Miracle-dz/UniFAR-FTUs huggingface dataset:
Microglial NFκB-TNFα hyperactivation induces obsessive–compulsive behavior in mouse models of progranulin-deficient frontotemporal dementia

Significance Frontotemporal dementia (FTD) is a disease characterized by degeneration of the frontal and/or temporal lobes of the brain. Symptoms of FTD include changes in personality, such as loss of social awareness and impulse control. A significant portion of inherited FTD cases are due to mutations in progranulin (PGRN). These mutations lead to a decrease in the production of PGRN. How lower levels of PGRN lead to FTD is unknown. Here, we show that humans carrying PGRN mutations and mice lacking PGRN display obsessive–compulsive disorders (OCDs). In mice, OCD behavior results partially from elevated levels of the cytokine TNFα and aberrant activation of immune cells of the brain known as microglia. Our findings provide evidence that targeting innate immune pathways could be a new therapeutic strategy to treat FTD. Frontotemporal dementia (FTD) is the second most common dementia before 65 years of age. Haploinsufficiency in the progranulin (GRN) gene accounts for 10% of all cases of familial FTD. GRN mutation carriers have an increased risk of autoimmune disorders, accompanied by elevated levels of tissue necrosis factor (TNF) α. We examined behavioral alterations related to obsessive–compulsive disorder (OCD) and the role of TNFα and related signaling pathways in FTD patients with GRN mutations and in mice lacking progranulin (PGRN). We found that patients and mice with GRN mutations displayed OCD and self-grooming (an OCD-like behavior in mice), respectively. Furthermore, medium spiny neurons in the nucleus accumbens, an area implicated in development of OCD, display hyperexcitability in PGRN knockout mice. Reducing levels of TNFα in PGRN knockout mice abolished excessive self-grooming and the associated hyperexcitability of medium spiny neurons of the nucleus accumbens. In the brain, PGRN is highly expressed in microglia, which are a major source of TNFα. We therefore deleted PGRN specifically in microglia and found that it was sufficient to induce excessive grooming. Importantly, excessive grooming in these mice was prevented by inactivating nuclear factor κB (NF-κB) in microglia/myeloid cells. Our findings suggest that PGRN deficiency leads to excessive NF-κB activation in microglia and elevated TNFα signaling, which in turn lead to hyperexcitability of medium spiny neurons and OCD-like behavior.
Discovery of an O-mannosylation pathway selectively serving cadherins and protocadherins

Significance The large superfamily of cadherins serve essential roles in cell–cell interactions and guidance. The extracellular cadherin (EC) domains responsible for the biological functions are decorated with O-linked mannose glycans, but the functions of these O-glycans are poorly understood. Here we describe an O-mannosylation pathway orchestrated by four homologous TMTC1–4 genes that is dedicated selectively to the cadherin superfamily. Mutations in the TMTC3 gene cause cobblestone lissencephaly, demonstrating the importance of this type of O-mannosylation. The cadherin (cdh) superfamily of adhesion molecules carry O-linked mannose (O-Man) glycans at highly conserved sites localized to specific β-strands of their extracellular cdh (EC) domains. These O-Man glycans do not appear to be elongated like O-Man glycans found on α-dystroglycan (α-DG), and we recently demonstrated that initiation of cdh/protocadherin (pcdh) O-Man glycosylation is not dependent on the evolutionary conserved POMT1/POMT2 enzymes that initiate O-Man glycosylation on α-DG. Here, we used a CRISPR/Cas9 genetic dissection strategy combined with sensitive and quantitative O-Man glycoproteomics to identify a homologous family of four putative protein O-mannosyltransferases encoded by the TMTC1–4 genes, which were found to be imperative for cdh and pcdh O-Man glycosylation. KO of all four TMTC genes in HEK293 cells resulted in specific loss of cdh and pcdh O-Man glycosylation, whereas combined KO of TMTC1 and TMTC3 resulted in selective loss of O-Man glycans on specific β-strands of EC domains, suggesting that each isoenzyme serves a different function. In addition, O-Man glycosylation of IPT/TIG domains of plexins and hepatocyte growth factor receptor was not affected in TMTC KO cells, suggesting the existence of yet another O-Man glycosylation machinery. Our study demonstrates that regulation of O-mannosylation in higher eukaryotes is more complex than envisioned, and the discovery of the functions of TMTCs provide insight into cobblestone lissencephaly caused by deficiency in TMTC3.
Functional Optimization of Broadly Neutralizing HIV-1 Antibody 10E8 by Promotion of Membrane Interactions

ABSTRACT The 10E8 antibody targets a helical epitope in the membrane-proximal external region (MPER) and transmembrane domain (TMD) of the envelope glycoprotein (Env) subunit gp41 and is among the broadest known neutralizing antibodies against HIV-1. Accordingly, this antibody and its mechanism of action valuably inform the design of effective vaccines and immunotherapies. 10E8 exhibits unusual adaptations to attain specific, high-affinity binding to the MPER at the viral membrane interface. Reversing the charge of the basic paratope surface (from net positive to net negative) reportedly lowered its neutralization potency. Here, we hypothesized that by increasing the net positive charge in similar polar surface patches, the neutralization potency of the antibody may be enhanced. We found that an increased positive charge at this paratope surface strengthened an electrostatic interaction between the antibody and lipid bilayers, enabling 10E8 to interact spontaneously with membranes. Notably, the modified 10E8 antibody did not gain any apparent polyreactivity and neutralized virus with a significantly greater potency. Binding analyses indicated that the optimized 10E8 antibody bound with a higher affinity to the epitope peptide anchored in lipid bilayers and to Env spikes on virions. Overall, our data provide a proof of principle for the rational optimization of 10E8 via manipulation of its interaction with the membrane element of its epitope. However, the observation that a similar mutation strategy did not affect the potency of the first-generation anti-MPER antibody 4E10 shows possible limitations of this principle. Altogether, our results emphasize the crucial role played by the viral membrane in the antigenicity of the MPER-TMD of HIV-1. IMPORTANCE The broadly neutralizing antibody 10E8 blocks infection by nearly all HIV-1 isolates, a capacity which vaccine design seeks to reproduce. Engineered versions of this antibody also represent a promising treatment for HIV infection by passive immunization. Understanding its mechanism of action is therefore important to help in developing effective vaccines and biologics to combat HIV/AIDS. 10E8 engages its helical MPER epitope where the base of the envelope spike submerges into the viral membrane. To enable this interaction, this antibody evolved an unusual property: the ability to interact with the membrane surface. Here, we provide evidence that 10E8 can be made more effective by enhancing its interactions with membranes. Our findings strengthen the idea that to elicit antibodies similar to 10E8, vaccines must reproduce the membrane environment where these antibodies perform their function.
Reduced Hippocampal Functional Connectivity During Episodic Memory Retrieval in Autism

Abstract Increasing recent research has sought to understand the recollection impairments experienced by individuals with autism spectrum disorder (ASD). Here, we tested whether these memory deficits reflect a reduction in the probability of retrieval success or in the precision of memory representations. We also used functional magnetic resonance imaging (fMRI) to study the neural mechanisms underlying memory encoding and retrieval in ASD, focusing particularly on the functional connectivity of core episodic memory networks. Adults with ASD and typical control participants completed a memory task that involved studying visual displays and subsequently using a continuous dial to recreate their appearance. The ASD group exhibited reduced retrieval success, but there was no evidence of a difference in retrieval precision. fMRI data revealed similar patterns of brain activity and functional connectivity during memory encoding in the 2 groups, though encoding‐related lateral frontal activity predicted subsequent retrieval success only in the control group. During memory retrieval, the ASD group exhibited attenuated lateral frontal activity and substantially reduced hippocampal connectivity, particularly between hippocampus and regions of the fronto‐parietal control network. These findings demonstrate notable differences in brain function during episodic memory retrieval in ASD and highlight the importance of functional connectivity to understanding recollection‐related retrieval deficits in this population.
Randomized controlled trial comparing efficacy of conventional and new single larger dose of intra-articular viscosupplementation in management of knee osteoarthritis

Background: Intra-articular hyaluronic acid (HA) injection is used in management of knee, hand and hip osteoarthritis. While HA injection is included in the list of evaluated therapies, its efficacy and optimum dosing still have no consensus. This study was conducted to explore the possibility of using single injection HA to increase patient convenience while maintaining the therapeutic efficacy. Methods: We present a prospective, open label, non-blinded, randomized controlled trial performed in accordance with guidelines in principles of good clinical practice. Block randomization was done for patients to receive either single 5 ml GO-ON injection or the conventional three injections of 2.5 ml GO-ON at weekly interval. Baseline Western Ontario McMaster University Osteoarthritis (WOMAC) scores were evaluated and recorded. All subjects were re-evaluated at 3 months and the WOMAC score recorded again as primary end points. Data analyses were performed with IBM SPSS Statistics for Windows software (version 21.0, IBM Corp, Armonk, New York, USA). Results: In the cohort of 127 patients, 33 were males and 94 females. The mean age was 59.1 years (standard deviation (SD) = 7.25) in single injection arm and 60.1 years (SD = 7.72) in triple injection arm. The two groups were recorded to have no significant difference in age (p = 0.46) and Kellgren–Lawrence radiological grade (p = 0.694). There was significant increase in the WOMAC scores from the baseline (pre-injection) to that recorded 3 months after injection (p < 0.001) in patients of both groups. However, there was no statistically significant difference noticed in this clinical improvement between the two arms (p = 0.889). Conclusion: The study shows single 5 ml dose regime comparing well with conventional three doses of 2.5 ml of intra-articular GO-ON HA injected at weekly intervals and confirms good efficacy, tolerability and safety of single larger dose of GO-ON knee intra-articular injection.
Understanding localness of knowledge sharing: a study of Naver KiN 'here'

In location-based social Q&A, the questions related to a local community (e.g. local services and places) are typically answered by local residents (i.e. who have the local knowledge). In this work, we wanted to deepen our understanding of the localness of knowledge sharing through investigating the topical and typological patterns related to the geographic characteristics, geographic locality of user activities, and motivations of local knowledge sharing. To this end, we analyzed a 12-month period Q&A dataset from Naver KiN "Here" and a supplementary survey dataset from 285 mobile users. Our results revealed several unique characteristics of location-based social Q&A. When compared with conventional social Q&A sites, Naver KiN "Here" had very different topical/typological patterns. Naver KiN "Here" exhibited a strong spatial locality where the answerers mostly had 1-3 spatial clusters of contributions, the topical distributions varied widely across different districts, and a typical cluster spanned a few neighboring districts. In addition, we uncovered unique motivators, e.g. ownership of local knowledge and sense of local community. The findings reported in the paper have significant implications for the design of Q&A systems, especially location-based social Q&A systems.
Experience Shapes the Development of Neural Substrates of Face Processing in Human Ventral Temporal Cortex

Abstract In adult humans, the ventral temporal cortex (VTC) represents faces in a reproducible topology. However, it is unknown what role visual experience plays in the development of this topology. Using functional magnetic resonance imaging in children and adults, we found a sequential development, in which the topology of face‐selective activations across the VTC was matured by age 7, but the spatial extent and degree of face selectivity continued to develop past age 7 into adulthood. Importantly, own‐ and other‐age faces were differentially represented, both in the distributed multivoxel patterns across the VTC, and also in the magnitude of responses of face‐selective regions. These results provide strong evidence that experience shapes cortical representations of faces during development from childhood to adulthood. Our findings have important implications for the role of experience and age in shaping the neural substrates of face processing in the human VTC.
Modelling and Verification of Mutual Exclusion Algorithms

This paper proposes modelling and exhaustive verification of mutual exclusion algorithms using timed automata (TA) and the popular UPPAAL toolbox. The proposal allows to check all the properties of a mutual exclusion algorithm also along the time dimension. Both the classic case of atomic read/write operations on memory cells and the non determinism of reading a memory cell during one or multiple write operations on it as it may occur in modern multi-port memories are considered. The approach is then applied to some algorithms proposed in the literature of which known properties are confirmed but also new ones are revealed.
Recurrent attacks of acute hepatic porphyria: major role of the chronic inflammatory response in the liver

Acute intermittent porphyria (AIP) is an inherited disorder of haem metabolism characterized by life‐threatening acute neurovisceral attacks due to the induction of hepatic δ‐aminolevulinic acid synthase 1 (ALAS1) associated with hydroxymethylbilane synthase (HMBS) deficiency. So far, the treatment of choice is hemin which represses ALAS1. The main issue in the medical care of AIP patients is the occurrence of debilitating recurrent attacks.
Non-surgical periodontal treatment in conjunction with 3 or 7 days systemic administration of amoxicillin and metronidazole in severe chronic periodontitis patients. A placebo-controlled randomized clinical study.

AIM To evaluate the effect of 3 or 7 days systemic administration of amoxicillin (AMX) and metronidazole (MET) or placebo as adjunct to non-surgical periodontal treatment in severe chronic periodontitis patients. METHODS One hundred and two patients with severe chronic periodontitis [e.g. ≥1 site with probing pocket depth (PD) ≥ 6 mm per quadrant] were randomly divided into three equally sized groups and treated with either scaling and root planing within 24 h (SRP) + placebo (Group A) or SRP + AMX + MET (both 500 mg × 3 times daily) for 3 days (Group B) or SRP + AMX + MET (both 500 mg × 3 times daily) for 7 days (Group C). PD, clinical attachment level (CAL), bleeding on probing (BOP), full-mouth plaque scores (FMPS) and gingival bleeding index (GBI) were assessed prior to treatment (baseline), and at 3 and 6 months post-treatment. The primary outcome variable was the difference (Δ) in the number of sites with PD ≥ 6 mm. RESULTS Ninety-one patients completed the study. At both 3 and 6 months, all three treatment protocols resulted in statistically significant improvements compared to baseline for all evaluated clinical parameters (p < 0.001). At 6 months, a statistically significantly greater reduction in the mean number of sites with PD ≥ 6 mm was observed in group B (28.62 ± 15.32 sites) and group C (30.45 ± 15.04 sites) compared to the placebo group (17.10 ± 14.68 sites). Furthermore, both the 3- and the 7-day antibiotic regimen resulted in statistically significantly higher clinical improvements compared to the placebo group (p < 0.05). CONCLUSION The present findings indicate that in patients with severe chronic periodontitis, non-surgical periodontal therapy in conjunction with a 3 or 7 days systemic administration of AMX + MET may lead to significantly greater clinical improvements compared to non-surgical therapy alone.
Detecting and discriminating novel objects: The impact of perirhinal cortex disconnection on hippocampal activity patterns

Perirhinal cortex provides object‐based information and novelty/familiarity information for the hippocampus. The necessity of these inputs was tested by comparing hippocampal c‐fos expression in rats with or without perirhinal lesions. These rats either discriminated novel from familiar objects (Novel‐Familiar) or explored pairs of novel objects (Novel‐Novel). Despite impairing Novel‐Familiar discriminations, the perirhinal lesions did not affect novelty detection, as measured by overall object exploration levels (Novel‐Novel condition). The perirhinal lesions also largely spared a characteristic network of linked c‐fos expression associated with novel stimuli (entorhinal cortex→CA3→distal CA1→proximal subiculum). The findings show: I) that perirhinal lesions preserve behavioral sensitivity to novelty, whilst still impairing the spontaneous ability to discriminate novel from familiar objects, II) that the distinctive patterns of hippocampal c‐fos activity promoted by novel stimuli do not require perirhinal inputs, III) that entorhinal Fos counts (layers II and III) increase for novelty discriminations, IV) that hippocampal c‐fos networks reflect proximal‐distal connectivity differences, and V) that discriminating novelty creates different pathway interactions from merely detecting novelty, pointing to top‐down effects that help guide object selection. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc.
Undergraduate Students' Adoption of Website-service Quality by Applying the Unified Theory of Acceptance and Use of Technology (UTAUT) in Jordan

Websites design and quality becomes a critical success factor especially for Electronic University (E-University) and/or Mobile University (M-University) as a part of E-Government and/or M-Government; because websites are the main interface between the universities and its students and stakeholders. This study presents factors that affect undergraduate studentsâ? adoption of website-service quality by applying the Unified Theory of Acceptance and Use of Technology (UTAUT) in Jordan. The proposed model was empirically tested using data collected from a survey containing 24 questions. Out of the 450 questionnaires that were randomly distributed, 422 were returned (93.8%). The structural equation modeling technique (SEM), by using the WarpPLS 3.0 software, was used to evaluate the causal model. Results show that student adoption and use of university website services can be predicted from the studentsâ? behavioral intentions, which are affected significantly by performance expectancy and effort expectancy. The results show that social influence, website quality, and facilitating conditions have no direct significant effect on behavioral intention to use university website services even they have a medium grand mean for the scores of responses statements. Finally, as an ultimate aspiration, it was found that there is a direct effect between behavioral intention and actual behavioral to use university website services. Furthermore, the authors hope that understanding the underlying assumptions and theoretical constructs through the use of the UTAUT will assist developers in building, developing and maintaining a university website.
Tudor staphylococcal nuclease is a structure-specific ribonuclease that degrades RNA at unstructured regions during microRNA decay

Tudor staphylococcal nuclease (TSN) is an evolutionarily conserved ribonuclease in eukaryotes that is composed of five staphylococcal nuclease-like domains (SN1–SN5) and a Tudor domain. TSN degrades hyper-edited double-stranded RNA, including primary miRNA precursors containing multiple I•U and U•I pairs, and mature miRNA during miRNA decay. However, how TSN binds and degrades its RNA substrates remains unclear. Here, we show that the C. elegans TSN (cTSN) is a monomeric Ca2+-dependent ribonuclease, cleaving RNA chains at the 5′-side of the phosphodiester linkage to produce degraded fragments with 5′-hydroxyl and 3′-phosphate ends. cTSN degrades single-stranded RNA and double-stranded RNA containing mismatched base pairs, but is not restricted to those containing multiple I•U and U•I pairs. cTSN has at least two catalytic active sites located in the SN1 and SN3 domains, since mutations of the putative Ca2+-binding residues in these two domains strongly impaired its ribonuclease activity. We further show by small-angle X-ray scattering that rice osTSN has a flexible two-lobed structure with open to closed conformations, indicating that TSN may change its conformation upon RNA binding. We conclude that TSN is a structure-specific ribonuclease targeting not only single-stranded RNA, but also unstructured regions of double-stranded RNA. This study provides the molecular basis for how TSN cooperates with RNA editing to eliminate duplex RNA in cell defense, and how TSN selects and degrades RNA during microRNA decay.
State-based SHOSLIF for indoor visual navigation

Vision-based navigation is investigated using SHOSLIF that incorporates states and a visual attention mechanism. The problem is formulated as an observation-driven Markov model (ODMM) which is realized through recursive partitioning regression. A stochastic recursive partition tree (SRPT), which maps a preprocessed current input raw image and the previous state into the current state and the next control signal is used for efficient recursive partitioning regression. The SRPT learns incrementally: each learning sample is rejected or learned "on-the-fly". The proposed scheme has been successfully applied to indoor navigation.
Peer Victimization Trajectories at the Adolescent Transition: Associations Among Chronic Victimization, Peer-Reported Status, and Adjustment

The current study demonstrated that chronic peer victimization, as compared to time-limited victimization, is particularly associated with peer status and peer-reported adjustment at the adolescent transition. Using a cohort sequential design, a sample of 653 adolescents (48% female, 87% Caucasian) in Grades 6–8 were assessed at 3 annual time points; data captured indices of peer victimization, likeability, popularity, and several peer-reported indices of internalizing (e.g., sadness, worry) and externalizing (e.g., anger, fighting) symptoms across Grades 6–10. Four trajectories of victimization experiences were identified—chronic, high decreasing, low increasing, and low stable—suggesting instability in victimization experiences over time. Adolescents who experienced chronic victimization, as compared to those with low-stable, decreasing, or increasing levels of victimization, were rated by peers more often on indices of maladjustment and less often on measures of popularity and likeability. Findings highlight negative associations with chronic victimization and underscore the need for targeted interventions to prevent chronic victimization. Overall, findings further emphasize the role of chronicity in victimization and highlight the importance of identifying chronic victims for intervention and prevention efforts.