The rapid advancement of technology has facilitated the integration of artificial intelligence(AI) into various domains, including the genetic medicine and healthcare industry. This integration has paved the way for AI to contribute significantly to research efforts focused on intellectual disability. AI has the potential to aid medical professionals in the early detection of genetic variations and the identification of underlying causes of diseases. The issue of intellectual disability becomes more pronounced when attempting to provide education to individuals with intellectual disabilities in the context of mainstream schooling. It is worth mentioning that AI and its approaches have the potential to diagnose and identify cognitive impairments and mental health conditions. This work aims to provide a systematic review of intellectual disability, encompassing its various varieties, and explore the utilization of AI approaches for diagnosing intellectual impairment through text-mining techniques. This article also examines the correlation between AI and intellectual disability while also acknowledging the potential for improved prospects for individuals with intellectual disabilities. This study also highlights the challenges and issues of AI in intellectual disabilities

Systematic insight into cellular dysfunction can improve understanding of disease etiology, risk assessment, and patient stratification. We present a multiparametric high-content imaging platform enabling quantification of low-density lipoprotein (LDL) uptake and lipid storage in cytoplasmic droplets of primary leukocyte subpopulations. We validate this platform with samples from 65 individuals with variable blood LDL-cholesterol (LDL-c) levels, including familial hypercholesterolemia (FH) and non-FH subjects. We integrate lipid storage data into another readout parameter, lipid mobilization, measuring the efficiency with which cells deplete lipid reservoirs. Lipid mobilization correlates positively with LDL uptake and negatively with hypercholesterolemia and age, improving differentiation of individuals with normal and elevated LDL-c. Moreover, combination of cell-based readouts with a polygenic risk score for LDL-c explains hypercholesterolemia better than the genetic risk score alone. This platform provides functional insights into cellular lipid trafficking and has broad possible applications in dissecting the cellular basis of metabolic disorders.

Objective:To identify the residue determinants of the serospecificity and sero-cross-reactivity of dengue virus(DENV)envelope protein domain 3(ED3),which contains two major putative epitopes of DENV.Methods:We constructed ED3 from DENV3(3ED3)and DENV4(4ED3),and six epitope-grafted variants,where we transferred epitope 1(L304I,K305D,V309M,and S310A)and/or epitope 2(D383N,K384S,K387T,and N389H)of 4ED3 onto 3ED3 and vice-versa.Swiss albino mice aged 3-4 weeks were immunized against wildtype and epitope-grafted ED3 variants and anti-ED3 IgG antibody responses were determined using ELISA.Results:Mouse immunization using 3ED3 and 4ED3 generated serotype-specific antisera,as expected.Similarly,most epitope-grafted ED3s produced antisera serospecific to the template ED3 with little or no cross-recognition of ED3 of the serotype from which the epitopes were taken.These indicated that a mere grafting of the epitope was not sufficient to transfer serospecificity,contrary to our expectations.However,one epitope-grafted ED3 mutant,where epitope 1 of 3ED3 was grafted onto 4ED3(4ED3epi1),generated antisera that was serospecific to both 4ED3 and 3ED3.Conclusions:The 4ED3epi1 is a chimeric ED3 that produces antisera possessing serospecificity to both 3ED3 and 4ED3 onto a common 4ED3 scaffold.The 4ED3epi1,therefore,provides a unique tool for analyzing serospecificity and sero-cross-reactivity in dengue.We believe that chimeric ED3 may provide a template for future recombinant ED3 possessing serospecificity of multiple DENVs onto a single scaffold and may pave a way developing tri-and/or tetravalent anti-DENV antisera.

Identifying secreted mediators that drive the cognitive benefits of exercise holds great promise for the treatment of cognitive decline in ageing or Alzheimer's disease (AD). Here, we show that irisin, the cleaved and circulating form of the exercise-induced membrane protein FNDC5, is sufficient to confer the benefits of exercise on cognitive function. Genetic deletion of Fndc5/irisin (global Fndc5 knock-out (KO) mice; F5KO) impairs cognitive function in exercise, ageing and AD. Diminished pattern separation in F5KO mice can be rescued by delivering irisin directly into the dentate gyrus, suggesting that irisin is the active moiety. In F5KO mice, adult-born neurons in the dentate gyrus are morphologically, transcriptionally and functionally abnormal. Importantly, elevation of circulating irisin levels by peripheral delivery of irisin via adeno-associated viral overexpression in the liver results in enrichment of central irisin and is sufficient to improve both the cognitive deficit and neuropathology in AD mouse models. Irisin is a crucial regulator of the cognitive benefits of exercise and is a potential therapeutic agent for treating cognitive disorders including AD.

Neuregulin (NRG)1 - ErbB receptor signaling has been shown to play an important role in the biological function of peripheral microvascular endothelial cells. However, little is known about how NRG1/ErbB signaling impacts brain endothelial function and blood-brain barrier (BBB) properties. NRG1/ErbB pathways are affected by brain injury; when brain trauma was induced in mice in a controlled cortical impact model, endothelial ErbB3 gene expression was reduced to a greater extent than that of other NRG1 receptors. This finding suggests that ErbB3-mediated processes may be significantly compromised after injury, and that an understanding of ErbB3 function would be important in the of study of endothelial biology in the healthy and injured brain. Towards this goal, cultured brain microvascular endothelial cells were transfected with siRNA to ErbB3, resulting in alterations in F-actin organization and microtubule assembly, cell morphology, migration and angiogenic processes. Importantly, a significant increase in barrier permeability was observed when ErbB3 was downregulated, suggesting ErbB3 involvement in BBB regulation. Overall, these results indicate that neuregulin-1/ErbB3 signaling is intricately connected with the cytoskeletal processes of the brain endothelium and contributes to morphological and angiogenic changes as well as to BBB integrity.

We previously demonstrated that a protein’s immunogenicity could be substantially increased by attaching a hydrophobic solubility controlling peptide tag (SCP-tag) producing small sub-visible aggregates. Here, we report the oligomerization of Dengue envelop protein domain 3 (ED3), and consequently, its immunogenicity increase by mixing ED3s attached with SCP-tags of opposite charges at equimolar concentration. We used ED3 of serotype 3 (D3ED3) and serotype 4 (D4ED3), which are, respectively, moderately and poorly immunogenic, and their SCP tagged variants constructed by attaching either a C-termini 5-Aspartic acid (C5D) or a 5-Lysine (C5K) tag. Light scattering indicated that the isolated tagged ED3s remained monomeric, but mixing the C5D and C5K tagged ED3s at equimolar concentration generated sub-visible aggregates or oligomers of ~500 nm through electrostatic interaction. In addition, the oligomerized ED3s remained in a native-like state, as assessed by fluorescence spectroscopy and circular dichroism. The in vivo immunogenicity of the D3ED3 and D4ED3 oligomers generated by the charged tags increased by 5 and 16 fold, respectively. Furthermore, injection of heterotypic ED3 oligomers (D3C5D+D4C5K) induced an immune response against both D3ED3 and D4ED3 in 3 of 4 responsive mice, and the IgG titer of the bivalent anti-D3C5D-D4C5K sera was over 100 times higher than that generated by co-injecting the untagged D3ED3 and D4ED3 (D3+D4). Altogether, these observations suggest that SCP-tags could be used as a platform for producing a long-sought tetravalent dengue vaccine.

Purposes: Dengue fever, a mosquito-borne viral disease, is a global public health burden affecting millions of people each year and over 40% of world populations are at risk of dengue. Therefore, prompt and accurate dengue diagnosis is inevitable for disease surveillance and for aiding disease management. In this study we report dengue virus (DENV) seroprevalence in Chittagong, Bangladesh along with clinical manifestation of dengue infections. Methods: All samples included in this study were selected based on dengue NS1-based diagnosis, clinical sign and symptoms were judged by expert clinical physicians and infecting DENV serotyping was done by RT-PCR. The blood cells (Platelet, Haematocrit, WBC etc) were analyzed using Haematology cell counter. Results: First, among the 112 DENV infected serum samples tested by RT-PCR, 42 were DENV positive where 76% samples had single DENV serotype infection and 24% were concurrently infected with two or more DENV serotypes, indicating that all four DENVs were present in a single dengue session in Chittagong, Bangladesh. Then, DENV4 was the most prevailed serotype, followed by DENV2, DENV1 and DENV3 in single DENV serotype infections. However, in almost 90% cases of concurrent multiple DENV infections DENV1 serotype was present. A detail analysis of clinical data clearly indicated that DENV1 and DENV2 resulted very similar patterns of clinical symptoms which were quite different from those caused by DENV3 and DENV4. For example, ache and pain were absent in DENV3 infection and diarrhea was absent in DENV4 infections. Furthermore, DENV3, both in single and concurrent multiple DENV infections, might increase dengue disease severity as observed highly reduced platelet counts along with increased WBC in patients infected with DENV3 serotype. Conclusion: All four DENV serotypes, both as single and concurrent multiple DENV infections, were present in single dengue session in Bangladesh. Despite having very similar sequences and structures all four DENVs might produce different disease spectra, ranging from classical dengue fever to dengue hemorrhagic fever. Concurrent multiple DENV infections could contribute increased dengue disease severity in dengue outbreaks in Bangladesh. Bioresearch Commu. 8(1): 1042-1048, 2022 (January)

Objective Identification of cellular defects underlying hypercholesterolemia in individual persons remains challenging. We aimed at establishing high-content assays for the quantitative assessment of lipid uptake and removal in accessible primary human cells to obtain new insights into the disease. Approach and Results We set up a multiparametric imaging platform for the quantification of LDL uptake and lipid storage in cytoplasmic droplets of leukocyte populations from peripheral blood. The 39 individuals from the FINRISK2012 cohort and 23 heterozygous familial hypercholesterolemia (He-FH) patients from the METSIM cohort displayed variable LDL uptake, including patients carrying identical LDLR mutations. Moreover, He-FH patients that remained hypercholesterolemic despite statin treatment displayed low monocyte LDL uptake. In non-FH individuals, reduced LDL uptake correlated with higher body mass index (BMI) and larger hip circumference. Cellular lipid droplet quantifications enabled us to define a new parameter, lipid mobilization, describing the efficiency with which cells depleted their lipid reservoirs. Lipid mobilization correlated positively with LDL uptake and negatively with hypercholesterolemia and age, differentiating individuals with normal and elevated LDL-cholesterol (LDL-c) better than LDL uptake. Moreover, combination of cell-based readouts with a polygenic risk score for LDL-c explained hypercholesterolemia better than the genetic risk score alone. Conclusions This study demonstrates how multiplexed cell-based assays, including novel quantifiable parameters for lipid removal, provide handles to dissect the hetereogeneity of defects contributing to hypercholesterolemia at the level of individuals. Graphical Abstract

Recombinant proteins are an attractive choice as a safe alternative to traditional live attenuated vaccines. However, most small-size proteins are poorly immunogenic, and adjuvants, whose mode of action remain to be fully clarified, are needed for increasing their immunogenicity. Here, we report the effects of short solubility controlling peptide tags (SCP-tags) on the immunogenicity of DENV3 envelope protein domain 3 (3ED3; 103 residues, 11.46 kDa) in ICR and Swiss albino model mice. The attachment of a 4-Ile SCP-tag (C4I-tag) increased the hydrodynamic radius of 3ED3 from 2.2 ± 0.09 to 111 ± 146 nm as assessed by dynamic light scattering in phosphate buffered saline at 37°C, indicating that the C4I-tag oligomerized 3ED3. Immunization at 30 μg/dose showed that the untagged 3ED3 was not or poorly immunogenic, whereas the C4I-tag increased its immunogenicity by up to 39-fold as assessed by the IgG level measured using ELISA. Moreover, the increased antibody level was sustained for over 6 months after immunization and a high number of effector and central memory T cells were generated. These observations provide solid and quantitative evidence for the hypothesis that subvisible aggregates with hydrodynamic radii of 100 nm can increase immunogenicity and that SCP-tag can establish a long-term, target-specific immune response in a way adequate for the development of a peptide/protein-based DENV vaccine.

Article History Received: 3 August 2020 Revised: 16 September 2020 Accepted: 28 September 2020 Published: 8 October 2020

BACKGROUND:Despite considerable research on exercise-induced neuroplasticity in the brain, a major ongoing challenge in translating findings from animal studies to humans is that clinical and preclinical settings employ very different techniques.OBJECTIVE:Here we aim to bridge this divide by using diffusion tensor imaging MRI (DTI), an advanced imaging technique commonly applied in human studies, in a longitudinal exercise study with mice.METHODS:Wild-type mice were exercised using voluntary free-wheel running, and MRI scans were at baseline and after four weeks and nine weeks of running.RESULTS:Both hippocampal volume and fractional anisotropy, a surrogate for microstructural directionality, significantly increased with exercise. In addition, exercise levels correlated with effect size. Histological analysis showed more PDGFRα+ oligodendrocyte precursor cells in the corpus callosum of running mice.CONCLUSIONS:These results provide compelling in vivo support for the concept that similar adaptive changes occur in the brains of mice and humans in response to exercise.

Objective To determine if CSF and plasma levels of soluble vascular endothelial (sVE)-cadherin are associated with functional outcome after subarachnoid hemorrhage (SAH) and to investigate sVE-cadherin effects on microglia. Methods Serial CSF and plasma were collected from prospectively enrolled patients with nontraumatic SAH from a ruptured aneurysm in the anterior circulation and who required an external ventricular drain for clinical indications. Patients with normal-pressure hydrocephalus without SAH served as controls. For prospective assessment of long-term outcomes at 3 and 6 months after SAH, modified Rankin Scale scores (mRS) were obtained and dichotomized into good (mRS ≤ 2) vs poor (mRS > 2) outcome groups. For SAH severity, Hunt and Hess grade was assessed. Association of CSF sVE-cadherin levels with long-term outcomes, HH grade, and CSF tumor necrosis factor (TNF)-α levels were evaluated. sVE-cadherin effects on microglia were also studied. Results sVE-cadherin levels in CSF, but not in plasma, were higher in patients with SAH and were associated with higher clinical severity and higher CSF TNF-α levels. Patients with SAH with higher CSF sVE-cadherin levels over time were more likely to develop worse functional outcome at 3 months after SAH. Incubation of cultured microglia with sVE-cadherin resulted in increased inducible nitric oxide synthase, interleukin-1β, reactive oxygen species, cell soma size, and metabolic activity, consistent with microglia activation. Microinjection of sVE-cadherin fragments into mouse brain results in an increased number of microglia surrounding the injection site, compared to injection of denatured vascular endothelial–cadherin fragments. Conclusions These results support the existence of a novel pathway by which sVE-cadherin, released from injured endothelium after SAH, can shift microglia into a more proinflammatory phenotype and contribute to neuroinflammation and poor outcome in SAH.

Segmented regression is a standard statistical procedure used to estimate the effect of a policy intervention on time series outcomes. This statistical method assumes the normality of the outcome variable, a large sample size, no autocorrelation in the observations, and a linear trend over time. Also, segmented regression is very sensitive to outliers. In a small sample study, if the outcome variable does not follow a Gaussian distribution, then using segmented regression to estimate the intervention effect leads to incorrect inferences. To address the small sample problem and non-normality in the outcome variable, including outliers, we describe and develop a robust statistical method to estimate the policy intervention effect in a series of longitudinal data. A simulation study is conducted to demonstrate the effect of outliers and non-normality in the outcomes by calculating the power of the test statistics with the segmented regression and the proposed robust statistical methods. Moreover, since finding the sampling distribution of the proposed robust statistic is analytically difficult, we use a nonparametric bootstrap technique to study the properties of the sampling distribution and make statistical inferences. Simulation studies show that the proposed method has more power than the standard t-test used in segmented regression analysis under the non-normality error distribution. Finally, we use the developed technique to estimate the intervention effect of the Istanbul Declaration on illegal organ activities. The robust method detected more significant effects compared to the standard method and provided shorter confidence intervals.

The electromagnetic radiation from the mobile phone is a subject of recent study because of the enormous increase in mobile phone use throughout the world. The objective of this experiment was therefore to investigate the biochemical and histopathological effects of mobile phone radiation on male Swiss albino mice's liver. Male mice were categorized into three groups in this research: control group (A), exposed group for 40 minutes (B) and exposed group for 60 minutes (C). Experimental groups were exposed to radiation per day for 60 days from 4G connected mobile phones. The control group received no radiation. At the end of the radiation exposure, biochemical (alanine transaminase (ALT) and aspartate transaminase (AST)) and histological tests were performed. The results indicated that there was significant (P<0.05) increase in mean values of ALT and AST in both radiation-exposed groups of mice if compared to the control group. Histopathologically marked infiltration of mononuclear cellular aggregates were present surrounding the bile duct and hepatic artery in the liver of 60-minute-exposure group, whereas in 40-minute-exposure group congestion was observed in the portal vein and the central vein of the liver. The findings revealed and evidenced that mobile phone radiation has harmful effects on enzyme activity and liver tissue.

Direct unimolar one-step valeroylation of methyl α-d-mannopyranoside (MDM) furnished mainly 6-O-valeroate. However, similar reaction catalyzed by DMAP resulted 3,6-di-O-valeroate (21%) and 6-O-valeroate (47%) indicating reactivity sequence as 6-OH>3-OH>2-OH,4-OH. To get potential antimicrobial agents, 6-O-valeroate was converted into four 2,3,4-di-O-acyl esters, and 3,6-di-O-valeroate was converted into 2,4-di-O-acetate. Direct tetra-O-valeroylation of MDM gave a mixture of 2,3,4,6-tetra-O-valeroate and 2,3,6-tri-O-valeroate indicating that the C2-OH is more reactive than the equatorial C4-OH. The activity spectra analysis along with in vitro antimicrobial evaluation clearly indicated that these novel MDM esters had better antifungal activities over antibacterial agents. In this connection, molecular docking indicated that these MDM esters acted as competitive inhibitors of sterol 14α-demethylase (CYP51), an essential enzyme for clinical target to cure several infectious diseases. Furthermore, pharmacokinetic studies revealed that these MDM esters may be worth considering as potent candidates for oral and topical administration. Structure activity relationship (SAR) affirmed that saturated valeric chain (C5) in combination with caprylic (C8) chains was more promising CYP51 inhibitor over conventional antifungal antibiotics.

BACKGROUND:A severe shortage in donor organs is the major driver for organ transplantation-related crimes. The Declaration of Istanbul 2008 (DOI) was created to stop such crimes. We investigated the impact of DOI on Internet reporting of transplantation-related crimes.METHODS:We conducted Google Advanced Searches to collect data on "kidney trade," "kidney sale," "organ trafficking," and "transplant tourism" in 15 original participant and 10 nonparticipant countries, 6 years prior through 8 years after the promulgation of DOI. The data were normalized for population and transformed to a logarithmic scale. Interrupted time series analysis (ITSA) was applied to estimate the changes in slopes of the outcome variables before and after DOI, and then the overall intervention impact was calculated by meta-analysis.RESULTS:The combined results indicated that the overall impact of DOI on the reporting of "organ trafficking" and "transplant tourism" was statistically negative (reporting reduced significantly) as intended but on "kidney sale" and "kidney trade" was statistically positive (reporting increased significantly), and the increase was higher in the nonparticipant countries compared to the participant countries. The rate of reporting on "transplant tourism" declined in the participant countries more pronouncedly than in the nonparticipant countries.CONCLUSIONS:DOI has a positive impact on the reporting of "organ trafficking" and "transplant tourism" but not on the reporting of "kidney sale" and "kidney trade." The increased reporting of "kidney sale" and "kidney trade" can be indicative of an impact of DOI on public awareness and increased reporting of the residual transplantation-related crimes.

Poor immunogenicity of small proteins is a major hurdle in developing vaccines or producing antibodies for biopharmaceutical usage. Here, we systematically analyzed the effects of 10 solubility controlling peptide tags (SCP-tags) on the immunogenicity of a non-immunogenic model protein, bovine pancreatic trypsin inhibitor (BPTI-19A; 6 kDa). CD, fluorescence, DLS, SLS, and AUC measurements indicated that the SCP-tags did not change the secondary structure content nor the tertiary structures of the protein nor its monomeric state. ELISA results indicated that the 5-proline (C5P) and 5-arginine (C5R) tags unexpectedly increased the IgG level of BPTI-19A by 240- and 73-fold, respectively, suggesting that non-oligomerizing SCP-tags may provide a novel method for increasing the immunogenicity of a protein in a highly specific manner.

Sub-visible aggregates of proteins are suspected to cause adverse immune response, and a recent FDA guideline has recommended the monitoring of micrometer-size aggregates (2-10 μm) though recognizing that the underlying mechanism behind aggregation and immunogenicity remains unclear. Here, we report a correlation between the immunogenicity and the size of nanometer-scale aggregates of a small 6.5 kDa model protein, Bovine Pancreatic Trypsin Inhibitor (BPTI) variant. BPTI-19A, a monomeric and non-immunogenic protein, was oligomerized into sub-visible aggregates with hydrodynamic radii ( R h) of 3~4 nm by attaching hydrophobic solubility controlling peptide (SCP) tags to its C-terminus. The results showed that the association of non-immunogenic BPTI into nanometer-size aggregates made it highly immunogenic, as assessed by the IgG antibody titers of the mice’s sera. Overall, the study emphasizes that sub-visible aggregates, as small as a few nanometers, which are presently ignored, are worth monitoring for deciphering the origin of undesired immunogenicity of therapeutic proteins.

Small proteins are generally non-immunogenic, which can be a major hurdle in developing protein and peptide vaccines or producing antibodies for biopharmaceutical usage. For improving a protein’s immunogenicity, we previously proposed to use short Solubility Controlling Peptide (SCP) tags that oligomerize proteins into soluble aggregates. Here, we systematically analyzed the effect of SCP-tags that do not induce oligomerization on the immunogenicity of a small, non-immunogenic, model protein, Bovine Pancreatic Trypsin Inhibitor (BPTI-19A; 6 kDa). We assessed the effect of the following ten SCP-tags: Six tags made of five consecutive Arg, Lys, His, Asp, Asn, Pro; one made of seven Pro; two tags made of consecutive Arg-lle and Asn-Ile, all attached at the C-terminus of BPTI-19A; and a 5-proline tag attached at the N-terminus. Circular dichroism, fluorescence, dynamic light scattering measurements, and analytical ultra-centrifugation indicated that the addition of the SCP-tags did not change the secondary structure content nor the tertiary structures of the protein nor its monomeric state. On the other hand, the C-terminus 5-proline (C5P) tag unexpectedly increased the immunogenicity (IgG level) of BPTI-19A by up to 240 fold as assessed by ELISA. Additionally, the 5-arginine tag (C5R) increased the titer by up to 73 fold. The titer increase lasted for several weeks, and the effect was cumulative to that of the Freund’s adjuvant, which is commonly used to boost a protein’s immunogenicity. Altogether, SCP-tags that do not oligomerize proteins substantially increased the immunogenicity of a non-immunogenic protein, suggesting that the 5-proline and the 5-arginine SCP-tags may provide a novel tool for facilitating the production of antibodies or improving the effectiveness of protein-based vaccines. ### Competing Interest Statement The authors have declared no competing interest. * BPTI : Bovine Pancreatic Trypsin Inhibitor CD : Circular Dichroism DLS : Dynamic Light Scattering SLS : Static Light Scattering AUC : Analytical Ultra Centrifugation SCP-tags : Solubility Controlling Peptide tags ELISA : Enzyme-Linked Immunosorbent Assay

There is increasing interest in using various indices to assess soil health; however, the nature of the within‐field variation in such indices, and their relationship with soil properties, are generally unknown. This study examined the spatial variation of 15 soil health indices in a 21‐ha commercial potato field in New Brunswick, Canada. Soil samples (0–15 cm depth) were collected in spring of 2016 at 154 geo‐referenced locations within the field. With the exception of CaCl 2 extractable NH 4 –N, all soil parameters demonstrated strong or moderate spatial dependence. Several soil properties were significantly correlated, for example, soil organic carbon was strongly positively correlated with indices of soil C availability, soil N availability and soil physical properties. Principal Component Analysis suggested that the parameters fell into three major groups: PC1 (39.9% of total variance) was associated primarily with parameters related to the quantity of soil organic matter; PC2 (15.3% of total variance) with parameters related to soil organic matter quality; and PC3 (10.3% of total variance) with parameters related to soil structure. In comparison, the spatial pattern of total tuber yield was related to soil texture and soil drainage and was most strongly correlated with indices of soil organic matter quality (PC2). Soil management zones and mapped soil series were both generally effective in capturing the spatial variation in soil health indices and can be used to stratify the sampling of soil health indices in spatially variable fields.