bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic modifiers and ascertainment drive variable expressivity of complex disorders
Authors: Jensen Matthew , Smolen Corrine , Tyryshkina Anastasia , Pizzo Lucilla , Banerjee Deepro , Oetjens Matthew , Shimelis Hermela , Taylor Cora M. , Pounraja Vijay Kumar , Song Hyebin , Rohan Laura , Huber Emily , El Khattabi Laila , van de Laar Ingrid , Tadros Rafik , Bezzina Connie , van Slegtenhorst Marjon , Kammeraad Janneke , Prontera Paolo , Caberg Jean-Hubert , Fraser Harry , Banka Siddhartha , Van Dijck Anke , Schwartz Charles , Voorhoeve Els , Callier Patrick , Mosca-Boidron Anne-Laure , Marle Nathalie , Lefebvre Mathilde , Pope Kate , Snell Penny , Boys Amber , Lockhart Paul J. , Ashfaq Myla , McCready Elizabeth , Nowacyzk Margaret , Castiglia Lucia , Galesi Ornella , Avola Emanuela , Mattina Teresa , Fichera Marco , Bruccheri Maria Grazia , Mandarà Giuseppa Maria Luana , Mari Francesca , Privitera Flavia , Longo Ilaria , Curró Aurora , Renieri Alessandra , Keren Boris , Charles Perrine , Cuinat Silvestre , Nizon Mathilde , Pichon Olivier , Bénéteau Claire , Stoeva Radka , Martin-Coignard Dominique , Blesson Sophia , Le Caignec Cedric , Mercier Sandra , Vincent Marie , Martin Christa , Mannik Katrin , Reymond Alexandre , Faivre Laurence , Sistermans Erik , Kooy R. Frank , Amor David J. , Romano Corrado , Andrieux Joris , Girirajan Santhosh 
Published: August 2024

SUMMARYVariable expressivity of disease-associated variants implies a role for secondary variants that modify clinical features. We assessed the effects of modifier variants towards clinical outcomes of 2,252 individuals with primary variants. Among 132 families with the 16p12.1 deletion, distinct rare and common variant classes conferred risk for specific developmental features, including short tandem repeats for neurological defects and SNVs for microcephaly, while additional disease-associated variants conferred multiple genetic diagnoses. Within disease and population cohorts of 773 individuals with the 16p12.1 deletion, we found opposing effects of secondary variants towards clinical features across ascertainments. Additional analysis of 1,479 probands with other primary variants, such as 16p11.2 deletion andCHD8variants, and 1,084 without primary variants, showed that phenotypic associations differed by primary variant context and were influenced by synergistic interactions between primary and secondary variants. Our study provides a paradigm to dissect the genomic architecture of complex disorders towards personalized treatment.
Load and muscle dependent changes in triceps surae motor unit firing properties and motor unit firing-torque relationships in individuals with non-insertional Achilles tendinopathy
Authors: Contreras-Hernandez Ignacio , Falla Deborah , Arvanitidis Michail , Negro Francesco , Jimenez-Grande David , Martinez-Valdes Eduardo 
Published: August 2024

ABSTRACTNon-insertional Achilles tendinopathy (NIAT) induces morpho-mechanical changes to the Achilles tendon (AT). However, evidence on how triceps surae motor unit firing properties are influenced by altered tendon mechanics in NIAT is limited. This study investigated motor unit firing properties (mean discharge rate (DR), recruitment and de-recruitment thresholds, and discharge rate variability (COVisi)), motor unit firing-torque relationships (cross-correlation coefficient between cumulative spike train (CST) and torque, and neuromechanical delay), and neural drive distribution (connectivity strength and functional networks) of the medial gastrocnemius (MG), lateral gastrocnemius (LG), and soleus (SO) muscles during isometric plantarflexion contractions at 10%, 40%, and 70% maximal voluntary contraction (MVC) using high-density surface electromyography on 26 individuals with NIAT and 25 healthy controls. Furthermore, AT’s morpho-mechanical properties (thickness, cross-sectional area, length and stiffness) were assessed via ultrasound imaging. NIAT individuals showed reduced tendon stiffness and increased thickness (p<0.01). Motor unit properties changed in a load and muscle-dependent manner. LG DR increased (p=0.002) and de-recruitment threshold decreased (p=0.039) at 70%MVC in the NIAT group compared to controls. The CST-torque cross-correlation coefficient of the LG decreased at 10%MVC (p<0.0001) and increased at 70%MVC (p=0.013) in the NIAT group. Connectivity strength for the 0-5 Hz and 5-15 Hz frequency bands decreased (p<0.01) in the NIAT group at 10%MVC. This study shows that individuals with NIAT exhibit load-dependent changes in motor unit firing properties, motor unit-torque relationships, and neural drive distribution to the triceps surae. These alterations may be due to muscle-specific compensations for the modified mechanical properties of the AT.KEY POINTS-Individuals with non-insertional Achilles tendinopathy (NIAT) have changes of the neural drive to the lateral gastrocnemius (LG) muscle and altered contribution of the LG to the net plantarflexion torque.-Individuals with NIAT show a more uneven distribution of neural drive to the triceps surae muscle at low force levels, characterized by reduced intermuscular coherence between the medial and lateral gastrocnemius in the 0-5 Hz and 5-15 Hz bands compared to the control group.-Our findings support the idea that the LG may have a central role in the pathophysiology of this condition, possibly affecting the load transmission to the Achilles tendon (AT).
Association between choroidal microvasculature in the eye and Alzheimer’s disease risk in cognitively healthy midlife adults: a pilot study
Authors: Burke Jamie , Gibbon Samuel , Low Audrey , Hamid Charlene , Reid-Schachter Megan , Muniz-Terrera Graciela , Ritchie Craig W , Dhillon Baljean , O’Brien John T , King Stuart , MacCormick Ian JC , MacGillivray Thomas J 
Published: August 2024

AbstractINTRODUCTIONWe explored associations between measurements of the ocular choroid microvasculature and Alzheimer’s disease risk.METHODSWe measured the choroidal vasculature appearing in optical coherence tomography scans of 69 healthy, mid-life individuals in the PREVENT Dementia cohort. The cohort was prospectively split into low, medium, and high-risk groups based on the presence of known risk factors (APOE4 genotype and family history of dementia). We used ordinal logistic regression to test for cross-sectional associations between choroidal measurements and Alzheimer’s disease risk.RESULTSChoroidal vasculature was progressively larger between ordinal risk groups, and significantly associated with risk group prediction. APOE4 carriers had thicker choroids and larger vascularity compared to non-carriers. Similar trends were observed for those with a family history of dementia.DISCUSSIONSOur results suggest a potential link between the choroidal vasculature and Alzheimer’s disease risk. However, these exploratory findings should be replicated in a larger sample.
Loss to follow-up of ambulatory patients in the transition to telemedicine in the COVID-19 pandemic at a reference center for mental health in Lima, Peru
Authors: Ruiz-Grosso Paulo , Sagastegui Abel , Zevallos-Bustamante Sonia 
Published: August 2024

AbstractProblem StatementDuring the COVID-19 pandemic, health care services were limited by the restrictive measures implemented. As an adaptation mechanism, telemedicine was introduced for ambulatory care at the Honorio Delgado Hideyo Noguchi National Institute of Mental Health (NIMH). This study aimed to estimate the survival function (SF) for loss to follow-up (LTFU) over two years before and after the onset of the COVID-19 pandemic, and its association with clinical and sociodemographic variables.Study DesignA single-cohort study was conducted, following a random sample of adult ambulatory patients at NIHM from April 15, 2018, to April 15, 2022. Patients were followed until LTFU, referral to another institution, death, or the end of study. The main analysis involved estimating the SF for LTFU for the overall follow up period, as well as separately for the periods pre and post implementation of telemedicine. Also, risk factors hypotheses were tested using Cox’s regression.ResultsData from 4887 visits of 356 patients were collected. A total of 118 (33.1%) presented LTFU, with SF of 53.9% during the overall four years of follow-up. After two years of follow-, those starting treatment at NIMH before the implementation of telemedicine had a higher SF (77.3 vs 63%). A higher hazard ratio (HR) for LTFU was found in the group that started care at NIMH after the implementation of telemedicine, compared to those who started previously (HR=2.53; 95% CI: 1.55-4.51). Additionally, receiving care in the anxiety disorders (HR=1.86; 95% CI: 1.03-3.33) and personality disorders programs (HR=1.81; 95% CI: 1.02-3.22) was associated with a higher risk of LTFU compared to the psychosis program. No significant difference was found in the risk of LTFU between telemedicine vs. face-to face attention.ConclusionsA significant association was found between LTFU and starting treatment at NIMH after the onset of the COVID-19 pandemic and implementation of telemedicine. However, no evidence supports that this might be due to the practice of telemedicine. A different clinical profile of patients that started treatment at NIMH following the government implementation of changes to the public health system might explain these findings and should be studied.Significant Outcomes-A moderate association was found between starting treatment at NIMH and loss to follow up in the period after the implementation of telemedicine due to the onset of COVID-19.-This, however, does not seem to be related to the practice of telemedicine, but to changes in the characteristics of patients across pre and post COVID 19.Limitations-The reason for loss to follow up (death, return to a lower-level health service, improvement of symptoms, etc.), our main outcome variable, could not be determined using the clinical and administrative data available.
A fluorescent probe enables the discovery of improved antagonists targeting the intracellular allosteric site of the chemokine receptor CCR7
Authors: Wurnig Silas L. , Huber Max E. , Weiler Corinna , Baltrukevich Hanna , Merten Nicole , Stötzel Isabel , Chang Yinshui , Klammer René H. L. , Baumjohann Dirk , Kiermaier Eva , Kolb Peter , Kostenis Evi , Schiedel Matthias , Hansen Finn K. 
Published: August 2024

ABSTRACTIntracellularly acting ligands of G protein-coupled receptors (GPCRs) are gaining significant interest in GPCR drug discovery. In this study, we report the development of the fluorescent ligand Mz437 (4) targeting the CC chemokine receptor CCR7 at an intracellular allosteric site. We demonstrate its experimental power by applying4to identify two improved intracellular CCR7 antagonists, SLW131 (10) and SLW132 (21m), developed by converting two weakly active antagonists into single- or double-digit nanomolar ligands with minimal modifications. The thiadiazoledioxide10was derived from the CCR7 antagonist Cmp2105 by removing a methyl group from the benzamide moiety, while the squaramide21mwas obtained from the CXCR1/CXCR2 antagonist and clinical candidate navarixin by replacing the ethyl substituent by atert-butyl group to engage a lipophilic subpocket. We show that10and21mqualify to probe CCR7 biology both in recombinant cells and in the endogenous signaling environment of immune cells. Our novel probes are expected to facilitate the design of next-generation intracellular CCR7 ligands and serve as molecular tools to interrogate CCR7 biology in human and murine endogenous settings.Entry for the Table of Contents
A robust evaluation of TDP-43, poly GP, cellular pathology and behavior in a AAV-C9ORF72 (G4C2)66mouse model
Authors: Thompson Emily G. , Spead Olivia , Akerman S. Can , Curcio Carrie , Zaepfel Benjamin L. , Kent Erica R. , Philips Thomas , Vijayakumar Balaji G. , Zacco Anna , Zhou Weibo , Nagappan Guhan , Rothstein Jeffrey D. 
Published: August 2024

AbstractThe G4C2hexanucleotide repeat expansion inC9ORF72is the major genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Despite considerable efforts, the development of mouse models of C9-ALS/FTD useful for therapeutic development has proven challenging due to the intricate interplay of genetic and molecular factors underlying this neurodegenerative disorder, in addition to species differences. This study presents a robust investigation of the cellular pathophysiology and behavioral outcomes in a previously described AAV mouse model of C9-ALS expressing 66 G4C2hexanucleotide repeats. Despite displaying key molecular ALS pathological markers including RNA foci, dipeptide repeat (DPR) protein aggregation, p62 positive stress granule formation as well as mild gliosis, the AAV-(G4C2)66mouse model in this study exhibits negligible neuronal loss, no motor deficits, and functionally unimpaired TAR DNA-binding protein-43 (TDP-43). While our findings indicate and support that this is a robust and pharmacologically tractable model for investigating the molecular mechanisms and cellular consequences of (G4C2) repeat driven DPR pathology, it is not suitable for investigating the development of disease associated neurodegeneration, TDP-43 dysfunction, gliosis, and motor performance. Our findings underscore the complexity of ALS pathogenesis involving genetic mutations and protein dysregulation and highlight the need for more comprehensive model systems that reliably replicate the multifaceted cellular and behavioral aspects of C9-ALS.
BICC1 Interacts with PKD1 and PKD2 to Drive Cystogenesis in ADPKD
Authors: Tran Uyen , Streets Andrew J , Smith Devon , Decker Eva , Kirschfink Annemarie , Izem Lahoucine , Hassey Jessie M. , Rutland Briana , Valluru Manoj K , Bräsen Jan Hinrich , Ott Elisabeth , Epting Daniel , Eisenberger Tobias , Ong Albert CM , Bergmann Carsten , Wessely Oliver 
Published: August 2024

ABSTRACTBackgroundAutosomal dominant polycystic kidney disease (ADPKD) is primarily of adult-onset and caused by pathogenic variants inPKD1orPKD2. Yet, disease expression is highly variable and includes very early-onset PKD presentationsin uteroor infancy. In animal models, the RNA-binding molecule Bicc1 has been shown to play a crucial role in the pathogenesis of PKD.MethodsTo study the interaction betweenBICC1, PKD1 and PKD2we combined biochemical approaches, knockout studies in mice andXenopus,genetic engineered human kidney cells as well as genetic association studies in a large ADPKD cohort.ResultsWe first demonstrated that BICC1 physically binds to the proteins Polycystin-1 and -2 encoded byPKD1andPKD2via distinct protein domains. Furthermore, PKD was aggravated in loss-of-function studies inXenopusand mouse models resulting in more severe disease whenBicc1was depleted in conjunction withPkd1 or Pkd2. Finally, in a large human patient cohort, we identified a sibling pair with a homozygousBICC1variant and patients with very early onset PKD (VEO-PKD) that exhibited compound heterozygosity ofBICC1in conjunctionwith PKD1 and PKD2variants. Genome editing demonstrated that theseBICC1variants were hypomorphic in nature and impacted disease-relevant signaling pathways.ConclusionsThese findings support the hypothesis thatBICC1cooperates functionally withPKD1 and PKD2, and thatBICC1variants may aggravate disease severity highlighting RNA metabolism as an important new concept for disease modification in ADPKD.
Genomes of nitrogen-fixing eukaryotes reveal a non-canonical model of organellogenesis
Authors: Frail Sarah , Steele-Ogus Melissa , Doenier Jon , Moulin Solène L.Y. , Braukmann Tom , Xu Shouling , Yeh Ellen 
Published: August 2024

SUMMARYEndosymbiotic gene transfer and import of host-encoded proteins are considered hallmarks of organelles necessary for stable integration of two cells. However, newer endosymbiotic models have challenged the origin and timing of such genetic integration during organellogenesis. Epithemia diatoms contain diazoplasts, obligate endosymbionts that are closely related to recently-described nitrogen-fixing organelles and share similar function as integral cell compartments. We report genomic analyses of two species which are highly divergent but share a common ancestor at the origin of the endosymbiosis. We found minimal evidence of genetic integration in E.clementina: nonfunctional diazoplast-to-nucleus DNA transfers and 6 host-encoded proteins of unknown function in the diazoplast proteome, far fewer than detected in other recently-acquired endosymbionts designated organelles. Epithemia diazoplasts are a valuable counterpoint to existing organellogenesis models, demonstrating that endosymbionts can function as integral compartments absent significant genetic integration. The minimal genetic integration makes diazoplasts valuable blueprints for bioengineering endosymbiotic compartments de novo.
Loss of the tumor suppressor NUMB drives aggressive bladder cancer through hyperactivation of a RhoA/ROCK/YAP signaling circuitry
Authors: Tucci F. A. , Pennisi R. , Rigiracciolo D. C. , Filippone M. G. , Bonfanti R. , Romeo F. , Freddi S. , Soriani C. , Rodighiero S. , Jodice G. , Sanguedolce F. , Renne G. , Fusco N. , Di Fiore P.P. , Pruneri G. , Musi G. , Vago G. , Tosoni D. , Pece S. 
Published: August 2024

ABSTRACTBladder cancer (BCa) is one of the most challenging and costly cancers to treat, yet little progress has been made on the development of predictive biomarkers and targeted therapies. Here, we uncover a critical function of Numb as a tumor suppressor in the bladder, identifying loss of Numb expression as a causal alteration in BCa that underlies biological aggressiveness and disease progression. Through retrospective cohort studies, we established that a Numb-deficient tumor status correlates with worse overall survival in post-cystectomy muscle-invasive bladder cancer (MIBC) patients and increased risk of MIBC progression in non-muscle-invasive bladder cancer (NMIBC) patients. The prognostic value of Numb loss can be attributed to its crucial role as a determinant of aggressive bladder tumorigenesis, as demonstrated in mouse and human models. TargetedNumbablation in the basal layer of the urothelium was alone sufficient to trigger spontaneous bladder tumorigenesis and drive progression from preneoplastic to preinvasive and, ultimately, overtly invasive tumors. Additionally,Numbablation sensitized the urothelium to other oncogenic insults, accelerating tumor onset and progression. Using 3D-Matrigel organoid cultures to recapitulate bladder tumorigenesisin vitro, we found that Numb loss heightens the proliferative and invasive potential of both mouse and human BCa cells. Integrative transcriptomic and functional analyses revealed that downregulation of the canonical Hippo pathway, resulting in enhanced YAP transcriptional activity, underlies the biological aggressiveness of Numb-deficient BCa. These molecular events are dependent on the activation of RhoA/ROCK signaling subsequent to Numb loss. Thus, a dysfunctional Numb–RhoA/ROCK–Hippo/YAP regulatory network is at play in aggressive Numb-deficient BCa and represents a therapeutic vulnerability. A 27-gene prognostic signature capable of identifying high-risk Numb-deficient patients could provide the basis of a clinical tool to stratify patients for innovative RhoA/ROCK/YAP targeted therapies.One Sentence SummaryNumb loss-directed hyperactivation of RhoA/ROCK/YAP underlies aggressive bladder cancer biology.
Vibrio choleraeRbmB is an α−1,4-polysaccharide lyase with biofilm-dispersal activity against Vibrio Polysaccharide (VPS)
Authors: Weerasekera Ranjuna , Moreau Alexis , Huang Xin , Nam Kee-Myoung , Hinbest Alex , Huynh Yun , Liu Xinyu , Ashwood Christopher , Pepi Lauren E. , Paulson Eric , Cegelski Lynette , Yan Jing , Olson Rich 
Published: August 2024

AbstractMany pathogenic bacteria form biofilms as a protective measure against environmental and host hazards. The underlying structure of the biofilm matrix consists of secreted macromolecules, usually including exopolysaccharides. To escape the biofilm, bacteria may produce a number of matrix-degrading enzymes, including glycosidic enzymes that digest exopolysaccharide scaffolds. The human pathogenVibrio choleraeassembles and secretes an exopolysaccharide called VPS (Vibriopolysaccharide) which is essential in most cases for the formation of biofilms and consists of a repeating tetrasaccharide unit. Previous studies have indicated that a secreted glycosidase called RbmB is involved inVibrio choleraebiofilm dispersal, although the mechanism by which this occurs is not understood. To approach the question of RbmB function, we recombinantly expressed and purified RbmB and tested its activity against purified VPS. Using a fluorescence-based biochemical assay, we show that RbmB specifically cleaves VPSin vitrounder physiological conditions. Analysis of the cleavage products using mass spectrometry, solid-state NMR, and solution NMR indicates that RbmB cleaves VPS at a specific site (at the α−1,4 linkage between D-galactose and a modified L-guluronic acid) into a mixture of tetramers and octamers. We demonstrate that the product of the cleavage contains a double bond in the modified-guluronic acid ring, strongly suggesting that RbmB is cleaving using a glycoside lyase mechanism. Finally, we show that recombinant RbmB fromVibrio choleraeand the related aquatic speciesVibrio coralliilyticusare both able to disperse livingVibrio choleraebiofilms. Our results support the role of RbmB as a polysaccharide lyase involved in biofilm dispersal as well as an additional glycolytic enzyme to add to the toolbox of potential therapeutic antibacterial enzymes.Author summaryBiofilms are protective sheaths produced by many bacteria that play important roles in survival in the environment and in hosts during infection. Understanding how biofilms form and disperse is essential in the fight against harmful bacterial pathogens.Vibrio choleraeis a historically significant human pathogen that forms biofilms made of a polysaccharide called VPS and secreted accessory proteins. Within theV. choleraebiofilm gene cluster is a gene encoding a protein called RbmB, which is known to play a role in biofilm dispersal. Using a combination of biochemical and analytical tools, we show that RbmB indeed cleaves VPS into 4- and 8-monosaccharide fragments at a unique site and demonstrate that it falls into the family of polysaccharide lyase enzymes (as opposed to the more common hydrolases). Furthermore, recombinant RbmB disperses livingV. choleraebiofilms further indicating that it may play a role in VPS processing or degradation.
Comparison of retinol binding protein 1 with cone specific G-protein as putative effector molecules in cryptochrome signalling
Authors: Yee Chad , Bartölke Rabea , Görtemaker Katharina , Schmidt Jessica , Leberecht Bo , Mouritsen Henrik , Koch Karl-Wilhelm 
Published: August 2024

AbstractVision and magnetoreception in navigating songbirds are strongly connected as recent findings link a light dependent radical-pair mechanism in cryptochrome proteins to signalling pathways in cone photoreceptor cells. A previous yeast-two-hybrid screening approach identified six putative candidate proteins showing binding to cryptochrome type 4a. So far, only the interaction of the cone specific G-protein transducin α-subunit was investigated in more detail. In the present study, we compare the binding features of the G-protein α-subunit with those of another candidate from the yeast-two-hybrid screen, cellular retinol binding protein. Purified recombinant European robin retinol binding protein bound retinol with high affinity, displaying an EC50of less than 5 nM, thereby demonstrating its functional state. We applied surface plasmon resonance and a Förster resonance transfer analysis to test for interactions between retinol binding protein and cryptochrome 4a. In the absence of retinol, we observed no robust binding events, which contrasts the strong interaction we observed between cryptochrome 4a and the G-protein α-subunit. We conclude that retinol binding protein is unlikely to be involved in the primary magnetosensory signalling cascade.