bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploring Polygenic Neuroimaging Derived Scores in a Longitudinal Attention-deficit/hyperactivity disorder Sample
Authors: van der Es Tim , Sprooten Emma , Soheili-Nezhad Sourena , Damatac Christienne G , Franke Barbara , Buitelaar Jan , Mota Nina Roth 
Published: June 2022

AbstractGenome-wide association studies (GWAS) indicate neuropsychiatric disorders to be highly polygenic. Polygenicity refers to the additive influence of multiple genes on variation in a disorder. GWAS have identified many single-nucleotide polymorphisms (SNPs) across the genome associated with neuropsychiatric disorders, each explaining a very small part of individual variance within a trait. This complicates the understanding of the genetic architecture and biological mechanisms underlying these disorders. Previous studies have successfully used common genetic variants associated psychiatric disorders to generate Polygenic Risk scores (PRS). PRSs estimate the aggregate genetic liability of an individual for a particular disorder or trait based on a genome-wide association study (GWAS) of said trait. Here, we present a novel bottom-up approach to polygenic scoring that starts at the brain, rather than at behavior or clinical diagnosis. We used GWAS of structural brain imaging derived phenotypes (IDPs) from the UK Biobank as a basis to generate polygenic imaging derived scores (PIDS). As a proof-of-concept of its application, we applied PIDS to quantify differences in the genetic influence on brain structure between persons with ADHD and unaffected controls. 94 IDPs were selected using the subcortical segmentation atlas and the Desikan-Killiany cortical atlas from FreeSurfer. In the polygenic model training stage, 72 out 94 PIDS were associated with their respective IDP in an independent sample. Global measures such as cerebellum white matter, cerebellum cortex and cerebral white matter ranked amongst the highest in variance explained ranging between 3% and 5.7%. Our results indicate that a majority of GWAS of structural neuroimaging traits are becoming sufficiently powered to enable reliable and meaningful use of polygenic scoring applications that accurately reflect the underlying polygenic architecture well. Larger discovery GWAS will further improve upon this. Conversely, our associations with ADHD were relatively weak. Larger target samples are required to establish robust links of PIDS with behavioral or clinical traits like ADHD. With this novel approach to polygenic risk scoring we provide a new tool for other researchers to build on in the field of psychiatric genetics.
Disease stages and therapeutic hypotheses in two decades of neurodegenerative disease clinical trials
Authors: Mortberg Meredith A. , Vallabh Sonia M. , Minikel Eric Vallabh 
Published: June 2022

Structured AbstractBackgroundNeurodegenerative disease is increasing in prevalence and remains without disease-modifying therapies, and most trials of new drugs fail. Proposed solutions include aiming upstream: targeting molecular root causes of disease and testing therapies earlier, even at pre-symptomatic stages. We sought to understand what disease stages were eligible to enroll in neurodegenerative disease clinical trials in recent years and what molecular targets were tested in these trials.MethodsWe combined automated analysis and manual curation of trial registrations from ClinicalTrials.gov for Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia / amyotrophic lateral sclerosis, and Huntington’s disease.Findings3,241 trials from 2000-2020 were curated. Industry-sponsored drug trials, a minority (34%) of trials but a majority (61%) of patient-years, were more likely to complete, to have specified phase, and to have placebo or standard-of-care control arms. The mean number of inclusion and exclusion criteria more than doubled over this period, and eligible score ranges shrank. Trials have shifted towards less severely impaired participants, but only 2.7% of trials were open to pre-symptomatic individuals and these were depleted for industry sponsors (OR = 0.32) and for drug trials (OR = 0.59), instead being enriched for behavioral interventions (OR = 3.1). 16 novel, genetically supported therapeutic hypotheses have been tested in drug trials, with a mean lag of 13 years from genetic association to first trial. Such trials comprised just 18% of patient-years.InterpretationEligibility criteria for trials have shifted towards earlier, milder disease stages but are still overwhelmingly focused on symptomatic patients, particularly for industry-sponsored drug trials. Drugs targeting disease genes supported by human genetics comprise just a fraction of drug development effort, and their success may be hindered by a focus on symptomatic patients, where the relevance of the target to the rate of disease progression is less clear.
Strategies for using antigen rapid diagnostic tests to reduce transmission of SARS-CoV-2 in low- and middle-income countries: a mathematical modelling study applied to Zambia
Authors: Han Alvin X. , Girdwood Sarah , Khan Shaukat , Sacks Jilian A. , Toporowski Amy , Huq Naushin , Hannay Emma , Russell Colin A. , Nichols Brooke E. 
Published: June 2022

SummaryBackgroundIncreasing the availability of antigen rapid diagnostic tests (Ag-RDTs) in low- and middle-income countries (LMICs) is key to alleviating global SARS-CoV-2 testing inequity (median testing rate in December 2021-March 2022 when the Omicron variant was spreading in multiple countries; high-income countries=600 tests/100,000 people/day; LMICs=14 tests/ 100,000 people/day). However, target testing levels and effectiveness of asymptomatic community screening to impact SARS-CoV-2 transmission in LMICs are unclear.MethodsWe used PATAT, an LMIC-focused agent-based model to simulate COVID-19 epidemics, varying the amount of Ag-RDTs available for symptomatic testing at healthcare facilities and asymptomatic community testing in different social settings. We assumed that testing was a function of access to healthcare facilities and availability of Ag-RDTs. We explicitly modelled symptomatic testing demand from non-SARS-CoV-2 infected individuals and measured impact based on the number of infections averted due to test-and-isolate.ResultsTesting symptomatic individuals yields greater benefits than any asymptomatic community testing strategy until most symptomatic individuals who sought testing have been tested.Meeting symptomatic testing demand likely requires at least 200-400 tests/100,000 people/day on average as symptomatic testing demand is highly influenced by non-SARS-CoV-2 infected individuals. After symptomatic testing demand is satisfied, excess tests to proactively screen for asymptomatic infections among household members yields the largest additional infections averted.ConclusionsTesting strategies aimed at reducing transmission should prioritize symptomatic testing and incentivizing test-positive individuals to adhere to isolation to maximize effectiveness.
The seroprevalence of neutralizing antibodies against the adeno-associated virus capsids in Japanese hemophiliacs
Authors: Kashiwakura Yuji , Baatartsogt Nemekhbayar , Yamazaki Shoji , Nagao Azusa , Amano Kagehiro , Suzuki Nobuaki , Matsushita Tadashi , Sawada Akihiro , Higasa Satoshi , Yamazaki Naoya , Fujii Teruhisa , Ogura Taemi , Takedani Hideyuki , Taki Masashi , Matsumoto Takeshi , Yamanouchi Jun , Sakai Michio , Nishikawa Masako , Yatomi Yutaka , Yada Koji , Nogami Keiji , Watano Ryota , Hiramoto Takafumi , Hayakawa Morisada , Kamoshita Nobuhiko , Kume Akihiro , Mizukami Hiroaki , Ishikawa Shizukiyo , Sakata Yoichi , Ohmori Tsukasa 
Published: June 2022

AbstractAdeno-associated virus (AAV) vectors are promising modalities of gene therapy to address unmet medical needs. However, anti-AAV neutralizing antibodies (NAbs) hamper the vector-mediated therapeutic effect. Therefore, the NAb prevalence in the target population is vital in designing clinical trials with AAV vectors. Hence, updating the seroprevalence of anti-AAV NAbs, herein we analyzed sera from 100 healthy individuals and 216 hemophiliacs in Japan. In both groups, the overall seroprevalence against various AAV serotypes was 20%–30%, and the ratio of NAb-positive population increased with age. The seroprevalence did not differ between healthy participants and hemophiliacs and was not biased by the concomitant blood-borne viral infections. The high neutralizing activity, which strongly inhibits the transduction with all serotypesin vitro, was mostly found in the 60s or older age. The multivariate analysis suggested that “60s or older age” was the only independent factor related to the high titer of NAbs. Conversely, a large proportion of younger hemophiliacs was seronegative, rendering them eligible for AAV-mediated gene therapy in Japan. Compared with our previous study, the peak of seroprevalences has shifted to older populations, indicating natural AAV exposure in the elderly has occurred in their youth but not during the last decade.
An update on oral clinical courses among patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: A clinical follow-up (a prospective prevalent cohort) study
Authors: Gebretsadik Heron Gezahegn 
Published: June 2022

AbstractIntroductionContemporary literature has revealed that Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes acute sialadenitis and related symptoms, such as discomfort, pain, swelling, and secretory dysfunction in salivary glands. The secretory dysfunction is due to SARS-CoV-2 infection-induced xerostomia and other associated clinical courses such as sore tongue, mucosal ulcer, and gingivitis in the oral cavity. Furthermore, it has been reported that COVID-19 causes the development of other oral manifestations.Materials and MethodsA prospective clinical follow-up (a prevalent cohort) study was conducted to identify the possible oral manifestations of SARS-CoV-2 infection among patients admitted at the Eka General Hospital COVID-19 treatment center. Furthermore, the study aimed to calculate the prevalence rate of oral clinical courses in the cohorts. The study had two follow-up phases: Hospital and patient-home-based.ResultsA total of 55 patients (36 males and 19 females) met the inclusion criteria and were followed for 7.5 weeks. The 3.5 weeks’ hospital-based prospective follow-up study documented an 18% (n=10) prevalence rate of oral clinical courses among the cohorts. Twelve oral symptoms appeared in these ten patients. The manifested oral symptoms were oral mucosal lesions (n=6), xerostomia (n=5), and thickening of saliva (n=1). The oral mucosal lesions per se consisted of aphthous lesions (n=3), candidiasis (n=1), geographic tongue (n=1), and localized gingivitis (n=1). On the other hand, the four weeks’ home-based follow-up study disclosed four newly manifested oral symptoms: hemorrhagic crust, bulla, buccal mucositis, and petechiae. These manifestations appeared among six patients (four males and two females) who had not manifested any oral symptoms during the hospital-based follow-up. Accordingly, the overall prevalence of oral clinical courses among patients presented with SARS-CoV-2 is raised from 18% (n=10) to 29% (n=16). Similarly, the number of clinical courses increased from 12 to 16 after four additional weeks of follow-up.DiscussionThe study’s findings suggest the importance of initiating oral health care for patients with COVID-19. Therefore, multidisciplinary healthcare approaches should be delivered to assure optimal health outcomes. Accordingly, oral health professionals must be a substantial part of the interdisciplinary approach in caring for patients with COVID-19.
Disrupting cellular memory to overcome drug resistance
Authors: Harmange Guillaume , Reyes Hueros Raúl A. , Schaff Dylan , Emert Benjamin , Saint-Antoine Michael , Nellore Shivani , Fane Mitchell E. , Alicea Gretchen M. , Weeraratna Ashani T. , Singh Abhyudai , Shaffer Sydney M. 
Published: June 2022

AbstractPlasticity enables cells to change their gene expression state in the absence of a genetic change. At the single-cell level, these gene expression states can persist for different lengths of time which is a quantitative measurement referred to as gene expression memory. Because plasticity is not encoded by genetic changes, these cell states can be reversible, and therefore, are amenable to modulation by disrupting gene expression memory. However, we currently do not have robust methods to find the regulators of memory or to track state switching in plastic cell populations. Here, we developed a lineage tracing-based technique to quantify gene expression memory and to identify single cells as they undergo cell state transitions. Applied to human melanoma cells, we quantified long-lived fluctuations in gene expression that underlie resistance to targeted therapy. Further, we identified the PI3K and TGF-β pathways as modulators of these state dynamics. Applying the gene expression signatures derived from this technique, we find that these expression states are generalizable to in vivo models and present in scRNA-seq from patient tumors. Leveraging the PI3K and TGF-β pathways as dials on memory between plastic states, we propose a “ pretreatment” model in which we first use a PI3K inhibitor to modulate the expression states of the cell population and then apply targeted therapy. This plasticity informed dosing scheme ultimately yields fewer resistant colonies than targeted therapy alone. Taken together, we describe a technique to find modulators of gene expression memory and then apply this knowledge to alter plastic cell states and their connected cell fates.
A role for axon-glial interactions and Netrin-G1 signaling in the formation of low-threshold mechanoreceptor end organs
Authors: Meltzer Shan , Comeau Katelyn , Osei-Asante Emmanuella , Handler Annie , Zhang Qiyu , Sano Chie , Itohara Shigeyoshi , Ginty David D. 
Published: June 2022

AbstractLow-threshold mechanoreceptors (LTMRs) and their cutaneous end organs convert light mechanical forces acting on the skin into electrical signals that propagate to the central nervous system. In mouse hairy skin, hair follicle-associated longitudinal lanceolate complexes, which are end organs comprising of LTMR axonal endings that intimately associate with terminal Schwann cell (TSC) processes, mediate LTMR responses to hair deflection and skin indentation. Here, we characterized developmental steps leading to the formation of Aβ RA-LTMR and Aδ-LTMR lanceolate complexes. During early postnatal development, Aβ RA-LTMRs and Aδ-LTMRs extend and prune cutaneous axonal branches in close association with nascent TSC processes. Netrin-G1 is expressed in these developing Aβ RA-LTMR and Aδ-LTMR lanceolate endings, and Ntng1 ablation experiments indicate that Netrin-G1 functions in sensory neurons to promote lanceolate ending elaboration around hair follicles. The Netrin-G ligand (NGL-1), encoded by Lrrc4c, is expressed in TSCs, and ablation of Lrrc4c phenocopies the lanceolate complex deficits observed in Ntng1 mutants. Moreover, NGL-1–Netrin-G1 signaling is a general mediator of LTMR end organ formation across diverse tissue types demonstrated by the fact that Aβ RA-LTMR endings associated with Meissner corpuscles and Pacinian corpuscles are also compromised in the Ntng1 and Lrrc4c mutant mice. Thus, axon-glia interactions mediated by NGL-1–Netrin-G1 signaling promote LTMR end organ formation.Significance statementOur sense of touch is essential for fundamental tasks ranging from object recognition to social exchange. Yet, touch remains one of the least understood senses at the developmental level. Here, we investigate the formation of lanceolate complexes, which are mechanosensory end organs associated with hair follicles. The axons of touch sensory neurons innervating hairy skin extend into the skin at late embryonic and neonatal times, prune excessive branches during early postnatal development, and closely associate with non-myelinating glial cells, called terminal Schwann cells (TSCs) during formation of mature endings around hair follicles. Moreover, NGL-1 and its receptor Netrin-G1 mediate a molecular dialogue between nascent TSCs and sensory neuron axonal endings to promote mechanosensory end organ formation in both hairy and non-hairy (glabrous) skin.
Mutant SF3B1 promotes PDAC malignancy through TGF-β resistance
Authors: Simmler Patrik T. , Mengis Tamara , Lehmann Kjong-Van , Kahles André , Thomas Tinu , Rätsch Gunnar , Stoffel Markus , Schwank Gerald 
Published: June 2022

ABSTRACTThe splicing factor SF3B1 is recurrently mutated in various tumors, including pancreatic ductal adenocarcinoma (PDAC). The impact of the hotspot mutation SF3B1K700E on the PDAC pathogenesis, however, remains elusive. Here, we demonstrate that Sf3b1K700E alone is insufficient to induce malignant transformation of the murine pancreas, but increases aggressiveness of PDAC if it co-occurs together with mutated KRAS and p53. We further demonstrate that SF3B1K700E reduces epithelial–mesenchymal transition (EMT) and confers resistance to TGF-β1-induced cell death, and provide evidence that this phenotype is in part mediated through aberrant splicing of Map3k7. Taken together, our work suggests that SF3B1K700E acts as an oncogenic driver in PDAC through enhancing resistance to the tumor suppressive effects of TGF-β.
Depletion of FH, an essential TCA cycle enzyme, drives proliferation in a two-step model
Authors: Solaimuthu Balakrishnan , Lichtenstein Michal , Hayashi Arata , Khatib Anees , Plaschkes Inbar , Nevo Yuval , Tanna Mayur , Lavi Shirel , Pines Ophry , Shaul Yoav D. 
Published: June 2022

AbstractSeveral tumor suppressor genes do not follow the canonical function of cell cycle repressors. For example, fumarate hydratase (FH) is an evolutionary conserved TCA cycle enzyme that reversibly catalyzes the hydration of fumarate to L-malate and has a moonlight function in the DNA damage response (DDR). Interestingly, despite this enzyme’s essential role in central carbon metabolism, FH is inactive or absent in several tumors, such as hereditary leiomyomatosis and renal cell cancer (HLRCC). Accordingly, FH has a contradictory cellular function, as it is pro-survival through its role in the TCA cycle, yet its loss can drive tumorigenesis. These observations have supported the role of FH as a tumor suppressor. Here, we solved this contradiction by determining the molecular mechanisms that allow the cells to survive and even proliferate upon FH loss. We found that the cells’ response to FH loss is separated into two distinct time frames based on cell proliferation and DNA damage repair. During the early stages of FH loss, the cells’ proliferation and DNA damage repair are inhibited. However, over time the cells overcome the FH loss and form knockout clones, indistinguishable from WT cells in their proliferation rate. Due to the FH loss effect on DNA damage repair, we assumed that the recovered cells bear adaptive mutations. Therefore, we applied whole-exome sequencing to identify such mutated genes systematically. Indeed, we identified recurring mutations in genes belonging to the central oncogenic signaling pathways, such as JAK/STAT, which we validated to be impaired in FH-KO clones. Intriguingly, we demonstrated that these adaptive mutations are responsible for FH-KO cell proliferation under TCA cycle malfunction.
Engineered bacteria recruit and orchestrate anti-tumor immunity
Authors: Savage Thomas M. , Vincent Rosa L. , Rae Sarah S. , Huang Lei Haley , Ahn Alexander , Pu Kelly , Li Fangda , Coker Courtney , Danino Tal , Arpaia Nicholas 
Published: June 2022

ABSTRACTTumors employ multiple mechanisms to actively exclude or suppress adaptive immune cells involved in anti-tumor immunity. Strategies focused on overcoming these immunosuppressive or exclusion signals – through localized delivery of chemokines that directly recruit immune cells into the tumor microenvironment – remain limited due to an inability to target therapeutics specifically to the tumor. Synthetic biology enables engineering of cells and microbes for tumor localized delivery, offering therapeutic candidates previously unavailable using conventional systemic administration techniques. Here, we engineer bacteria to produce and intratumorally release chemokines to attract adaptive immune cells into the tumor environment. Intravenous or intratumoral delivery of bacteria expressing an activating mutant of the human chemokine CXCL16 (hCXCL16K42A) leads to the recruitment of activated T cells within tumors and offers therapeutic benefit in multiple mouse tumor models. Furthermore, we rationally target an additional step in the immune activation cascade – specifically, the presentation of tumor-derived antigens by dendritic cells – using a second engineered bacterial strain expressing CCL20. This combined targeting approach led to the recruitment of type 1 conventional dendritic cells and effectively synergized with hCXCL16K42A-induced T cell recruitment to provide additional therapeutic benefit. In summary, we engineer bacteria to cooperatively recruit and activate both innate and adaptive anti-tumor immune responses, offering a new cancer immunotherapy strategy.
Multimodal monitoring of human cortical organoids implanted in mice using transparent graphene microelectrodes reveal functional connection between organoid and mouse visual cortex
Authors: Wilson Madison N. , Thunemann Martin , Liu Xin , Lu Yichen , Puppo Francesca , Adams Jason W. , Kim Jeong-Hoon , Pizzo Donald P. , Djurovic Srdjan , Andreassen Ole A. , Mansour Abed A. , Gage Fred H. , Muotri Alysson R. , Devor Anna , Kuzum Duygu 
Published: June 2022

AbstractHuman cortical organoids, three-dimensional neuronal cell cultures derived from human induced pluripotent stem cells, have recently emerged as promising models of human brain development and dysfunction. Transplantation of human brain organoids into the mouse brain has been shown to be a successful in vivo model providing vascularization for long term chronic experiments. However, chronic functional connectivity and responses evoked by external sensory stimuli has yet to be demonstrated, due to limitations of chronic recording technologies. Here, we develop an experimental paradigm based on transparent graphene microelectrode arrays and two-photon imaging for longitudinal, multimodal monitoring of human organoids transplanted in the mouse cortex. The transparency of graphene microelectrodes permits visual and optical inspection of the transplanted organoid and the surrounding cortex throughout the chronic experiments where local field potentials and multi-unit activity (MUA) are recorded during spontaneous activity and visual stimuli. These experiments reveal that visual stimuli evoke electrophysiological responses in the organoid, matching the responses from the surrounding cortex. Increases in the power of the gamma and MUA bands as well as phase locking of MUA events to slow oscillations evoked by visual stimuli suggest functional connectivity established between the human and mouse tissue. Optical imaging through the transparent microelectrodes shows vascularization of the organoids. Postmortem histological analysis exhibits morphological integration and synaptic connectivity with surrounding mouse cortex as well as migration of organoid cells into the surrounding cortex. This novel combination of stem cell and neural recording technologies could serve as a unique platform for comprehensive evaluation of organoids as models of brain development and dysfunction and as personalized neural prosthetics to restore lost, degenerated, or damaged brain regions.