bluuebunny/crossref_metadata_2025_split huggingface dataset:
Touch receptor end-organ innervation and function requires sensory neuron expression of the transcription factor Meis2
Authors: Desiderio Simon , Schwaller Fred , Tartour Kevin , Padmanabhan Kiran , Lewin Gary R. , Carroll Patrick , Marmigère Frédéric 
Published: May 2022

AbstractTouch sensation is primarily encoded by mechanoreceptors, called Low-Threshold Mechanoreceptors (LTMRs), with their cell bodies in the Dorsal Root Ganglia (DRG). Because of their great diversity in terms of molecular signature, terminal endings morphology and electrophysiological properties, mirroring the complexity of tactile experience, LTMRs are a model of choice to study the molecular cues differentially controlling neuronal diversification. While the transcriptional codes that define different LTMR subtypes have been extensively studied, the molecular players that participate in their late maturation and in particular in the striking diversity of their end-organ morphological specialization are largely unknown. Here we identified the TALE homeodomain transcription factor Meis2 as a key regulator of LTMRs target-field innervation.Meis2is specifically expressed in cutaneous LTMRs and its expression depends on target-derived signals. While LTMRs lackingMeis2survived and are normally specified, their end-organ innervations, electrophysiological properties and transcriptome are differentially and markedly affected, resulting in impaired sensory-evoked behavioral responses. These data establishMeis2as a major transcriptional regulator controlling the orderly formation of sensory neurons innervating peripheral end-organs required for light touch.
Tracing the substrate translocation mechanism in P-glycoprotein
Authors: Gewering Theresa , Waghray Deepali , Parey Kristian , Jung Hendrik , Tran Nghi N.B. , Zapata Joel , Zhao Pengyi , Chen Hao , Januliene Dovile , Hummer Gerhard , Urbatsch Ina L. , Moeller Arne , Zhang Qinghai 
Published: May 2022

AbstractP-glycoprotein (Pgp) is a prototypical ABC transporter of great biological and clinical significance that confers cancer multidrug resistance and mediates the bioavailability and pharmacokinetics of many drugs1–3. Decades of structural and biochemical studies have provided insights into how Pgp binds diverse compounds4–9, but how they are translocated through the membrane has remained elusive. Here, we covalently attached a cyclic substrate to discrete sites of Pgp and determined multiple complex structures in inward- and outward-facing states by cryoEM. In conjunction with molecular dynamics simulations, our structures trace the substrate passage across the membrane and identify conformational changes in transmembrane helix 1 (TM1) as regulators of substrate transport. In mid-transport conformations, TM1 breaks at glycine 72. Mutation of this residue significantly impairs drug transport of Pgp in vivo, corroborating the importance of its regulatory role. Importantly, our data suggest that the cyclic substrate can exit Pgp without the requirement of a wide-open outward-facing conformation, diverting from the common efflux model for Pgp and other ABC exporters. The substrate transport mechanism of Pgp revealed here pinpoints critical targets for future drug discovery studies of this medically relevant system.
Chemical ecology of Himalayan eggplant variety’s antixenosis: Identification of geraniol as an oviposition deterrent against the eggplant shoot and fruit borer
Authors: Ghosh Rituparna , Metze Dennis , Shaikh Maroof , Deshpande Ashish , Firake Dnyaneshwar M. , Pandit Sagar 
Published: May 2022

SummaryEggplant (Solanum melongena) suffers severe losses due to a multi-insecticide resistant lepidopteran pest, shoot and fruit borer (SFB,Leucinodes orbonalis). Heavy and combinatorial application of pesticides for SFB control renders eggplant risky for human consumption.We observed that 1) ovipositing SFB females can find even solitary plants of susceptible varieties and 2) they do not oviposit on Himalayan eggplant variety RC-RL-22 (RL22). We hypothesized that the olfactory cues influence ovipositing female’s host choice.To find these cues, leaf volatile blends of seven eggplant varieties were profiled using GCMS. Seven compounds were present in >2.5-fold concentrations in RL22 than the other varieties. In choice assays, oviposition deterrence efficacies of these candidate compounds were independently tested by their foliar application on SFB-susceptible varieties. Complementation of geraniol, which was exclusively found in RL22, reduced oviposition (>90%). To validate geraniol’s role in RL22’s SFB-deterrence, we silenced RL22’s geraniol synthase gene using virus-induced gene silencing. Geraniol biosynthesis suppression rendered RL22 SFB-susceptible; foliar geraniol application on the geraniol synthase-silenced plants restored oviposition deterrence.We infer that geraniol is RL22’s SFB oviposition deterrent. The use of natural compounds like geraniol, which influence the chemical ecology of oviposition can reduce the load of hazardous larvicidal pesticides.
Causal associations between iron status and sepsis: a Mendelian randomisation analysis
Authors: Hamilton Fergus , Mitchell Ruth , Ahmed Haroon , Ghazal Peter , Timpson Nic 
Published: May 2022

AbstractIron deficiency is associated with a substantial burden of morbidity. However, supplementation of iron has been linked to increased rates of serious infection in randomised trials of children in sub-Saharan Africa. Randomised trials in other settings have been inconclusive and it is unknown if changes in levels of iron biomarkers – a mark of setpoint changes in iron homeostasis - are linked to sepsis in these other settings. We used genetic variants associated with levels of iron biomarkers as instrumental variables in a Mendelian randomisation (MR) analysis to test the hypothesis that increasing levels of iron biomarkers increase the risk of sepsis. In observational and MR analyses we found that increases in iron biomarkers increase the risk of sepsis. In stratified analyses, we show that this risk may be larger in those with iron deficiency and/or anaemia. Taken together, results here suggest a required caution in supplementation of iron and underline the role of iron homeostasis in severe infection.
Effectiveness of Covid-19 vaccines against SARS-CoV-2 Omicron variant (B.1.1.529): A systematic review with meta-analysis and meta-regression
Authors: Pratama Nando Reza , Wafa Ifan Ali , Budi David Setyo , Sutanto Henry , Asmarawati Tri Pudy , Wungu Citrawati Dyah Kencono 
Published: May 2022

SummaryBackgroundThere is a need for evaluation regarding vaccine effectiveness (VE) and the urgency of booster vaccination against Covid-19 B.1.1.529 (Omicron) variant.MethodsSystematic search was conducted on April 6th, 2022, on databases (PubMed, ScienceDirect, CENTRAL, Web of Science, Scopus). VE difference (VED) estimates were assessed using random-effects model and DerSimonian-Laird tau estimators. Two models result, i.e., within 3 months and within 3 months or more, are compared. VE versus time meta-regression analysis was evaluated using mixed-effects model with Restricted-Maximum Likelihood tau estimators and Hartung-Knapp adjustments.FindingsAd26.COV2.S, BNT162b2, ChAdOx1 nCov-19, and mRNA-1273 vaccines were included in the analyses. Compared to full dose, booster dose of overall vaccines provided better protection against any (VED=22% (95%CI 15%-29%), p<0.001), severe (VED=20% (95%CI 8%-32%), p=0.001) and symptomatic (VED=22% (95%CI 11%-34%), p<0.001) Omicron infections within 3 months, as well as within 3 months or more (VED=30% (95%CI 24%-37%), p<0.001 for any, VED=18% (95%CI 13%-23%), p<0.001 for severe and VED=37% (95%CI 29%-46%), p<0.001 for symptomatic infections). The meta-regression analysis of overall vaccines revealed that the full dose VE against any and symptomatic Omicron infections were significantly reduced each month by 3.0% (95%CI 0.9%-4.8%, p=0.004) and 5.2% (95%CI 3.3%-7.1%, p=0.006), respectively; whereas booster dose effectiveness against severe and symptomatic Omicron infections were decreased by 3.7% (95%CI 5.1%-12.6%, p=0.030) and 3.9% (95%CI 1.2%-6.5%, p=0.006), respectively.InterpretationCompared to full dose only, a booster dose addition provides better protection against B.1.1.529 infection. Although the VE estimates of Ad26.COV2.S, BNT162b2, ChAdOx1 nCov-19, and mRNA-1273 vaccines against B.1.1.529 infection after both full and booster doses are generally moderate, and the booster dose provides excellent protection against severe infection, it is important to note that the VE estimates decline over time, suggesting the need for a regular Covid-19 booster injection after certain period of time to maintain VE.
Multi-center evaluation of baseline neutrophil:lymphocyte (NLR) ratio as an independent predictor of mortality and clinical risk stratifier in Idiopathic Pulmonary Fibrosis
Authors: Mikolasch Theresia A , George Peter M. , Sahota Jagdeep , Nancarrow Thomas , Barratt Shaney L , Woodhead Felix A. , Kouranos Vasilis , Cope Victoria S A , Creamer Andrew W , Fidan Silan , Ganeshan Balaji , Hoy Luke , Mackintosh John A , Shortman Robert , Duckworth Anna , Fallon Janet , Garthwaite Helen , Heightman Melissa , Adamali Huzaifa I , Lines Sarah , Win Thida , Wollerton Rebecca , Renzoni Elisabetta A , Steward Matthew , Wells Athol U. , Gibbons Michael , Groves Ashley M , Gooptu Bibek , Scotton Chris J. , Porter Joanna C. 
Published: May 2022

SummaryBackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive, fatal disorder with a variable disease trajectory. The aim of this study was to assess the potential of neutrophil-to-lymphocyte ratio (NLR) to predict outcomes for people with IPF.MethodWe adopted a two-stage discovery and validation design using patients from the UCL partners (UCLp) cohort. For the discovery analysis, we included 71 patients from UCLH. In the validation analysis, we included 928 people with IPF, using real-life data from UCLH and 5 other UK centres. Data were collected from patients presenting over a 13-year period with a mean follow up time of 3.7 years.FindingsIn the discovery analysis, we showed that values of NLR (<2.9 vs >/=2.9) were associated with increased risk of mortality (HR 2.04, 95% CI 1.09-3.81; p=0.025). In the validation cohort we confirmed this association of high NLR with mortality (HR 1.65, 95% CI 1.39-1.95; p<0·0001) and showed incorporation of baseline NLR in a modified GAP-stage/index (GAP/index)-plus improved predictive abilityInterpretationWe have identified NLR as a widely available test that significantly correlates with lung function, can predict outcomes in IPF and refines clinical GAP-staging. NLR may help ILD specialist centres prioritise at risk patients in a timely way, even in the absence of lung function.
Senescence-Induced Immune Remodeling Facilitates Metastatic Adrenal Cancer in a Sex-Dimorphic Manner
Authors: Warde Kate M. , Liu Lihua , Smith Lorenzo J. , Lohman Brian K. , Stubben Chris J. , Ekiz H. Atakan , Ammer Julia L. , Converso-Baran Kimber , Giordano Thomas J. , Hammer Gary D. , Basham Kaitlin J. 
Published: May 2022

AbstractAging is a carcinogen that markedly increases cancer risk, yet we have limited mechanistic understanding of cancer initiation in aged cells. Here, we demonstrate induction of the hallmark aging process cellular senescence, triggered by loss of Wnt inhibitor ZNRF3, remodels the tissue microenvironment and ultimately permits metastatic adrenal cancer. Detailed characterization reveals a striking sexual dimorphism. Males exhibit earlier senescence activation and a greater innate immune response. This results in high myeloid cell accumulation and lower incidence of malignancy. Conversely, females present a dampened immune response and are more prone to metastatic cancer. Senescence-recruited myeloid cells become increasingly depleted with advanced tumor progression, which is recapitulated in patients where a low myeloid signature is associated with worse outcome. Collectively, our study reveals a novel role for myeloid cells in restraining adrenal cancer progression with significant prognostic value, and provides a model for interrogating pleiotropic effects of cellular senescence in cancer.Graphical abstract created with BioRender.com
Nanobodies identify an activated state of the TRIB2 pseudokinase
Authors: Jamieson Sam A , Pudjihartono Michael , Horne Christopher R , Day Robert C , Murphy James M , Mace Peter D 
Published: May 2022

AbstractTribbles proteins (TRIB1–3) are a pseudokinase-only branch of the human kinome, which recruit substrates to the COP1 ubiquitin-ligase for ubiquitination. TRIB2 was the first Tribbles ortholog to be implicated as a myeloid leukaemia oncogene, by way of recruiting the C/EBPa transcription factor for degradation by COP1. Here we report selection and characterisation of nanobodies against the TRIB2 pseudokinase domain from a synthetic yeast surface-display library. We identified nanobodies that bind the TRIB2 pseudokinase domain with low nanomolar affinity. A crystal structure of Nb4.103 in complex with TRIB2 identified a mode of binding to the N-terminal lobe of the pseudokinase, in a manner that enables specific recognition of TRIB2 over TRIB1 and TRIB3. In the nanobody-stabilised state, TRIB2 adopts an activated conformation that is remarkably similar to the C/EBPa-bound state of TRIB1. Characterization in solution revealed that Nb4.103 can stabilise a TRIB2 pseudokinase domain dimer in a face-to-face manner. Conversely, a distinct nanobody (Nb4.101) binds through a similar epitope but does not readily promote dimerization. In combination, this study identifies features of TRIB2 that could be exploited for the development of inhibitors, and nanobody tools for future investigation of TRIB2 function.
Shock or jump: deimatic behaviour is repeatable and polymorphic in a yellow-bellied toad
Authors: Chiocchio Andrea , Martino Giuseppe , Bisconti Roberta , Carere Claudio , Canestrelli Daniele 
Published: May 2022

AbstractInter-individual variation in antipredatory strategies has long attracted curiosity among scientists. Deimatisms is a complex and time-structured antipredatory strategy consisting in prey suddenly unleashing unexpected defences to frighten predators and stop their attack. Being deimatism traditionally considered as a stereotyped antipredatory response, the inter-individual variation in phenotypic traits related to deimatic displays is almost unexplored. In this study, we employed common garden experiments on 71 yellow-bellied toad Bombina pachypus to investigate the extent and pattern of inter-individual variation in the unken-reflex behaviour, a deimatic display performed by some amphibians. Results show that deimatic displays consistently differ among individuals. Only about half of the individuals reacted to the predation stimuli by exhibiting the display, which varied in responsiveness, duration and intensity. All the investigated descriptors were repeatable (R > 0.50, p < 0.01). Finally, we found significant correlations between the measured parameters, defining two alternative behavioural profiles: individuals quickly doing unken-reflex, with high intensity and long duration of the display, and individuals avoiding unken-reflex but rather escaping. Such dichotomy resembles respectively the proactive and reactive coping styles. Such an unexpected variation in deimatic behaviour raises intriguing questions on the evolutionary processes shaping multiple adaptive responses to predation within populations.
EndophilinA-dependent coupling between activity-dependent calcium influx and synaptic autophagy is disrupted by a Parkinson-risk mutation
Authors: Bademosi Adekunle T. , Decet Marianna , Kuenen Sabine , Calatayud Carles , Swerts Jef , Gallego Sandra F , Schoovaerts Nils , Louros Nikolaos , Martin Ella , Karamanou Spyridoula , Sibarita Jean-Baptiste , Vints Katlijn , Gounko Natalia V. , Meunier Frédéric A. , Economou Anastassios , Versées Wim , Rousseau Frederic , Schymkowitz Joost , Soukup Sandra-F. , Verstreken Patrik 
Published: May 2022

AbstractNeuronal activity and neurotransmitter release cause use-dependent decline in protein function. However, it is unclear how this is coupled to local protein turnover and quality control mechanisms. Here we show that the endocytic protein Endophilin-A (EndoA/ENDOA1) couples activity-induced calcium influx to synaptic autophagy and neuronal survival. We identify single mutations in the EndoA flexible region that either increases EndoA diffusion and promotes autophagosome formation in the absence of calcium, or immobilizes EndoA and blocks autophagy, even in the presence of calcium. Hence, the EndoA flexible region is a switch that responds to calcium, regulating EndoA nanoscale synaptic organization and association with autophagosomes driving their formation. Interestingly, a pathogenic variant in the human ENDOA1 variable region that confers risk to Parkinson’s disease (PD), also confines ENDOA1 to the synaptic plasma membrane and equally blocks autophagy in flies in vivo and in induced human neurons. Thus, our work reveals a mechanism neurons use to connect neuronal activity to local protein turnover by autophagy, which is critical for neuronal survival.
Novel CRISPR-based detection of Leishmania species
Authors: Dueñas Eva , Nakamoto Jose A. , Cabrera-Sosa Luis , Huaihua Percy , Cruz María , Arévalo Jorge , Milón Pohl , Adaui Vanessa 
Published: May 2022

AbstractTegumentary leishmaniasis, a disease caused by protozoan parasites of the genus Leishmania, is a major public health problem in many regions of Latin America. Its diagnosis is difficult given other conditions resembling leishmaniasis lesions and co-occurring in the same endemic areas. A combination of parasitological and molecular methods lead to accurate diagnosis, with the latter being traditionally performed in centralized reference and research laboratories as they require specialized infrastructure and operators. CRISPR-Cas systems have recently driven innovative tools for nucleic acid detection that combine high specificity, sensitivity and speed and are readily adaptable for point-of-care testing. Here, we harnessed the CRISPR-Cas12a system for molecular detection of Leishmania spp., emphasizing medically relevant parasite species circulating in Peru and other endemic areas in Latin America, with L. (Viannia) braziliensis being the main etiologic agent of cutaneous and mucosal leishmaniasis. We developed two assays targeting multi-copy targets commonly used in the molecular diagnosis of leishmaniasis: the 18S ribosomal RNA gene (18S rDNA), highly conserved across Leishmania species, and a region of kinetoplast DNA (kDNA) minicircles conserved in the L. (Viannia) subgenus. Our CRISPR-based assays were capable of detecting down to 5 × 10−2 (kDNA) or 5 × 100 (18S rDNA) parasite genome equivalents/reaction with PCR preamplification. The 18S PCR/CRISPR assay achieved pan-Leishmania detection, whereas the kDNA PCR/CRISPR assay was specific for L. (Viannia) detection. No cross-reaction was observed with Trypanosoma cruzi strain Y or human DNA. We evaluated the performance of the assays using 49 clinical samples compared to a kDNA real-time PCR assay as the reference test. The kDNA PCR/CRISPR assay performed equally well as the reference test, with positive and negative percent agreement of 100%. The 18S PCR/CRISPR assay had high positive and negative percent agreement of 82.1% and 100%, respectively. The findings support the potential applicability of the newly developed CRISPR-based molecular tools for first-line diagnosis of Leishmania infections at the genus and L. (Viannia) subgenus levels.
Nipsnap1—A Regulatory Factor Required For Long-Term Maintenance of Non-Shivering Thermogenesis
Authors: Liu Yang , Qu Yue , Cheng Chloe , Tsai Pei-Yin , Edwards Kaydine , Xue Siwen , Pandit Supriya , Eguchi Sakura , Sanghera Navneet , Barrow Joeva J 
Published: May 2022

SUMMARYThe molecular activation of non-shivering thermogenesis (NST) has strong potential to combat obesity and metabolic disease. However, the mechanisms surrounding the maintenance of NST once it is fully activated, remain unexplored. Here, we present 4-Nitrophenylphosphatase Domain and Non-Neuronal SNAP25-Like 1 (Nipsnap1) as a critical regulator of long-term thermogenic maintenance in brown adipose tissue (BAT). Nipsnap1 localizes to the mitochondrial matrix and increases its transcript and protein levels in response to both chronic cold and β3 adrenergic signaling. Through the generation of BAT-specific Nipsnap1 knockout mice (N1-KO), we show that these mice are unable to sustain activated energy expenditure and fail to protect their body temperature in the face of an extended cold challenge. Mechanistically, we demonstrate that Nipsnap1 integrates with lipid metabolism and BAT-specific ablation of Nipsnap1 leads to severe defects in β-oxidation capacity. Our findings identify Nipsnap1 as a potent regulator of long-term NST maintenance.
Questioning the association of the STMN2 dinucleotide repeat with ALS
Authors: Ross Jay P. , Akcimen Fulya , Liao Calwing , Spiegelman Dan , Weisburd Ben , Dupré Nicolas , Dion Patrick A. , Rouleau Guy A. , Farhan Sali M. K. 
Published: May 2022

AbstractLowered expression of STMN2 is associated with TDP-43 pathology in amyotrophic lateral sclerosis (ALS). Recently, the number of dinucleotide CA repeats in an intron of the STMN2 gene was reported to be associated with increased risk for ALS. Here, we used a case-control cohort of whole genome sequencing (WGS) as well as WGS from populations in the gnomAD cohort to attempt to replicate this proposed association. We find that repeats well above the previously reported pathogenic threshold of 19 are commonly observed in unaffected individuals across different populations. Further, we did not observe an association between longer STMN2 CA repeats and ALS phenotype. In summary, our results do not support a role of STMN2 CA repeats towards ALS risk.DisclosuresNone to disclose
The mutational landscape of single neurons and oligodendrocytes reveals evidence of inflammation-associated DNA damage in multiple sclerosis
Authors: Motyer Allan , Jackson Stacey , Yang Bicheng , Harliwong Ivon , Tian Wei , Shiu Wingin , Shao Yunchang , Wang Bo , McLean Catriona , Barnett Michael , Kilpatrick Trevor J. , Leslie Stephen , Rubio Justin P. 
Published: May 2022

AbstractNeuroinflammation has been linked to DNA damage in multiple sclerosis (MS), but its impact on neural cell genomes at nucleotide resolution is unknown. To address this question, we performed single nucleus whole genome sequencing to determine the landscape of somatic mutation in 172 neurons and oligodendrocytes (OLs) extracted from post-mortem brain tissue from 5 MS cases and three controls. We identified two cases with a significant excess of somatic single nucleotide variants (sSNV) in neurons and OLs from MS inflammatory demyelinated lesions. For a case with primary progressive MS, this translated to a 68% increase in sSNV frequency and 32-year equivalent increase in biological age of lesion-resident cells. Mutational signature analysis conducted on all cells revealed that defective DNA repair and transcription-associated DNA damage are important mutagenic mechanism in both neurons and OLs in MS. Our findings provide the first evidence that inflammation in the brains of people with MS is associated with DNA damage, which may have implications for other neurodegenerative diseases and future drug development.