football Focus data from college football seasons 2013–2022 were paired with time zone data from Google Maps, weather data from gridMET, and Vegas spread data fromcollegefootballdata.com. GAM-based propensity scores were calculated from turf type, precipitation, humidity, temperature, and wind speed. These propensity scores orthogonalized the variables relationship to the treatments (i.e., game time and hours gained due to time zone change), consistent with the Potential Outcomes framework. The propensity scores were used to weight the observations in a GAM logistic regression, which modeled beating the Vegas spread as a function of a splined effect modification for game time and hours gained in travel. Since valid standard errors cannot be calculated from GAMs with weights, we used RI to compare the effect modification to a null model. We simulated 5,000 datasets of random treatments under the positivity assumption. Each RI dataset was analyzed with the same GAM used for the observed data to obtain a distribution of noiseF-statistics. The real dataF-statistic was contrasted to the RI distribution for inferences.

Results

The real data were compatible with the null hypothesis of no effect for hours lost/gained in travel and game time (P= 0.142).

Conclusion

We need to rigorously interrogate assumptions regarding what affects performance in team sports. There is no clear indication that jet lag and game time affect team performance when appropriate analyses are performed in a causal inference framework. Similarly, rigorous analysis should be undertaken to confirm or refute other assumptions in sport science, such as workload management, sleep practices, and dietary/supplementation regimens.
SARS-CoV-2 lineage-specific disease symptoms and disease severity in São Caetano do Sul city, Brazil
Authors: Sales Flavia Cristina da Silva , Prete Carlos Augusto , Abade Leandro , Buss Lewis Fletcher , Candido Darlan da Silva , Claro Ingra Morales , Moreira Filipe Romero Rebello , Manulli Erika Regina , Capuani Ligia , Maia Camila Alves da Silva , Oliveira Beatriz Araujo , Coletti Thais , Paiao Heuder Gustavo Oliveira , Costa Silvia Figueiredo , Correa Maria Cassia Mendes , Leal Fabio Eudes , Parag Kris Varun , Nascimento Vítor Heloiz , Faria Nuno Rodrigues , Sabino Ester Cerdeira
Published: October 2023

Background

The city of São Caetano do Sul, Brazil, established a web-based platform to provide primary care to suspected COVID-19 patients, integrating clinical and demographic data and sample metadata. Here we describe lineage-specific spatiotemporal dynamics of infections, clinical symptoms, and disease severity during the first year of the epidemic.

Methods

We selected and sequenced 879 PCR+ swab samples (8% of all reported cases), obtaining a spatially and temporally representative set of sequences. Daily lineage-specific prevalence was estimating using a moving-window approach, allowing inference of cumulative cases and symptom probability stratified by lineage using integrated data from the platform.

Results

Most infections were caused by B.1.1.28 (41.3%), followed by Gamma (31.7%), Zeta (9.6%) and B1.1.33 (9.0%). Gamma and Zeta were associated with larger prevalence of dyspnoea (respectively 81.3% and 78.5%) and persistent fever (84.7% and 61.1%) compared to B.1.1.28 and B.1.1.33. Ageusia, anosmia, and coryza were respectively 18.9%, 20.3% and 17.8% less commonly caused by Gamma, while altered mental status was 108.9% more common in Zeta. Case incidence was spatially heterogeneous and larger in poorer and younger districts.

Discussion

Our study demonstrates that Gamma was associated with more severe disease, emphasising the role of its increased disease severity in the heightened mortality levels in Brazil.
Isoniazid preventive therapy during infancy does not adversely effect growth among HIV-exposed uninfected children: secondary analysis of data from a randomized controlled trial
Authors: Cherkos Ashenafi Shumey , LaCourse Sylvia M , Enquobahrie Daniel A , Escudero Jaclyn N , Mecha Jerphason , Matemo Daniel , Kinuthia John , John-Stewart Grace
Published: October 2023

Background: Isoniazid preventive therapy (IPT) decreases risk of tuberculosis (TB) disease; impact on long-term infant growth is unknown. In a recent randomized trial (RCT), we assessed IPT effects on infant growth without known TB exposure. Methods: The infant TB Infection Prevention Study (iTIPS) trial was a non-blinded RCT among HIV-exposed uninfected (HEU) infants in Kenya. Inclusion criteria included age 6-10 weeks, birthweight >2.5 kg, and gestation >37 weeks. Infants in the IPT arm received 10 mg/kg isoniazid daily for 12 months, while the control trial received no intervention; post-trial observational follow-up continued through 24 months of age. We used intent-to-treat linear mixed-effects models to compare growth rates (weight-for-age z-score [WAZ] and height-for-age z-score [HAZ]) between trial arms. Results: Among 298 infants, 150 were randomized to IPT, 47.6% were females, median birthweight was 3.4 kg (interquartile range [IQR] 3.0-3.7), and 98.3% were breastfed. During the 12-month intervention period and 12-month post-RCT follow-up, WAZ and HAZ declined significantly in all children, with more HAZ decline in male infants. There were no growth differences between trial arms, including in sex-stratified analyses. In longitudinal linear analysis, mean WAZ (β=0.04 [95% CI:-0.14, 0.22]), HAZ (β=0.14 [95% CI:-0.06, 0.34]), and WHZ [β=-0.07 [95% CI:-0.26, 0.11]) z-scores were similar between arms as were WAZ and HAZ growth trajectories. Infants randomized to IPT had higher monthly WHZ increase (β to 24 months 0.02 [95% CI:0.01, 0.04]) than the no-IPT arm. Conclusion: IPT administered to HEU infants did not significantly impact growth outcomes in the first two years of life.
Handgrip strength as a screening tool for diabetes in resource-constrained settings: a potential solution to overcome barriers to diagnosis
Authors: Ojulari Lekan Sheriff , Sulaiman Swabirah Enimire , Ayinde Taofeek Olanrewaju , Kadir Eniola Riskat
Published: October 2023

Background Information

Diabetes mellitus is an escalating global health concern, especially in low and middle-income countries. The high cost and inaccessibility of diagnostic tools in resource-constrained settings have heightened the need for alternative screening methods. Handgrip strength (HGS), a measure of muscle strength, emerges as a potential non-invasive and affordable screening tool for diabetes, particularly in areas with limited healthcare access.

Objective

To investigate the relationship between handgrip strength and blood glucose regulation in non-diabetic young adults and to provide valuable insights into the potential of handgrip strength as a preventive and affordable approach to managing diabetes.

Methods

A cross-sectional study was conducted involving 59 students (aged 18-21) from the University of Ilorin, Nigeria. Handgrip strength was measured using a dynamometer, and its relationship with blood glucose regulatory markers, such as fasting blood glucose, 2-hour post-prandial glucose, and HbA1c, was analyzed. Multiple regression models were utilized to examine the potential associations.

Results

Findings revealed significant associations between HGS and glucose regulation markers, particularly FBS, among males. In females, the relationship was evident only after adjusting for body mass index (BMI). Furthermore, a notable relationship between HGS and 2-hour post-prandial glucose levels was observed in females but not in males. However, no significant associations were found between HGS and serum insulin levels across genders.

Conclusion

Our study introduces HGS as a practical and cost-effective screening tool for blood glucose regulation disorders, aligning with existing literature and offering a personalized approach to management. In resource-constrained settings, HGS becomes significant, addressing diagnostic barriers and potentially revolutionizing diabetes management. However, limitations include a small sample size of 59 students and restrictions to specific demographics, emphasizing the need for future studies in diverse populations to validate HGS’s efficacy in real-world, resource-constrained settings.
Head-to-head comparison of composite and individual biomarkers to predict clinical benefit to PD-1 blockade in Non-Small Cell Lung Cancer
Authors: Hummelink Karlijn , van der Noort Vincent , Muller Mirte , Schouten Robert D. , van den Heuvel Michel M. , Thommen Daniela S. , Smit Egbert F. , Meijer Gerrit A. , Monkhorst Kim
Published: October 2023

Background

Treatment with PD-(L)1 blocking agents has demonstrated durable efficacy in advanced NSCLC, but only in a minority of patients. Multiple biomarkers for predicting treatment benefit have been investigated, but their combined performance has not been extensively studied. Here, we assess the combined predictive performance of multiple biomarkers in a series of NSCLC patients treated with nivolumab.

Methods

Pretreatment samples from 135 patients treated with nivolumab were used to assess the predictive performance of CD8 tumor-infiltrating lymphocytes (TILs), intratumoral (IT) localization of CD8 TILs, PD-1 high expressing TILs (PD1TTILs), CD3 TILs, CD20 B-cells, tertiary lymphoid structures (TLS), PD-L1 tumor proportion score (TPS) and the Tumor Inflammation score (TIS). Patients were assigned to a training (n=55) and validation set (n=80). The primary outcome measure was Disease Control at 6 months (DC 6m) and the secondary outcome measure was DC at 12 months (DC 12m).

Results

In the validation cohort, the two best performing composite biomarkers (i.e. CD8+IT-CD8 and CD3+IT-CD8) demonstrated similar or lower sensitivity (64% and 83%) and NPV (76% and 85%) than the individual biomarkers PD-1TTILs and TIS (sensitivity: 72% and 83%, NPV: 86% and 84%) for DC 6m, respectively. Also, at 12 months, both selected composite biomarkers (CD8+IT-CD8 and CD8+TIS) showed less predictive performance compared to PD-1TTILs and TIS alone. PD-1TTILs and TIS showed high sensitivity (86% and 100%) and NPV (95% and 100%) for DC 12m. PD-1TTILs could better discriminate patients with no long-term benefit, since specificity was substantially higher as compared to TIS (74% versus 39%).

Conclusion

Composite biomarkers did not show improved predictive performance compared to PD-1TTILs and TIS alone for both the 6- and 12-months endpoint. PD-1TTILs and TIS identified patients with DC 12m with high sensitivity. Patients with no long-term benefit to PD-1 blockade were most accurately identified by PD-1TTILs.
Enrichment of the local synaptic translatome for genetic risk associated with schizophrenia and autism spectrum disorder
Authors: Clifton Nicholas E , Lin Julie Qiaojin , Holt Christine E , O’Donovan Michael C , Mill Jonathan
Published: October 2023

Background

Genes encoding synaptic proteins or mRNA targets of the RNA binding protein, Fragile X mental retardation protein (FMRP), have been linked to schizophrenia and autism spectrum disorder (ASD) through the enrichment of genetic variants conferring risk to these disorders. FMRP binds many transcripts with synaptic functions and is thought to be a key regulator of their local translation, a process which enables rapid and compartmentalized protein synthesis required for development and plasticity.

Methods

Here, we used summary statistics from large-scale genome-wide association studies to test the hypothesis that the subset of synaptic genes encoding localized transcripts is more strongly associated with schizophrenia and ASD than non-localized transcripts. We also postulated that this subset of synaptic genes is responsible for associations attributed to FMRP targets.

Results

We show that schizophrenia associations were enriched in genes encoding localized synaptic transcripts compared to the remaining synaptic genes, or to the remaining localized transcripts; this also applied to ASD associations, although only for transcripts observed after stimulation by fear conditioning. The genetic associations with either disorder captured by these gene sets were independent of those derived from FMRP targets. Furthermore, we found that schizophrenia association was related to FMRP interactions with mRNAs in somata, but not in dendrites, whilst ASD association was related to FMRP binding in either compartment.

Conclusions

Our data suggest that synaptic transcripts capable of rapid and compartmentalized local translation are particularly relevant to the pathogenesis of schizophrenia and ASD, but do not characterize the associations attributed to current sets of FMRP targets.
Dynamics of Hepatitis C Virus Seroprevalence: Evaluating Risk Factors among Sex Workers in Pakistan
Authors: Tirmizi Raza , Rashid Rida , Zaidi Nousheen
Published: October 2023

The current study investigates the seroprevalence of the Hepatitis C Virus (HCV) among sex workers in Pakistan, a challenging task due to social and cultural barriers. Our primary objectives were to gauge the extent of HCV exposure in this marginalized group, identify disparities in seroprevalence between sexes, and examine the association between seropositivity and various demographic and risk factors. A total of 1,000 participants were enrolled, with male sex workers comprising the majority (87.7%) and female sex workers accounting for 12.3%. Notably, a significant portion fell within the 26-35 age category (39.9%). A significant proportion (47.1%) had not received formal education. Overall, HCV antibodies were found in 15% of the participants. Disparities were evident, with a seroprevalence of 13% in male sex workers and a significantly higher 31% in female sex workers. HCV seropositivity increased with age, with female sex workers showing a sharper rise. A link between levels of formal education and HCV seroprevalence was observed, with female sex workers consistently exhibiting higher seroprevalence across educational levels. Risk factors such as shaving practices, blade sharing, surgical history, and other medical exposures were assessed, revealing higher HCV seropositivity rates among those exposed, especially pronounced among female participants. This research study paves the way for future investigations and interventions tailored to this population’s unique needs and vulnerabilities.
Active Suppression of the Nigrostriatal Pathway during Optogenetic Stimulation Revealed by Simultaneous fPET/fMRI
Authors: Haas Sabrina , Bravo Fernando , Ionescu Tudor M. , Gonzalez-Menendez Irene , Quintanilla-Martinez Leticia , Dunkel Gina , Kuebler Laura , Hahn Andreas , Lanzenberger Rupert , Weigelin Bettina , Reischl Gerald , Pichler Bernd J. , Herfert Kristina
Published: October 2023

The dopaminergic system is a central component of the brain’s neurobiological framework, governing motor control, reward responses, and playing an essential role in various brain disorders such as Parkinson’s disease and schizophrenia. Within this complex network, the nigrostriatal pathway represents a critical circuit for dopamine transmission from the substantia nigra to the striatum, a connection that is vital to understanding many of the disease-related dysfunctions. However, stand-alone functional magnetic resonance imaging (fMRI) is unable to study the intricate interplay between brain activation and its molecular underpinnings. In our study, the simultaneous use of [18F]FDG functional positron emission tomography (fPET)/BOLD-fMRI provided a new insight that allowed us to demonstrate an active suppression of the nigrostriatal activity during optogenetic stimulation via presynaptic autoinhibition. Ourin vivoobservation emphasizes that the observed BOLD signal depression during neuronal stimulation does not correlate with neuronal inactivity, but results from an active suppression of neuronal firing as shown by the high [18F]FDG signal increase. This result not only illustrates the potential of simultaneous fPET/fMRI to understand the molecular mechanisms of brain function but also provides a new perspective on how neurotransmitters such as dopamine influence hemodynamic responses in the brain.
A molecularly distinct cell type in the midbrain regulates intermale aggression behaviors in mice
Authors: Li Chunyang , Miao Cheng , Ge Yao , Wu Jiaxing , Gao Panpan , Yin Songlin , Zhang Pei , Yang Hongbin , Tian Bo , Chen Wenqiang , Chen Xiaoqian
Published: October 2023

Background

The periaqueductal gray (PAG) is a central hub for regulation of aggression, while little is known on the circuitry and molecular mechanisms that govern this regulation. We investigate the role of a distinct cell type,Tachykinin 2-expressing (Tac2+) neurons, located in the dorsomedial PAG (dmPAG), in modulating aggression in mice.

Methods

We combined activity mapping,in vivoCa2+recording, chemogenetic and pharmacological manipulation, and a viral-based translating ribosome affinity purification (TRAP) profiling using a mouse resident-intruder model.

Results

We reveal that the dmPAGTac2neurons were selectively activated during fighting behaviors. Activation of the dmPAGTac2neurons evoked, while inhibition or genetic ablation of the dmPAGTac2neurons suppressed fighting behaviors. TRAP profiling of dmPAGTac2neurons revealed that fighting behaviors specifically induced enrichment of serotonin-associated transcripts to the dmPAGTac2neurons. Last, we validated these findings by selectively delivering pharmacological agent into the dmPAG and reversed the behavioral outcomes induced by chemogenetic manipulation.

Conclusions

We identify that the dmPAGTac2neuron can regulate mouse aggressive behavior and thus suggest a distinct molecular target for the treatment of exacerbated aggressive behaviors in populations that exhibit high-level of violence.
Social Context and Reward Sensitivity Enhance Corticostriatal Function during Experiences of Shared Rewards
Authors: Zaff Ori , Wyngaarden James B. , Dennison Jeffrey B. , Sazhin Daniel , Chein Jason , McCloskey Michael , Alloy Lauren B. , Jarcho Johanna M. , Smith David V. , Fareri Dominic S.
Published: October 2023

Although prior research has demonstrated enhanced striatal response when sharing rewards with close social connections, less is known about how individual differences affect ventral striatal (VS) activation and connectivity when experiencing rewards within social contexts. Given that self-reported reward sensitivity and level of substance use have been associated with differences in VS activation, we set out to investigate whether these factors would be independently associated with enhancements to neural reward responses within social contexts. In this pre-registered study, participants (N=45) underwent fMRI while playing a card guessing game in which correct or incorrect guesses resulted in monetary gains and losses that were shared evenly with either a close friend, stranger (confederate), or non-human partner. Consistent with our prior work, we found increased VS activation when sharing rewards with a socially close peer as opposed to an out-of-network stranger. As self-reported reward sensitivity increased, the difference in VS response to rewards shared with friends and strangers decreased. We also found enhanced connectivity between the VS and temporoparietal junction when sharing rewards with close friends as opposed to strangers. Finally, exploratory analyses revealed that as reward sensitivity and sub-clinical substance use increase, the difference in VS connectivity with the right fusiform face area increases as a function of social context. These findings demonstrate that responsivity to the context of close friends may be tied to individual reward sensitivity or sub-clinical substance use habits; together these factors may inform predictions of risk for future mental health disorders.
Microbiome-Derived Prion-Like Proteins and Their Potential to Trigger Cognitive Dysfunction
Authors: Seira Curto Jofre , Dominguez Martinez Adan , Sotillo Sotillo Paula , Serrat Garcia Martina , Girona del Pozo Monica , Fernandez Maria Rosario , Sanchez de Groot Natalia
Published: October 2023

Our life is intricately connected to microorganisms through infection or symbiotic relationships. While the inter-species propagation of prion-like proteins is well-established, their presence in the microbiome and impact on the host remains largely unexplored. To address this, we conducted a systematic study integratingin silico,in vitro,andin vivoanalyses, showing that 63% of the gastrointestinal tract microbiome encodes prion-like sequences. These sequences can form amyloid fibrils capable of interfering with the aggregation of the Amyloid-beta-peptide and promoting the aggregation and propagation of the Sup35 prion. Finally, whenC. eleganswere fed with bacteria expressing chimeras of our prion candidates, it resulted in the loss of sensory memory, reproducing the Alzheimer’s model phenotype. In our model, memory impairment is linked to aggregate fragmentation and its susceptibility to degradation. Taken together, these findings show that the gut microbiota serves as a potential reservoir of prion-like sequences, supporting the idea that microbial products may influence the pathogenesis of neurodegenerative diseases.
Circadian oscillation of perireceptor events influence olfactory sensitivity in diurnal and nocturnal mosquitoes
Authors: De Tanwee Das , Pelletier Julien , Gupta Satyajeet , Kona Madhavinadha Prasad , Singh Om P. , Dixit Rajnikant , Ignell Rickard , Karmodiya Krishanpal
Published: October 2023

Olfaction and circadian rhythm gate different behaviors in mosquitoes that are important for their capacity to transmit disease. However, the mechanisms of odor detection, and the circadian-guided changes in olfactory sensitivity across different mosquito species, remain largely unexplored. To this end, we performed a circadian-dependent RNA-sequencing study of the peripheral olfactory- and brain tissues of femaleAnopheles culicifaciesandAedes aegyptimosquitoes. Data analysis revealed a significant upregulation of genes encoding: (a) odorant binding proteins (OBPs), required for transportation of odorant molecules towards the olfactory receptors, and (b) xenobiotic-metabolizing enzymes (XMEs) during the day time inAedes aegyptiand during the dusk-transition phase inAnopheles culicifacies. While XMEs primarily function in the elimination of toxic xenobiotics, concurrent elevation of XMEs and OBPs are hypothesized to act cumulatively to regulate perireceptor events and odorant sensitivity. Electroantennographic analysis with bothAnopheles gambiaeandAedes aegyptiagainst diverse behaviorally relevant odorants, combined with XMEs inhibitors and RNA interference, establish the proof-of-concept that XMEs function in perireceptor events during odorant detection and influence the odorant sensitivity in mosquitoes. Additionally, the RNA-sequencing and RNAi-mediated knockdown data revealed that daily temporal modulation of neuronal serine proteases may facilitate the consolidation of the brain function, and influence the odor detection process in both diurnal and nocturnal mosquitoes. These findings provide the impetus to further explore the species-specific rhythmic expression pattern of the neuro-olfactory encoded molecular factors, which could pave the way to develop and implement successful mosquito control methods.

Graphical Abstract

Highlights

Circadian oscillation of perireceptor proteins possibly influences time-of-day dependent change olfactory sensitivity in diurnal and nocturnal mosquitoes

Diurnal and nocturnal mosquitoes depict distinct dynamic change in perireceptor proteins

Inhibition of cytochrome P450 gene minimizes antennal response to different odorants

Neuronal serine protease may consolidate brain function and odor detection
ThepanC-encoded pantothenate synthetase to tackle carbapenem-resistant OprDPseudomonas aeruginosamutant revealed through Tn-Seq
Authors: Van Maele Cléophée , Caboche Ségolène , Moutel Marin , Bonnomet Arnaud , Moussalih Sophie , Luczka Emilie , Jacquier Hervé , Muggeo Anaëlle , Guillard Thomas
Published: October 2023

For the World Health Organization, carbapenem-resistantPseudomonas aeruginosa is a critical priority for which new antimicrobial drugs are needed. Consequently, understanding the underlying mechanisms of resistant bacteria infection will enable the identification of new therapeutic targets. Loss of the OprD porin is the main determinant of resistance to the last resort carbapenem antibiotics and has been described to enhance fitnessin vivoand virulence. Transposon sequencing is a high-throughput sequencing technique that makes it possible to identify essential genes (EGs) that may turn out to be therapeutic targets. However, such a strategy has not yet been used for OprD-deficientP. aeruginosa. In this study, we identified the EGs specific to PA14 OprD mutant for LB growth and we established a list of 30 EGs among these, we highlighted thepanCgene encoding pantothenate synthetase as a promising target. Using CRISPRi, we confirmed that silencingpanCreduced LB growth, and decreasedsigXexpression, whose overexpression is associated with membrane fluidity, as well as the expression of genes involved in the fatty acid synthesis (FAS). Taking into account the weakness of PA14 OprD mutant due to an altered membrane consecutive to a decrease in unsaturated FAS in the absence ofpanC,we showed that silencingpanCextended the destruction time of 16HBE airway cells. Overall, our findings highlighted the anti-virulence potential ofpanCinhibition and shed new light on its inhibition as a target for treating carbapenem-resistant OprD-defective PA lung infections.
Diurnal rhythmicity of fecal microbiota and metabolite profiles in the first year of life: a randomized controlled interventional trial with infant formula
Authors: Heppner Nina , Reitmeier Sandra , Heddes Marjolein , Merino Michael Vig , Schwartz Leon , Dietrich Alexander , List Markus , Gigl Michael , Meng Chen , Omer Hélène , Kleigrewe Karin , Schirmer Melanie , van der Veen Daan R , Kiessling Silke , Haller Dirk
Published: October 2023

Microbiota assembly in the infant gut is influenced by time and duration of dietary exposure to breast-milk, infant formula and solid foods. In this randomized controlled intervention study, longitudinal sampling of infant stool (n=998) showed similar development of fecal bacterial communities (16S rRNA/shallow metagenomics sequencing) between formula- and breast-fed infants during the first year of life (N=210). Infant formula supplemented with galacto-oligosaccharides (GOS) was most efficient to sustain high levels of bifidobacteria compared to formula containingB. longumandB. breveor placebo. In addition to primary endpoints, metabolite and bacterial profiling revealed 24-hour oscillations and data integration identified circadian networks. Rhythmicity in bacterial diversity, specific taxa and functional pathways increased with age and was strongest following breast-feeding and GOS-supplementation. Circadian rhythms in dominant taxa were discoveredex-vivoin a chemostat model. Hence, microbiota rhythmicity develops early in life, likely via bacterial intrinsic clock mechanism and is affected by diet.
FVIII interacts with cell surface to regulate endothelial cell functionality
Authors: Olgasi Cristina , Cucci Alessia , Molineris Ivan , Assanelli Simone , Anselmi Francesca , Borsotti Chiara , Sgromo Chiara , Lauria Andrea , Merlin Simone , Walker Gillian , Capasso Paola , Oliviero Salvatore , Follenzi Antonia
Published: October 2023

Haemophilia A (HA) is a rare bleeding disorder caused by factor 8 (F8) mutations. Clinical manifestations are spontaneous bleedings that primarily consist of hemarthrosis and intracranial haemorrhages. To date, the impairment of vessel stability in HA patients and the correlation between FVIII and endothelial functionality is poorly understood.

Here we show that FVIII plays a role in endothelial cell functionality. Blood Outgrowth endothelial cells (BOECs) knockout generated by CRISPR/Cas9, HA BOECs and HA iPSCs-derived ECs showed alteration of vessel-formation, endothelial cell migration, and vessel permeability. Importantly, the impaired EC phenotype was rescued by treatment with recombinant human FVIII or by lentiviral vector (LV) expressing FVIII. The FVIII function on endothelium was confirmed in vivo in a mouse model of severe HA which showed that an altered angiogenesis and vesselpermeability could be treated by exogenous FVIII. BOECstranscriptomic profiles revealed that FVIIIregulates the expression of endothelial basement membrane and extracellular matrix genes. Furthermore, exogenous expression of Nidogen2, identified as a FVIII regulated gene, restored the extracellular matrix integrity and EC functionality of HA ECs. In conclusion, FVIII is not only a coagulation factor but also an endothelial cell autocrine factor which promotes vessel stability.