bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rescue of FTLD-associated TDP-43 pathology and neurodegeneration by peripheral AAV-mediated expression of brain-penetrant progranulin
Authors: Reich Marvin , Simon Matthew J. , Polke Beate , Werner Georg , Schrader Christian , Paris Iñaki , Robinson Sophie , Davis Sonnet S. , de Melo Gabrielly Lunkes , Schlaphoff Lennart , Spieth Lena , Berghoff Stefan , Logan Todd , Nuscher Brigitte , Buschmann Katrin , Edbauer Dieter , Simons Mikael , Suh Jung H. , Sandmann Thomas , Kariolis Mihalis S. , DeVos Sarah L. , Lewcock Joseph W. , Paquet Dominik , Capell Anja , Paolo Gilbert Di , Haass Christian 
Published: July 2023

AbstractProgranulin (PGRN) haploinsufficiency is a major risk factor for frontotemporal lobar degeneration with TDP-43 pathology (FTLD-GRN). Multiple therapeutic strategies are in clinical development to restore PGRN levels in the CNS, including gene therapy. However, a limitation of current gene therapy approaches aimed to alleviate FTLD-associated pathologies may be their inefficient brain exposure and biodistribution. We therefore developed an adeno-associated virus (AAV) targeting the liver (L) to achieve sustained peripheral expression of a transferrin receptor (TfR) binding, brain-penetrant (b) PGRN variant (AAV(L):bPGRN) in two mouse models of FTLD-GRN, namelyGrnknockout andGrnxTmem106bdouble knockout mice. This therapeutic strategy avoids potential safety and biodistribution issues of CNS-administered AAVs while maintaining sustained levels of PGRN in the brain following a single dose. AAV(L):bPGRN treatment reduced several FTLD-GRNassociated disease pathologies including severe motor function deficits, aberrant TDP-43 solubility and phosphorylation, dysfunctional protein degradation, lipid metabolism, gliosis and neurodegeneration in the brain. Translatability of our findings was confirmed in a novel humanin vitromodel using co-cultured human induced pluripotent stem cell (hiPSC)-derived microglia lacking PGRN and TMEM106B and wild-type hiPSC-derived neurons. As in mice, aberrant TDP-43, lysosomal dysfunction and neuronal loss were ameliorated after treatment with exogenous TfR-binding protein transport vehicle fused to PGRN (PTV:PGRN). Together, our studies suggest that peripherally administered brain-penetrant PGRN replacement strategies can ameliorate FTLD-GRNrelevant phenotypes including TDP-43 pathology, neurodegeneration and behavioral deficits. Our data provide preclinical proof of concept for the use of this AAV platform for treatment of FTLD-GRNand potentially other CNS disorders.One sentence summaryPeripheral AAV-mediated delivery of brain-penetrant PGRN rescues TDP-43 pathology, neurodegeneration and motor phenotypes in FTLD-GRNmodels.
Recurrent chromosome destabilization through repeat-mediated rearrangements in a fungal pathogen
Authors: Fouché Simone , Oggenfuss Ursula , McDonald Bruce A. , Croll Daniel 
Published: July 2023

AbstractGenomic instability caused by chromosomal rearrangements has severe consequences for organismal fitness and progression of cancerous cell lines. The triggers of destabilized chromosomes remain poorly understood but are often assumed to be associated with fragile sites. Here, we retrace a runaway chromosomal degeneration process observed in a fungal pathogen using telomere-to-telomere assemblies across an experimental pedigree. We show that the same fragile sites triggered reproducible, large-scale rearrangements through non-allelic recombination. Across the four-generation pedigree, chromosomal rearrangements were accompanied by non-disjunction events and caused aneuploid progeny to carry up to four chromosomal copies. We identify a specific transposable element as the most likely trigger for the repeated chromosomal degeneration. The element is associated with higher virulence of the pathogen and has undergone a burst increasing copy numbers across the genome. Chromosome sequences are also targeted by a genome defense mechanism active on duplicated sequences, which may contribute to decay. Our work identifies the exact sequence triggers initiating chromosome instability and perpetuating degenerative cycles. Dissecting proximate causes leading to run-away chromosomal degeneration expands our understanding of chromosomal evolution beyond cancer lines.
Strong Positive Selection Biases Identity-By-Descent-Based Inferences of Recent Demography and Population Structure inPlasmodium falciparum
Authors: Guo Bing , Borda Victor , Laboulaye Roland , Spring Michele D. , Wojnarski Mariusz , Vesely Brian A. , Silva Joana C. , Waters Norman C. , O’Connor Timothy D. , Takala-Harrison Shannon 
Published: July 2023

AbstractMalaria genomic surveillance often estimates parasite genetic relatedness using metrics such as Identity-By-Decent (IBD). Yet, strong positive selection stemming from antimalarial drug resistance or other interventions may bias IBD-based estimates. In this study, we utilized simulations, a true IBD inference algorithm, and empirical datasets from different malaria transmission settings to investigate the extent of such bias and explore potential correction strategies. We analyzed whole genome sequence data generated from 640 new and 4,026 publicly availablePlasmodium falciparumclinical isolates. Our findings demonstrated that positive selection distorts IBD distributions, leading to underestimated effective population size and blurred population structure. Additionally, we discovered that the removal of IBD peak regions partially restored the accuracy of IBD-based inferences, with this effect contingent on the population’s background genetic relatedness. Consequently, we advocate for selection correction for parasite populations undergoing strong, recent positive selection, particularly in high malaria transmission settings.
Divergent evolution of head morphology between marine and freshwater sticklebacks
Authors: Fraimout Antoine , Chen Ying , Reid Kerry , Merilä Juha 
Published: July 2023

AbstractIntraspecific phenotypic differentiation is of common place occurrence, but the degree to which it reflects phenotypic plasticity or local adaptation remains often unclear. To be considered as adaptive, the differentiation must be genetically based and exceed what could be expected by neutral processes only. Using laboratory reared full-sib family data from replicate nine-spined stickleback (Pungitius pungitius) populations, we show that freshwater and marine fish display genetically based adaptive differentiation in head size and shape. Utilising identity-by-descent relationships among full-sibs as estimated with the aid of molecular markers, we further show that the studied traits are also highly heritable in all populations indicating and that they can respond to future episodes of natural selection. The head shape and size of pond fish suggests that observed adaptive differentiation has been driven by selection favoring limnetic feeding strategy among the pond fish. Analyses of gill-raker morphology were less conclusive: genetic differentiation was found in gill-raker length (pond > marine) and number, but the degree of divergence in these traits did not exceed neutral expectations. Yet, the direction of divergence in gill raker traits are suggestive of the limnetic feeding mode of pond fish, aligning with the inference from the head morphology analyses.
Microstructure-Based Modeling of Primary Cilia Mechanics
Authors: Mostafazadeh Nima , Resnick Andrew , Young Y.-N. , Peng Zhangli 
Published: July 2023

ABSTRACTA primary cilium, made of nine microtubule doublets enclosed in a cilium membrane, is a mechanosensing organelle that bends under an external mechanical load and sends an intracellular signal through transmembrane proteins activated by cilium bending. The nine microtubule doublets are the main load-bearing structural component, while the transmembrane proteins on the cilium membrane are the main sensing component. No distinction was made between these two components in all existing models, where the stress calculated from the structural component (nine microtubule doublets) was used to explain the sensing location, which may be totally misleading. For the first time, we developed a microstructure-based primary cilium model by considering these two components separately. First, we refined the analytical solution of bending an orthotropic cylindrical shell for individual microtubule, and obtained excellent agreement between finite element simulations and the theoretical predictions of a microtubule bending as a validation of the structural component in the model. Second, by integrating the cilium membrane with nine microtubule doublets, we found that the microtubule doublets may twist significantly as the whole cilium bends. Third, besides being cilium-length-dependent, we found the mechanical properties of the cilium are also highly deformation-dependent. More important, we found that the cilium membrane near the base is not under pure in-plane tension or compression as previously thought, but has significant local bending stress. This challenges the traditional model of cilium mechanosensing, indicating that transmembrane proteins may be activated more by membrane curvature than membrane stretching. Finally, we incorporated imaging data of primary cilia into our microstructure-based cilium model, and found that comparing to the ideal model with uniform microtubule length, the imaging-informed model shows the nine microtubule doublets interact more evenly with the cilium membrane, and their contact locations can cause even higher bending curvature in the cilium membrane than near the base.SIGNIFICANCEFactors regulating the mechanical response of a primary cilium to fluid flow remain unclear. Modeling the microtubule doublet as a composite of two orthotropic shells and the ciliary axoneme as an elastic shell enclosing nine such microtubule doublets, we found that the length distribution of microtubule doublets (inferred from cryogenic electron tomography images) is the primary determining factor in the bending stiffness of primary cilia, rather than just the ciliary length. This implies ciliary-associated transmembrane proteins may be activated by membrane curvature changes rather than just membrane stretching. These insights challenge the traditional view of ciliary mechanosensation and expands our understanding of the different ways in which cells perceive and respond to mechanical stimuli.
Structural basis for ssDNA-activated NADase activity of the prokaryotic SPARTA immune system
Authors: Zhang Jun-Tao , Wei Xin-Yang , Cui Ning , Tian Ruilin , Jia Ning 
Published: July 2023

AbstractArgonaute proteins (Agos), which use small RNAs or DNAs as guides to recognize complementary nucleic acid targets, mediate RNA silencing in eukaryotes. In prokaryotes, Agos are involved in immunity: the short prokaryotic Ago/TIR-APAZ (SPARTA) immune system triggers cell death by degrading NAD+in response to invading plasmids, but its molecular mechanisms remain unknown. Here, we used cryogenic electron microscopy to determine the structures of inactive monomeric and active tetramericCrenotalea thermophilaSPARTA complexes, revealing mechanisms underlying SPARTA assembly, RNA-guided recognition of target single-stranded DNA (ssDNA) and subsequent SPARTA tetramerization, as well as tetramerization-dependent NADase activation. The small RNA guides Ago to recognize its ssDNA target, inducing SPARTA tetramerization via both Ago- and TIR-mediated interactions and resulting in a two-stranded, parallel, head-to-tail TIR rearrangement primed for NAD+hydrolysis. Our findings thus identify the molecular basis for target ssDNA-mediated SPARTA activation, which will facilitate the development of SPARTA-based biotechnological tools.
De novoand inherited variants inDDX39Bcause a Novel Syndrome Characterized by Neurodevelopmental Delay, Short Stature, and Congenital Hypotonia
Authors: Booth Kevin T.A. , Jangam Sharayu V. , Chui Martin M.C. , Treat Kayla , Graziani Lorenzo , Soldano Alessia , White Kerry , Christensen Celanie K. , Lynnes Ty , Yamamoto Shinya , Kanca Oguz , Tsang Mandy H.Y. , Lynch Sally A. , Mullegama Sureni V. , Batista Julia , Iancu Daniela , Joss Shelag K. , Mak Christopher C.Y. , Kwong Anna Y. , Bellen Hugo J. ,   BCM Center for Precision Medicine Models, Conboy Erin , Sanges Remo , Wangler Michael F. , Chung Brian H.Y. , Vetrini Francesco 
Published: July 2023

AbstractDDX39Bis a member of the DEAD-box family of ATP-dependent RNA helicases. DEAD-box proteins are ubiquitously expressed from yeast to humans and perform essential functions associated with mRNA metabolism.DDX39Bis also a crucial component of the TRanscription-EXport (TREX) super protein complex, which recent studies have highlighted the important role of its subunits in neurodevelopmental disorders. Here, we describe six individuals from five families, four with novelde novomissense variants inDDX39B,and one carrying an inherited splicing variant, all presenting with mild to severe global developmental delay, congenital hypotonia, epilepsy, short stature, skeletal abnormalities and variable dysmorphic features. 3D molecular modeling predicts these variants would alter protein structure.DDX39Bis a conserved gene andDrosophila melanogaster(fruit flies) studies were conducted. We generated a new Hel25E Kozak-GAL4 allele which disrupts the fly gene and allows expression of transgenes. We also generated transgenicDDX39B-reference and variant flies. However, human referenceDDX39Bwhen overexpressed ubiquitously leads to lethality but the variants found in the patients do not recapitulate the lethality suggesting that the mutants are loss of function alleles. Blood transcriptomics revealed a significant excess of aberrant splicing events, indicating a disrupted mRNA processing as anticipated from the role ofDDX39Bin mRNA metabolism. Our human genetic data, coupled within silicoandin vivodata supports thatDDX39Bis a novel candidate gene in a potential group of disorders named TREX-complex-related neurodevelopmental syndrome.
Brain mechanisms explaining postural imbalance in traumatic brain injury: a systematic review
Authors: Hadi Zaeem , Mahmud Mohammad , Seemungal Barry M 
Published: July 2023

ABSTRACTPersisting imbalance and falls in community-dwelling traumatic brain injury (TBI) survivors – typically related to vestibular dysfunction - are linked to reduced long-term survival and re-employment rates. However, a detailed understanding of the impact of TBI upon the brain mechanisms mediating imbalance is lacking. To understand the state of the art concerning the brain mechanisms mediating imbalance in TBI, we performed a systematic review of the literature.PubMed, Web of Science, and Scopus were searched and peer-reviewed research articles in humans, with any severity of TBI (mild, moderate, severe, or concussion), that linked a postural balance assessment (objective or subjective) with brain imaging (via CT, MRI, MRS, SPECT, EEG, MEG, NIRS, and evoked potentials) were included. Out of 1940 articles, 60 were retrieved and screened, and 25 were included in the systematic review. 17 of those were MRI-based studies (e.g., DTI, fMRI), 4 EEG studies, 3 fNIRS studies, and 1 study used both MRI and EEG.The most consistent MRI finding was the link between imbalance and cerebellum, however, the regions within the cerebellum were not consistent. Functional changes in EEG studies were non-specific as all frequency bands were reportedly linked with balance. The findings from fNIRS studies were concentrated in frontal regions as these studies only used ROI analysis. Notably, only one study reported performing clinical vestibular assessment to exclude peripheral vestibular dysfunction.In conclusion, the lack of consistent findings could reflect that imbalance in TBI is due to a brain network dysfunction in contrast to focal cortical damage. Notably, the inconsistency in the reported findings may be attributed to heterogeneity of methodology e.g., data analytical techniques, small sample sizes, and choice of control groups. Future studies should include a detailed clinical phenotyping of vestibular function in TBI patients, ideally in an acute prospective manner, to exclude peripheral disorders. Choosing the appropriate control groups (i.e., well characterized patient subgroups as controls) would ensure that the findings are specific to imbalance rather than being non-specifically linked to TBI. Moreover, a whole-brain imaging analysis (vs ROI) is recommended to reduce selection bias and is also important since TBI affects the brain in a widespread manner.
Computed Tomography-Based Analysis of Foramen Magnum and Occipital Condyles in adult Nigerians: An Anatomical Study
Authors: Muhammad Fatima , Ahmad Umar , ZYOUD Tawfiq Yousef Tawfiq , Jibril Murtala Muhammad , Kwairanga Suleiman Hamidu 
Published: July 2023

AbstractBackgroundPrecise identification of craniometric points is pivotal in forensic and anthropological research for reliable and accurate gender determination. The foramen magnum and occipital condyles’ morphology offers valuable data for this purpose.AimThe study aimed to determine variations in the morphology of the foramen magnum and occipital condyles among a population of 100 individuals, using advanced Computed Tomography (CT) scan technology.MethodsWe assessed a prospective cohort of 100 individuals who underwent cranial CT scans. The study focused on the morphological variations of the foramen magnum and occipital condyles, recording shapes such as oval, round, egg, tetragon, pentagon, hexagon, and irregular for the foramen magnum, and kidney-type, oval, S-like, 8-like, ring-like, and triangular for the occipital condyles.ResultsNotably, males demonstrated higher measurement values for most parameters, with the exception of the width of the occipital condyle, where females presented larger dimensions. Furthermore, a strong positive correlation was observed between the measurements of the foramen magnum (length and width) and specific parameters of the occipital condyles.ConclusionsThe study underscores the utility of foramen magnum dimensions, especially length, as a determinant in gender identification, with a success rate of 68% in the studied population. This research enhances our understanding of cranial morphology and its applications in forensic and anthropological investigations.
Phytohemagglutinin-Activated CAR-T Cells: Prolonged Persistence and Enhanced Anti-Tumor Response in CD19-Specific Acute Lymphoblastic Leukemia
Authors: Sert Berranur , Gulden Gamze , Teymur Tarik , Ay Yasin , Turan Raife Dilek , Unaldi Onur Mert , Güzenge Elanur , Erdil Hamza Emir , Isik Sevim , Oz Pınar , Bozkurt Ilknur , Arpacı Tahire , Kamalı Osman , Ovalı Ercüment , Tarhan Nevzat , Tastan Cihan 
Published: July 2023

ABSTRACTIn recent times, chimeric antigen receptor (CAR)-T cell therapy has shown rapid advancements and gained clinical approval for use in cancer immunotherapy. CAR, a synthetic receptor integrated into autologous T cells, has yielded highly successful results in patients with leukemia. The significant potential of CAR-T cells has been validated through clinical trials in adult and pediatric cancer treatments. Our therapy developed specifically for CD19-specific Acute Lymphoblastic Leukemia (ALL) has shown promising results in in vitro and in vivo tests. To enhance the response against cancer, provide a bistimulatory effect, and increase stability, we designed two different CAR structures specific to CD19. These designs incorporate the CD28 and 41BB costimulatory domains. Through in vitro analysis, we evaluated the population ratios and cytotoxic activities of Central Memory T cells (TCM) and Stem Cell Memory T cells (TSCM) in CAR-T (CAR1928-T and CAR19BB-T) cells. Our initial design, CAR1928-T, produced an effective anti-tumor response. With our second design, CAR19BB-T, we not only achieved an anti-tumor effect but also conferred memory capabilities, leading to a comprehensive treatment approach. We demonstrated that CAR-T cells produced using Phytohemagglutinin (PHA) exhibited increased persistence in vitro and in vivo compared to anti-CD3 and anti-CD28 stimulation. The use of PHA to activate CAR19BB-T cells developed a long-lasting and effective CAR-T cell production method in vivo using cancerous animal models. CAR-T cell-treated mice survived tumor-free for up to 60 days, surpassing the survival of mice that received tumors only. Additionally, CAR19BB-T cell production with PHA remained stable over time. These results highlight a novel CAR-T cell production approach with a high-memory T cell profile capable of delaying or preventing cancer relapse. We optimized the method for the production of long-term and effective CAR-T cells and tested it in preclinical experiments. As a result, it was demonstrated that CAR-T cells generated with PHA, when administered as a co-stimulatory dose, can provide continuous proliferation and long-term persistence without compromising their anti-cancer efficacy. Preclinical studies have been completed to obtain valuable data for enhancing the long-term effectiveness of CAR-T therapy in clinical trials and transitioning to clinical applications.
Alterations in the gut microbiome of whiteleg shrimp (Penaeus vannamei) postlarvae following exposure to an AHPND-causing strain ofVibrio parahaemolyticus
Authors: Beltrán Manuel J. , Quimi Mujica Juan , Diringer Benoit , Barahona Sergio P. 
Published: July 2023

ABSTRACTAcute Hepatopancreatic Necrosis Disease (AHPND), attributed to the production of PirA/PirB toxins by certain Vibrio parahaemolyticus strains, poses a significant threat to global shrimp aquaculture, causing substantial mortality and economic losses. To enhance our understanding of this disease within a closed culture system on the northern coast of Peru, we conducted a comparative analysis of the gut microbiomes between healthy and diseased postlarvae. Diseased postlarvae were obtained through exposure to an AHPND-causing strain of V. parahaemolyticus. Five healthy and five diseased postlarvae were randomly sampled from experimental rearing tanks, and their medial guts were extracted. High-throughput sequencing targeting the V4 region of the 16S rRNA gene was employed for amplicon library construction, and assessments of alpha and beta diversities, as well as taxonomic composition, were conducted. Our results revealed reduced diversity and distinct compositional profiles in the gut microbiomes of diseased postlarvae. The order Rhodobacteriales was dominant in the gut microbiomes of healthy postlarvae, while the order Vibrionales (including an unassigned genus within Vibrionales, Vibrio, and Pseudoalteromonas) exhibited the highest abundance in diseased postlarvae. In conclusion, exposure to an AHPND-causing strain of V. parahaemolyticus induces significant dysbiosis in the gut microbiome of whiteleg shrimp postlarvae.