Miracle-dz/UniFAR-FTUs huggingface dataset:
A Systematic Review and Meta-Analysis of Autoantibodies for Diagnosis and Prognosis in Patients With Chronic Inflammatory Demyelinating Polyradiculoneuropathy

Objectives: To review the available evidence on sensitivity and specificity of anti-NF155 antibody detection in diagnosing a specific subset of patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and to calculate the frequencies of different autoantibodies to paranodal proteins. Background: Diagnosis of CIDP relies on clinical and neurophysiologic criteria and lacks useful diagnostic biomarkers. A subset of CIDP patients exhibit atypical clinical phenotypes and impaired response to conventional treatments. These patients were reported as having autoantibodies targeting paranodal protein neurofascin isoform 155 (NF155), contactin-1 (CNTN1), and contactin-associated protein-1 (CASPR1). Here, we conducted a meta-analysis to summarize evidence on the diagnostic and prognostic value of these autoantibodies, especially for anti-NF155 antibody. Methods: We searched the following electronic bibliographic databases: PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science. Eligible studies provided information to calculate the frequencies of anti-NF155 antibody and anti-CNTN1 antibody, the sensitivity and specificity of anti-NF155 antibody, and the incidence of improvement and deterioration among anti-NF155 antibody seropositive CIDP patients. Heterogeneity was assessed using Q and I2 statistics. Results: The pooled frequency of anti-NF155 autoantibody across 14 studies was 7% [95% confidence interval (CI): 0.05–0.10] with high heterogeneity; the overall pooled sensitivity and specificity of anti-NF155 antibody for the diagnosis of a specific subgroup of CIDP patients were 0.45 (95% CI: 0.29–0.63) and 0.93 (95% CI: 0.86–0.97), respectively. Conclusions: For diagnosing of a specific subset of CIDP characterized by poor response to intravenous immunoglobulin (IVIg), we found a moderate sensitivity and a high specificity. The anti-NF155 antibody test should be used as a confirmatory test rather than a screening test. Systematic Review Registration: PROSPERO, identifier: CRD42020203385 and CRD42020190789.
Near-Infrared Photoactivatable Immunomodulatory Nanoparticles for Combinational Immunotherapy of Cancer

As a promising treatment option for cancer, immunotherapy can eliminate local and distant metastatic tumors and even prevent recurrence through boosting the body’s immune system. However, immunotherapy often encounters the issues of limited therapeutic efficacy and severe immune-related adverse events in clinical practices, which should be mainly due to the non-specific accumulations of immunotherapeutic agents. Activatable immunomodulatory agents that are responsive to endogenous stimuli in tumor microenvironment can afford controlled immunotherapeutic actions, while they still face certain extent of off-target activation. Since light has the advantages of noninvasiveness, simple controllability and high spatio-temporal selectivity, therapeutic agents that can be activated by light, particularly near-infrared (NIR) light with minimal phototoxicity and strong tissue penetrating ability have been programmed for cancer treatment. In this mini review, we summarize the recent progress of NIR photoactivatable immunomodulatory nanoparticles for combinational cancer immunotherapy. The rational designs, constructions and working mechanisms of NIR photoactivatable agents are first briefly introduced. The uses of immunomodulatory nanoparticles with controlled immunotherapeutic actions upon NIR photoactivation for photothermal and photodynamic combinational immunotherapy of cancer are then summarized. A conclusion and discussion of the existing challenges and further perspectives for the development and clinical translation of NIR photoactivatable immunomodulatory nanoparticles are finally given.
Intestinal Growth in Glucagon Receptor Knockout Mice Is Not Associated With the Formation of AOM/DSS-Induced Tumors

Treatment with exogenous GLP-2 has been shown to accelerate the growth of intestinal adenomas and adenocarcinomas in experimental models of colonic neoplasia, however, the role of endogenous GLP-2 in tumor promotion is less well known. Mice with a global deletion of the glucagon receptor (Gcgr-/-) display an increase in circulating GLP-1 and GLP-2. Due to the intestinotrophic nature of GLP-2, we hypothesized that Gcgr-/- mice would be more susceptible to colonic dysplasia in a model of inflammation-induced colonic carcinogenesis. Female Gcgr-/- mice were first characterized for GLP-2 secretion and in a subsequent study they were given a single injection with the carcinogen azoxymethane (7.5 mg/kg) and treated with dextran sodium sulfate (DSS) (3%) for six days (n=19 and 9). A cohort of animals (n=4) received a colonoscopy 12 days following DSS treatment and all animals were sacrificed after six weeks. Disruption of glucagon receptor signaling led to increased GLP-2 secretion (p<0.0001) and an increased concentration of GLP-2 in the pancreas of Gcgr-/- mice, coinciding with an increase in small intestinal (p<0.0001) and colonic (p<0.05) weight. Increased villus height was recorded in the duodenum (p<0.001) and crypt depth was increased in the duodenum and jejunum (p<0.05 and p<0.05). Disruption of glucagon receptor signaling did not affect body weight during AOM/DSS treatment, neither did it affect the inflammatory score assessed during colonoscopy or the number of large and small adenomas present at the end of the study period. In conclusion, despite the increased endogenous GLP-2 secretion Gcgr-/- mice were not more susceptible to AOM/DSS-induced tumors.
Stable Epigenetic Programming of Effector and Central Memory CD4 T Cells Occurs Within 7 Days of Antigen Exposure In Vivo

T cell immunological memory is established within days of an infection, but little is known about the in vivo changes in gene regulatory networks accounting for their ability to respond more efficiently to secondary infections. To decipher the timing and nature of immunological memory we performed genome-wide analyses of epigenetic and transcriptional changes in a mouse model generating antigen-specific T cells. Epigenetic reprogramming for Th differentiation and memory T cell formation was already established by the peak of the T cell response after 7 days. The Th memory T cell program was associated with a gain of open chromatin regions, enriched for RUNX, ETS and T-bet motifs, which remained stable for 56 days. The epigenetic programs for both effector memory, associated with T-bet, and central memory, associated with TCF-1, were established in parallel. Memory T cell-specific regulatory elements were associated with greatly enhanced inducible Th1-biased responses during secondary exposures to antigen. Furthermore, memory T cells responded in vivo to re-exposure to antigen by rapidly reprograming the entire ETS factor gene regulatory network, by suppressing Ets1 and activating Etv6 expression. These data show that gene regulatory networks are epigenetically reprogrammed towards memory during infection, and undergo substantial changes upon re-stimulation.
Attenuated SIRT1 Activity Leads to PER2 Cytoplasmic Localization and Dampens the Amplitude of Bmal1 Promoter-Driven Circadian Oscillation

The circadian clock possesses robust systems to maintain the rhythm approximately 24 h, from cellular to organismal levels, whereas aging is known to be one of the risk factors linked to the alternation of circadian physiology and behavior. The amount of many metabolites in the cells/body is altered with the aging process, and the most prominent metabolite among them is the oxidized form of nicotinamide adenine dinucleotide (NAD+), which is associated with posttranslational modifications of acetylation and poly-ADP-ribosylation status of circadian clock proteins and decreases with aging. However, how low NAD+ condition in cells, which mimics aged or pathophysiological conditions, affects the circadian clock is largely unknown. Here, we show that low NAD+ in cultured cells promotes PER2 to be retained in the cytoplasm through the NAD+/SIRT1 axis, which leads to the attenuated amplitude of Bmal1 promoter-driven luciferase oscillation. We found that, among the core clock proteins, PER2 is mainly affected in its subcellular localization by NAD+ amount, and a higher cytoplasmic PER2 localization was observed under low NAD+ condition. We further found that NAD+-dependent deacetylase SIRT1 is the regulator of PER2 subcellular localization. Thus, we anticipate that the altered PER2 subcellular localization by low NAD+ is one of the complex changes that occurs in the aged circadian clock.
Redox Polymers for Tissue Engineering

This review will focus on the targeted design, synthesis and application of redox polymers for use in regenerative medicine and tissue engineering. We define redox polymers to encompass a variety of polymeric materials, from the multifunctional conjugated conducting polymers to graphene and its derivatives, and have been adopted for use in the engineering of several types of stimulus responsive tissues. We will review the fundamental properties of organic conducting polymers (OCPs) and graphene, and how their properties are being tailored to enhance material - biological interfacing. We will highlight the recent development of high-resolution 3D fabrication processes suitable for biomaterials, and how the fabrication of intricate scaffolds at biologically relevant scales is providing exciting opportunities for the application of redox polymers for both in-vitro and in-vivo tissue engineering. We will discuss the application of OCPs in the controlled delivery of bioactive compounds, and the electrical and mechanical stimulation of cells to drive behaviour and processes towards the generation of specific functional tissue. We will highlight the relatively recent advances in the use of graphene and the exploitation of its physicochemical and electrical properties in tissue engineering. Finally, we will look forward at the future of organic conductors in tissue engineering applications, and where the combination of materials development and fabrication processes will next unite to provide future breakthroughs.
Structural Design and Analysis of the RHOA-ARHGEF1 Binding Mode: Challenges and Applications for Protein-Protein Interface Prediction

The interaction between two proteins may involve local movements, such as small side-chains re-positioning or more global allosteric movements, such as domain rearrangement. We studied how one can build a precise and detailed protein-protein interface using existing protein-protein docking methods, and how it can be possible to enhance the initial structures using molecular dynamics simulations and data-driven human inspection. We present how this strategy was applied to the modeling of RHOA-ARHGEF1 interaction using similar complexes of RHOA bound to other members of the Rho guanine nucleotide exchange factor family for comparative assessment. In parallel, a more crude approach based on structural superimposition and molecular replacement was also assessed. Both models were then successfully refined using molecular dynamics simulations leading to protein structures where the major data from scientific literature could be recovered. We expect that the detailed strategy used in this work will prove useful for other protein-protein interface design. The RHOA-ARHGEF1 interface modeled here will be extremely useful for the design of inhibitors targeting this protein-protein interaction (PPI).
Intravitreal Gene Therapy vs. Natural History in Patients With Leber Hereditary Optic Neuropathy Carrying the m.11778G>A ND4 Mutation: Systematic Review and Indirect Comparison

Objective: This work aimed to compare the evolution of visual outcomes in Leber hereditary optic neuropathy (LHON) patients treated with intravitreal gene therapy to the spontaneous evolution in prior natural history (NH) studies. Design: A combined analysis of two phase three randomized, double-masked, sham-controlled studies (REVERSE and RESCUE) and their joint long-term extension trial (CLIN06) evaluated the efficacy of rAAV2/2-ND4 vs. 11 pooled NH studies used as an external control. Subjects: The LHON subjects carried the m.11778G>A ND4 mutation and were aged ≥15 years at onset of vision loss. Methods: A total of 76 subjects received a single intravitreal rAAV2/2-ND4 injection in one eye and sham injection in the fellow eye within 1 year after vision loss in REVERSE and RESCUE. Both eyes were considered as treated due to the rAAV2/2-ND4 treatment efficacy observed in the contralateral eyes. Best corrected visual acuity (BCVA) from REVERSE, RESCUE, and CLIN06 up to 4.3 years after vision loss was compared to the visual acuity of 208 NH subjects matched for age and ND4 genotype. The NH subjects were from a LHON registry (REALITY) and from 10 NH studies. A locally estimated scatterplot smoothing (LOESS), non-parametric, local regression model was used to modelize visual acuity curves over time, and linear mixed model was used for statistical inferences. Main Outcome Measures: The main outcome measure was evolution of visual acuity from 12 months after vision loss, when REVERSE and RESCUE patients had been treated with rAAV2/2-ND4. Results: The LOESS curves showed that the BCVA of the treated patients progressively improved from month 12 to 52 after vision loss. At month 48, there was a statistically and clinically relevant difference in visual acuity of −0.33 logarithm of the minimal angle of resolution (LogMAR) (16.5 ETDRS letters equivalent) in favor of treated eyes vs. NH eyes (p < 0.01). Most treated eyes (88.7%) were on-chart at month 48 as compared to 48.1% of the NH eyes (p < 0.01). The treatment effect at last observation remained statistically and clinically significant when adjusted for age and duration of follow-up (−0.32 LogMAR, p < 0.0001). Conclusions: The m.11778G>A LHON patients treated with rAAV2/2-ND4 exhibited an improvement of visual acuity over more than 4 years after vision loss to a degree not demonstrated in NH studies. Clinical Trial Registration: NCT02652767, NCT02652780, NCT03406104, and NCT03295071.
A Randomized Case Series Approach to Testing Efficacy of Interventions for Minimally Verbal Autistic Children

Background Randomized Controlled Trials (RCTs) are the gold standard for assessing whether an intervention is effective; however, they require large sample sizes in order to detect small effects. For rare or complex populations, we advocate a case series approach as a more realistic and useful first step for intervention evaluation. We consider the importance of randomization to such designs, and advocate for the use of Randomization Tests and Between Case Effect Sizes to provide a robust and statistically powerful evaluation of outcomes. In this tutorial, we describe the method, procedures, and analysis code necessary to conduct robust single case series, using an empirical example with minimally verbal autistic children. Method We applied a pre-registered (https://osf.io/9gvbs) randomized baseline design with between-case effect size to a case series (n = 19), to test the efficacy of a novel, parent-mediated, app-based speech production intervention (BabbleBooster) for minimally verbal autistic children. Parent-rated probe scores were used to densely sample performance accuracy over time. Results Parents were able to reliably code their children’s speech productions using BabbleBooster. A non-significant Randomization Test and small Between-Case Effect Size (d = 0.267), suggested there was no evidence that BabbleBooster improved speech production in minimally verbal autistic children, relative to baseline scores, during this brief period of intervention. Conclusion The current analyses exemplify a more robust approach to examining treatment effects in rare or complex populations, where RCT may be difficult or premature to implement. To facilitate adoption of this method by researchers and practitioners, we provide analysis code that can be adapted using open source R packages. Future studies could use this case series design to evaluate interventions aiming to improve speech and language outcomes for minimally verbal autistic children, and other heterogeneous and hard to reach populations.
Immediate Analgesic Effect of Acupuncture in Patients With Primary Dysmenorrhea: A fMRI Study

Primary dysmenorrhea (PDM) is a common gynecological disease characterized by lower abdominal pain. Acupuncture is considered a good alternative therapy for PDM. However, the central mechanism of the analgesic effect of acupuncture is largely unknown. In this study, eligible patients were randomized into the real and sham acupuncture groups using a computer-generated, permuted block randomization method. The study cohort comprised 34 patients: 19 in the real acupuncture group and 15 in the sham acupuncture group. The clinical characteristics of the patients during their menstrual period were collected, and imaging scans were performed during the first 3 days of the patients’ menstrual period. We analyzed task and resting functional magnetic resonance imaging (fMRI) data to investigate the potential central mechanism of the immediate effect of acupuncture intervention on the intensity of PDM pain. The task fMRI study found that the rostral anterior cingulate cortex (rACC) and right supplemental motor area were activated during real acupuncture. Using the resting-state functional connectivity (FC) method, we found a post- versus pre-treatment change in the FC of the rACC and left precentral gyrus in the comparison of real acupuncture versus sham acupuncture. In addition, the FC of the rACC–left precentral gyrus at baseline was negatively correlated with short-term analgesia, while the change in the FC of the rACC–left precentral gyrus was positively correlated with short-term analgesia after acupuncture treatment. These findings support the importance of rACC–left precentral gyrus resting-state FC in the modulation of the intensity of PDM pain through acupuncture, which may shed light on the central mechanism of acupuncture in the treatment of PDM.
Improvement of Physical Performance Following a 6 Week Change-of-Direction Training Program in Elite Youth Soccer Players of Different Maturity Levels

Background: Change-of-direction (CoD) is a necessary physical ability of a field sport and may vary in youth players according to their maturation status. Objectives: The aim of this study is: to compare the effectiveness of a 6-week CoD training intervention on dynamic balance (CS-YBT), horizontal jump (5JT), speed (10 and 30-m linear sprint times), CoD with (15 m-CoD + B) and without (15 m-CoD) the ball, in youth male soccer players at different levels of maturity [pre- and post-peak height velocity (PHV)]. Materials and Methods: Thirty elite male youth soccer players aged 10–17 years from the Tunisian first division participated in this study. The players were divided into pre- (G1, n = 15) and post-PHV (G2, n = 15) groups. Both groups completed a similar 6-week training program with two sessions per week of four CoD exercises. All players completed the following tests before and after intervention: CS-YBT; 5 JT; 10, 30, and 15 m-CoD; and 15 m-CoD + B, and data were analyzed using ANCOVA. Results: All 30 players completed the study according to the study design and methodology. Adherence rate was 100% across all groups, and no training or test-related injuries were reported. Pre-PHV and post-PHV groups showed significant amelioration post-intervention for all dependent variables (after test > before test; p < 0.01, d = 0.09–1.51). ANOVA revealed a significant group × time interaction only for CS-YBT (F = 4.45; p < 0.04; η2 = 0.14), 5JT (F = 6.39; p < 0.02; η2 = 0.18), and 15 m-CoD (F = 7.88; p < 0.01; η2 = 0.22). CS-YBT, 5JT, and 15 m-CoD improved significantly in the post-PHV group (+ 4.56%, effect size = 1.51; + 4.51%, effect size = 1.05; and -3.08%, effect size = 0.51, respectively), more than the pre-PHV group (+ 2.77%, effect size = 0.85; + 2.91%, effect size = 0.54; and -1.56%, effect size = 0.20, respectively). Conclusion: The CoD training program improved balance, horizontal jump, and CoD without the ball in male preadolescent and adolescent soccer players, and this improvement was greater in the post-PHV players. The maturity status of the athletes should be considered when programming CoD training for soccer players.
Intramuscular Expression of Plasmid-Encoded FVII-Fc Immunoconjugate for Tumor Immunotherapy by Targeting Tumoral Blood Vessels and Cells

Tissue factor (TF) has been confirmed to be specifically expressed by vascular endothelial cells (VECs) in solid tumors and certain types of malignant tumor cells. Coagulation factor VII (FVII) can specifically bind to TF with high affinity, so the FVII-TF interaction provides an ideal target for tumor therapy. Expression of proteins in skeletal muscles is a simple and economical avenue for continuous production of therapeutic molecules. However, it is difficult to treat solid tumors till now due to the limited number of therapeutic proteins produced by the intramuscular gene expression system. Herein, we strived to explore whether anti-tumor effects can be achieved via intramuscular delivery of a plasmid encoding a FVII-guided immunoconjugate (Icon) molecule by a previously established Pluronic L64/electropulse (L/E) technique. Our study exhibited several interesting outcomes. 1) The mouse light chain of FVII (mLFVII) molecule could guide red fluorescent protein (RFP) to accumulate predominantly at tumor sites in a TF-dependent manner. 2) Intramuscular expression of mLFVII-hFc (human IgG1 Fc) Icon could significantly inhibit the growth of both liver and lung cancers in nude mice, and the inhibition extent was proportional to the level of tumor-expressed TF. 3) The number of blood vessels and the amount of blood flow in tumors were significantly decreased in mLFVII-hFc Icon-treated mice. 4) This immunotherapy system did not display obvious side effects. Our study provided an efficient and economical system for tumor immunotherapy by targeting both blood vessels and tumor cells. It is also an open system for synergistic therapy by conveniently integrating other anticancer regimens.
Electrical properties of single-walled carbon nanotube networks produced by Langmuir-Blodgett deposition

This thesis investigates the use of the Langmuir-Blodgett (LB) deposition technique as a means for building up ultra-thin networks of single-walled carbon nanotubes (SWCNTs) on various substrates. Transfer from a water subphase is successfully demonstrated for a range of SWCNTs and the electrical properties of the networks are discussed in detail. In contrast to the majority of literature on LB networks of SWCNTs, transfer is completed without the addition of surfactants to the nanotube material. However, and as expected, improved deposition is achieved when SWCNTs are functionalised (through thermal oxidation) with carboxylic acid groups, decreasing their hydrophobicity. In-plane electrical data reveal preferential alignment of the nanotubes along the direction of dipping. Comprehensive studies of the current dependence on temperature and the field dependence of conductivity are presented for sorted metallic and semiconducting nanotubes in an attempt to reveal the dominant conduction mechanisms. For metallic nanotubes, typical metallic conductivity is observed with an increasing resistance with increasing temperature. The metallic nanotube temperature coefficient of resistance is 0.001/K. At high electricfield strengths (>10^6 V/m), conduction in semiconducting SWCNT networks is dominated by the Poole-Frenkel effect. Transistor structures are presented with SWCNTs as the active semiconducting layer. The best device shows p-type depletion mode behaviour with an on/offratio of around 8 and a carrier mobility of 0.3 cm^2/Vs.