Miracle-dz/UniFAR-FTUs huggingface dataset:
Molecular Therapies for Inherited Retinal Diseases—Current Standing, Opportunities and Challenges

Inherited retinal diseases (IRDs) are both genetically and clinically highly heterogeneous and have long been considered incurable. Following the successful development of a gene augmentation therapy for biallelic RPE65-associated IRD, this view has changed. As a result, many different therapeutic approaches are currently being developed, in particular a large variety of molecular therapies. These are depending on the severity of the retinal degeneration, knowledge of the pathophysiological mechanism underlying each subtype of IRD, and the therapeutic target molecule. DNA therapies include approaches such as gene augmentation therapy, genome editing and optogenetics. For some genetic subtypes of IRD, RNA therapies and compound therapies have also shown considerable therapeutic potential. In this review, we summarize the current state-of-the-art of various therapeutic approaches, including the pros and cons of each strategy, and outline the future challenges that lie ahead in the combat against IRDs.
Dispersion of Leishmania (Leishmania) infantum in central-southern Brazil: Evidence from an integrative approach

Leishmania (Leishmania) infantum is the zoonotic agent of visceral leishmaniasis (VL), a disease with a global distribution. The transmission scenario of VL has been undergoing changes worldwide, with the biologic cycle invading urbanized areas and dispersing the parasites into other previously free areas. The epidemiological cycle in Brazil has dispersed from the Northeast to other regions of the country. In this study, an integrative approach, including genotyping Brazilian strains of L. (L.) infantum for 14 microsatellite markers and reviewing historical records of the disease, was used to assess dispersion routes throughout central-southern Brazil. Our results support three L. (L.) infantum dispersion routes: A) dispersion from Bolivia to the states of Mato Grosso, Mato Grosso do Sul and São Paulo via the Bolivia-Brazil gas pipeline from 1998 to 2005; B) VL dispersion from Paraguay to the Brazilian side of the triple border (Foz do Iguaçu and Santa Terezinha de Itaipu) during after 2012; and C) emergence of a new L. (L.) infantum cluster in western Santa Catarina State and its dispersion to southern Paraná State (municipality of Pato Branco), after 2013. Hypotheses regarding possible entries of Leishmania (L.) infantum into the area of the triple border are presented and discussed. Understanding how VL has dispersed is vital to the development of control measures for this disease and to avoid future dispersion events.
MicroRNA-181a protects against pericyte apoptosis via directly targeting FOXO1: implication for ameliorated cognitive deficits in APP/PS1 mice

MicroRNAs (miRNAs) have emerged as critical regulators in the pathology of Alzheimer’s disease (AD). MiR-181a is associated with hippocampal memory formation and aberrantly expressed in patients with mild cognitive impairment (MCI), however, little is known about its role and underlying mechanism involved in AD. Here, we report that miR-181a expression declines in APP/PS1 mice, synchronous with the increase in amyloid β (Aβ) level, which suggests a reverse correlation between miR-181a level and AD development. Additionally, lentiviral overexpression of miR-181a via intrahippocampal injection ameliorates cognitive deficits and amyloid plaque deposition in APP/PS1 mice, indicating a beneficial role of miR-181a against AD progression. Moreover, miR-181a decelerates pericyte loss and blood-brain barrier breakdown in APP/PS1 mice. Furthermore, miR-181a protects against Aβ accumulation-induced pericyte apoptosis in vitro, which is attributed to the negative regulation of FOXO1 by miR-181a, since FOXO1 restoration abolishes miR-181a protective role against pericyte apoptosis. Altogether, these results may identify miR-181a as a novel regulator of AD pathology, and also implicate that the protection of miR-181a in blood-brain barrier pericytes may underlie its ameliorating effect on APP/PS1 mice.
TAFI deficiency causes maladaptive vascular remodeling after hemophilic joint bleeding.

Excessive vascular remodeling is characteristic of hemophilic arthropathy (HA) and may contribute to joint bleeding and the progression of HA. Mechanisms for pathological vascular remodeling after hemophilic joint bleeding are unknown. In hemophilia, activation of thrombin-activatable fibrinolysis inhibitor (TAFI) is impaired, which contributes to joint bleeding and may also underlie the aberrant vascular remodeling. Here, hemophilia A (FVIII-deficient) mice or TAFI-deficient mice with transient (antibody-induced) hemophilia A were used to determine the role of FVIII and TAFI in vascular remodeling after joint bleeding. Excessive vascular remodeling and vessel enlargement persisted in FVIII-deficient and TAFI-deficient but not in transient hemophilia WT mice after similar joint bleeding. TAFI-overexpression in FVIII-deficient mice prevented abnormal vessel enlargement and vascular leakage. Age-related vascular changes were observed with FVIII or TAFI deficiency, and correlated positively with bleeding severity after injury, supporting increased vascularity as a major contributor to joint bleeding. Antibody-mediated inhibition of uPA also prevented abnormal vascular remodeling, suggesting that TAFI's protective effects include inhibition of uPA-mediated plasminogen activation. In conclusion, the functional TAFI deficiency in hemophilia drives maladaptive vascular remodeling in the joints after bleeding. These new mechanistic insights allow targeted development of new strategies to normalize vascularity and control re-bleeding in HA.
When Randomized Clinical Trials and Real‐World Evidence Say the Same: Tocilizumab and Its Cardiovascular Safety

In this issue of Arthritis and Rheumatology, Giles et al. report much awaited data from the ENTRACTE trial. (1) The United States Food and Drug Administration (FDA)-required this post-marketing randomized controlled trial (RCT) to study the risk of major adverse cardiovascular events (MACE) in patients with rheumatoid arthritis (RA) treated with monthly tocilizumab (TCZ) 8mg/kg intravenous infusions compared to the risk in those treated with weekly etanercept 50mg subcutaneous injections. (1) This article is protected by copyright. All rights reserved.
Administration of an Immune Stimulant during the Transition Period Improved Lipid Metabolism and Rumination without Affecting Inflammatory Status

Simple Summary Immune stimulants are widely used to address immune dysfunctions that occur in transitioning dairy cows, reducing the likelihood they will develop infectious diseases. This study elucidates the effectiveness of an immune stimulant in promoting rumination recovery, reducing lipid mobilization and ketogenesis, and affecting the levels of circulating antioxidant systems in early lactation. These findings highlight the stimulant’s potential effect in treating metabolic disorders of the transition period in dairy cows. Abstract Omnigen-AF (OAF) increases leukocyte functions in immunosuppressed animal models and reduces incidence of infectious diseases in early lactating dairy cows, although its mode of action is still unclear. This study aims to provide a wider perspective of the metabolic effect of OAF to test its potential as a strategy to address metabolic disorders of the transition period. A group of 10 Holstein dairy cows were divided into 2 groups: The treated group (IMS; 5 cows) received 32.5 g of OAF twice a day (65 g d−1) as top-dress in the morning and afternoon feeds from −55 to 42 days from calving (DFC), whereas the control group (CTR; 5 cows) received no supplementation. From −62 to 42 DFC, body condition score, body weight, dry matter intake, rumination time and milk yield were measured; blood samples were collected weekly to assess a wide hematochemical profile and to test white blood cell functions by ex-vivo challenge assays. At 30 DFC, rumen fluid was collected and analyzed for pH, volatile fatty acids composition, urea nitrogen, and lactate contents. Data were submitted to ANOVA using a mixed model for repeated measures, including treatment, time, and their interaction as fixed effects. OAF decreased blood nonesterified fatty acids and beta hydroxybutyrate concentrations and increased rumination time in early lactation. Leukocytes from IMS cows had lower lactate production and lower glucose consumption after ex-vivo stimulation. OAF did not reduce the acute phase response indicators and reduced the blood concentrations of albumin and antioxidants after calving, suggesting impairment of hepatic functions related to protein synthesis and antioxidant management. Nevertheless, the lack of effect on bilirubin and liver enzymes refutes the possibility of severe liver damage occurring with OAF supplementation. Positive effects in reducing mobilization of body fats and ketogenesis and in increasing rumination time after calving suggest OAF effectiveness in preventing metabolic disorders of the transition period.
Closed form for the delay in an intermittent network node

We derive a simple, closed, equation for the delay caused by random outages or downtimes that affect a node in a communications network. The model is an M/G/1 queue with nonexhaustive interruptions, in which the server goes on and off successively, at random times, no matter whether the current job is finished or not. The arrival process is Poisson; while the distributions of service and on/off times are arbitrary. The formula is a tool for the analysis and simulation of a variety of phenomena that cause random interruptions in communication networks, such as unreliable equipment, fading, dynamic obstructions of line-of-sight in mobile systems, and many others.
Geophytism in monocots leads to higher rates of diversification.

Geophytes, plants with buds on underground structures, are found throughout the plant tree of life. These below ground structures allow plants to inhabit highly seasonal and disturbance-prone environments across ecosystems. Past researchers have hypothesized the bulbous, cormous and tuberous habits promote diversification, but this had yet to be tested. Using a comprehensive monocot data set of almost 13,000 taxa, we investigated the effects of the geophytic habit on diversification using both state-dependent and state-independent models. We found that geophytes exhibit increased rates of diversification relative to non-geophytes. State-dependent analyses recovered higher yet similar rates of diversification for bulbous, cormous and tuberous taxa compared to rhizomatous and non-geophytic taxa. However, the state-independent model returned no difference in rates among the different traits. Geophytism shows higher rates of diversification relative to non-geophytes but we find little support for the hypothesis that the evolution of the bulb, corm or tuber appears to provide a diversification increase relative to rhizomatous and non-geophytic taxa. Our broad scale analysis highlights the overall evolutionary importance of the geophytic habit (i.e., belowground bud placement). However, our results also suggest that belowground morphological diversity alone cannot explain this rate increase. In order to further test the evolutionary significance of these underground structures, future studies should consider them in combination with other biotic and abiotic factors. This article is protected by copyright. All rights reserved.
Maternal psychosocial stress during early gestation impairs fetal structural brain development in sheep

Abstract Maternal stress, especially during early pregnancy, predisposes offspring to neuropsychiatric disorders. We hypothesized that maternal psychosocial stress (MPS) during pregnancy affects fetal structural neurodevelopment depending on the gestational age of exposure. Fetal sheep brains were harvested at 130 days gestation (dG, term 150 dG) from ewes frequently isolated from flock-mates during early gestation (first and second trimester; n = 10) or late gestation (third trimester; n = 10), or from control flock-mates (n = 8). Immunohistochemistry for formation of neuronal processes, myelination, synaptic density, cell proliferation and programed cell death was performed on brain tissue sections. Sections of the cortical gray matter, the hippocampal CA3 region and the superficial, subcortical and deep white matter were examined morphometrically. Stress effects depended on the brain region and time of exposure. Stress during early gestation but not during late gestation reduced the amount of neuronal processes in the cerebral cortex and hippocampus by 36.9 ± 10.1% (p < 0.05, mean ± SEM) and 36.9 ± 15.8% (p < 0.05), respectively, accompanied by a decrease in synaptic density in the cerebral cortex and hippocampus by 39.8 ± 23.1% (p < 0.05) and 32.9 ± 13.4% (p < 0.01). Myelination was decreased in white matter layers on average by 44.8 ± 11.7% (p < 0.05) accompanied by reduced (glial) cell proliferation in the deep white matter by 83.6 ± 12.4% (p < 0.05). In contrast, stress during the third trimester had no effect in any brain region. Chronic MPS during the first and second trimester induced prolonged effects on neuronal network and myelin formation which might contribute to disturbed neurobehavioral, cognitive and motor development in offspring of stressed mothers. Lay summary Many women are exposed to stressful events during pregnancy. Maternal stress especially during early pregnancy predisposes for offspring’s neuropsychiatric disorders. In our sheep study, we show that disturbance of fetal brain development is a potential mechanism and is worst during 1st and 2nd trimester.
Complete Genome Sequences of Penicillin-Resistant Bacillus anthracis Strain PCr, Isolated from Bone Powder

Bacillus anthracis, the etiologic agent of anthrax, is susceptible to beta-lactam antibiotics, but few cases of naturally occurring penicillin-resistant strains have been reported. We report the genome sequence of penicillin-resistant strain Bacillus anthracis PCr, isolated from imported bone powder in 1978 in Japan. ABSTRACT Bacillus anthracis, the etiologic agent of anthrax, is susceptible to beta-lactam antibiotics, but few cases of naturally occurring penicillin-resistant strains have been reported. We report the genome sequence of penicillin-resistant strain Bacillus anthracis PCr, isolated from imported bone powder in 1978 in Japan.
THE INFLUENCE OF CONTROL STRATEGY ON EVENT SEGMENTATION

iii ACKNOWLEDGEMENTS . v LIST OF TABLES. viii LIST OF FIGURES. ix CHAPTER ONE: COGNITIVE CONTROL . 1 CHAPTER TWO: MEASURING COGNITIVE CONTROL . 5 CHAPTER THREE: DUAL MECHANISMS OF COGNITIVE CONTROL FRAMEWORK . 10 CHAPTER FOUR: PROACTIVE AND REACTIVE MODES OF CONTROL IN THE AX-CPT . 15 CHAPTER FIVE: SWITCHING BETWEEN MODES OF CONTROL . 17 Individual Differences. 20 Group Differences . 23 Situational Differences . 26 Inducing Proactive Mode of Control . 27 Inducing Reactive Mode of Control . 27 CHAPTER SIX: EVENT SEGMENTATION AND COGNITIVE CONTROL . 31 Event Segmentation and Proactive Control . 33 Event Segmentation and Reactive Control . 37 CHAPTER SEVEN: PRESENT STUDY . 41 CHAPTER EIGHT: METHOD . 45 Participants . 45 Design . 45
Principal Component Analysis Based on Graph Laplacian and Double Sparse Constraints for Feature Selection and Sample Clustering on Multi-View Data

Principal component analysis (PCA) is a widely used method for evaluating low-dimensional data. Some variants of PCA have been proposed to improve the interpretation of the principal components (PCs). One of the most common methods is sparse PCA which aims at finding a sparse basis to improve the interpretability over the dense basis of PCA. However, the performances of these improved methods are still far from satisfactory because the data still contain redundant PCs. In this paper, a novel method called PCA based on graph Laplacian and double sparse constraints (GDSPCA) is proposed to improve the interpretation of the PCs and consider the internal geometry of the data. In detail, GDSPCA utilizes L2,1-norm and L1-norm regularization terms simultaneously to enforce the matrix to be sparse by filtering redundant and irrelative PCs, where the L2,1-norm regularization term can produce row sparsity, while the L1-norm regularization term can enforce element sparsity. This way, we can make a better interpretation of the new PCs in low-dimensional subspace. Meanwhile, the method of GDSPCA integrates graph Laplacian into PCA to explore the geometric structure hidden in the data. A simple and effective optimization solution is provided. Extensive experiments on multi-view biological data demonstrate the feasibility and effectiveness of the proposed approach.
The role of the amygdala in emotional experience during retrieval of personal memories

ABSTRACT Although the role of the amygdala in emotional memory retrieval has long been established, how such engagement varies depending on valence and retrieval context is less clearly understood. Participants retrieved personal memories associated with primarily positive, primarily negative, and mixed-valence images, pressing a button when successful. The button press divided trials into search and elaboration phases. Participants provided positivity and negativity ratings immediately following each trial, and then again in a post-retrieval survey. The relation between amygdala recruitment and emotionality exhibited a four-way interaction, with no other significant main effects or interactions. The interaction was driven by a temporal shift in the role of amygdala recruitment during retrieval of memories associated with mixed-valence images: Negativity ratings were supported more by search-related activity whereas positivity was more strongly associated with elaboration. Amygdala activity during retrieval relates to emotional experience in more complicated ways than previously understood. When participants were able to consider positive and negative aspects of the same event, amygdala recruitment during search and elaboration were associated with opposite behavioural effects. Such findings suggest that the amygdala may support distinct aspects of emotional experience for the same memory depending on when during retrieval it is recruited.
Precision Cancer Theranostic Platform by In Situ Polymerization in Perylene Diimide-Hybridized Hollow Mesoporous Organosilica Nanoparticles.

Phototheranostics refers to advanced photonics-mediated theranostic methods for cancer and includes imaging-guided photothermal/chemo therapy, photothermal/photodynamic therapy, and photodynamic/chemo therapy, which are expected to provide a paradigm of modern precision medicine. In this regard, various phototheranostic drug delivery systems with excellent photonic performance, controlled drug delivery/release, and precise photo-imaging guidance have been developed. In this study, we reported a special "in situ framework growth" method to synthesize novel phototheranostic hollow mesoporous nanoparticles by ingenious hybridization of perylene diimide (PDI) within the framework of small-sized hollow mesoporous organosilica (HMO). The marriage of PDI and HMO endowed the phototheranostic silica nanoparticles (HMPDINs) with largely amplified fluorescence and photoacoustic signals, which can be used for enhanced fluorescence and photoacoustic imaging. The organo-silica shell can be chemically chelated with isotope 64Cu for positron emission tomography imaging. Moreover, in situ polymer growth was introduced in the hollow structure of the HMPDINs to produce thermosensitive polymer (TP) in the cavity of HMPDINs to increase the loading capacity and prevent unexpected leakage of the hydrophobic drug SN38. Furthermore, the framework-hybridized PDI generated heat under near-infrared laser irradiation to trigger the deformation of TP for controlled drug release in the tumor region. The fabricated hybrid nanomedicine with organic-inorganic characteristic not only increases the cancer theranostic efficacy but also offers an attractive solution for designing powerful theranostic platforms.
Predictors of Outcomes in Patients with EGFR-Mutated Non-Small Cell Lung Cancer Receiving EGFR Tyrosine Kinase Inhibitors: A Systematic Review and Meta-Analysis

Some commonly available patient or disease characteristics may be associated with progression-free survival (PFS) and overall survival (OS) in EGFR-mutant non-small cell lung cancer (NSCLC) patients receiving EGFR-TKIs (epidermal growth factor receptor - tyrosine kinase inhibitors). We performed a systematic review and meta-analysis of randomized control trials (RCTs) to explore differences in outcomes associated with EGFR-TKIs among subgroups of EGFR-mutant NSCLC patients. Pooled HRs for progression or death (PFS-HRs) and pooled HRs for death (OS-HRs) were compared among sub-groups defined according to baseline clinical and demographic variables as well as type of EGFR mutation. In the entire assessable population of 4465 EGFR-mutant NSCLC patients, significant interactions with PFS were found for gender (males vs. females; pooled ratio of the PFS-HRs = 1.2; 95% CI 1.12–1.56), smoking history (smokers vs. non-smokers; pooled ratio of the PFS-HRs = 1.26; 95% CI 1.05–1.51), and type of EGFR mutation (patients with exon 21 L858R mutation vs. exon 19 deletion; pooled ratio of the PFS-HRs = 1.39; 95% CI 1.18–1.63). Male patients, smokers and patients with EGFR exon 21 L858R mutation may derive less benefit from EGFR-TKIs compared to female patients, non-smokers and patients with EGFR exon 19 deletion.
The Role of Active-Site Residues Phe98, His239, and Arg243 in DNA Binding and in the Catalysis of Human Uracil–DNA Glycosylase SMUG1

Human SMUG1 (hSMUG1) hydrolyzes the N-glycosidic bond of uracil and some uracil lesions formed in the course of epigenetic regulation. Despite the functional importance of hSMUG1 in the DNA repair pathway, the damage recognition mechanism has been elusive to date. In the present study, our objective was to build a model structure of the enzyme–DNA complex of wild-type hSMUG1 and several hSMUG1 mutants containing substitution F98W, H239A, or R243A. Enzymatic activity of these mutant enzymes was examined by polyacrylamide gel electrophoresis analysis of the reaction product formation and pre-steady-state analysis of DNA conformational changes during enzyme–DNA complex formation. It was shown that substitutions F98W and H239A disrupt specific contacts generated by the respective wild-type residues, namely stacking with a flipped out Ura base in the damaged base-binding pocket or electrostatic interactions with DNA in cases of Phe98 and His239, respectively. A loss of the Arg side chain in the case of R243A reduced the rate of DNA bending and increased the enzyme turnover rate, indicating facilitation of the product release step.
Embedded Memory Test Strategies and Repair

The demand of self- testing proportionally increases with memory size in System on Chip (SoC). SoC architecture normally occupies the majority of its area by memories. Due to increase in density of embedded memories, there is a need of self- testing mechanism in SoC design. Therefore, this research study focuses on this problem and introduces a smooth solution for self- testing. In the proposed memory test algorithm, the self-testing as well as self-repair mechanisms are incorporated. This scheme repairs the detected faults and is easily integrated with SoC design. Here, an attempt has been made to implement the memory built- in-self- repair (MBISR) architecture to test and repair the faults from the embedded memories. It is little, and it supports at-fast test without timing penalty during its operation. The proposed method is a better alternative in speed and low area overhead. Thus, it plays a significant role in yield improvement.