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Several therapies have shown obvious effects on structural conservation contributing to motor functional recovery after spinal cord injury (SCI). Nevertheless, neither strategy has achieved a convincing effect. We purposed a combined therapy of immunomodulatory peptides that individually have shown significant effects on motor functional recovery in rats with SCI. The objective of this study was to investigate the effects of the combined therapy of monocyte locomotion inhibitor factor (MLIF), A91 peptide, and glutathione monoethyl ester (GSH-MEE) on chronic-stage spinal cord injury. Female Sprague-Dawley rats underwent a laminectomy of the T9 vertebra and a moderate contusion. Six groups were included: sham, PBS, MLIF + A91, MLIF + GSH-MEE, A91 + GSH-MEE, and MLIF + A91 + GSH-MEE. Two months after injury, motor functional recovery was evaluated using the open field test. Parenchyma and white matter preservation was evaluated using hematoxylin & eosin staining and Luxol Fast Blue staining, respectively. The number of motoneurons in the ventral horn and the number of axonal fibers were determined using hematoxylin & eosin staining and immunohistochemistry, respectively. Collagen deposition was evaluated using Masson’s trichrome staining. The combined therapy of MLIF, A91, and GSH-MEE greatly contributed to motor functional recovery and preservation of the medullary parenchyma, white matter, motoneurons, and axonal fibres, and reduced the deposition of collagen in the lesioned area. The combined therapy of MLIF, A91, and GSH-MEE preserved spinal cord tissue integrity and promoted motor functional recovery of rats after SCI. This study was approved by the National Commission for Scientific Research on Bioethics and Biosafety of the Instituto Mexicano del Seguro Social under registration number R-2015-785-116 (approval date November 30, 2015) and R-2017-3603-33 (approval date June 5, 2017).

Tuberculosis is one of the leading causes of mortality in the world despite multiple control and treatment strategies. Disseminated tuberculosis corresponds to 5% of cases. We report the first case in literature of an adolescent patient with type 1 diabetes mellitus and disseminated tuberculosis, who had constitutional symptoms associated with low back pain and was initially, interpreted initially as noninfectious sacroiliitis and a probable inflammatory bowel disease.

Using distribution data of 131 terrestrial bird species on 17 islands of the Archipelago Sabana–Camagüey, Cuba, we tested for non–randomness in presence–absence matrices with respect to co–occurrence and nestedness. We conducted separate analyses for the whole assemblage and sub–matrices according to trophic levels and residence status (breeding and migratory). We also explored the influence of weighting factors such as island area and isolation. The C–occurrence analyses were susceptible to the species subsets and the weighting factors. Unweighted analyses revealed a significant negative co–occurrence pattern for the entire assemblage and for most sub–matrices. The area weighted analyses always indicated strong non–random structure. However, an analysis with intra–guild species pairs showed that most pairs were randomly assembled; very few pairs had a significant segregated pattern. Bird assemblages followed a nested subset structure across islands. Nestedness was strongly correlated with area and unrelated with island isolation. Overall, this study suggests that terrestrial bird assemblages were shaped by extinction processes mediated through area effects rather than interspecific trophic guild competition. Data suggest that conservation of largest islands will guarantee high terrestrial bird richness on the archipelago.

The deep study of archaeological human bone could provide relevant information to biomaterials science, as it could tell how the implant process of bioglasses and bioresorbable ceramics is. In this paper, we propose to study, by means of different microscopic, spectroscopic, and X-ray diffraction techniques, the histological and mineral bone variability throughout ontogeny. Extrapolating this data, we could have a better knowledge of biodegradable materials implant. In different ages, we could notice different tissues in cortical bone: fibrolamellar bone is characteristic of early stages of life while secondary or harvesian bone is in adult individuals. Raman and infrared spectroscopy suggest an increase of critallinity in the inorganic matrix during live. Finally, the X-ray diffraction study of bone tissue shows β-calcium phosphate and hydroxyapatite as the main mineral bone components.El estudio en profundidad del hueso humano arqueológico puede aportar información relevante a la ciencia de los biomateriales, al informar sobre la evolución del proceso de implante de biovidrios o biocerámicas reabsorbibles. En este trabajo, se propone una aproximación, mediante diferentes técnicas de microscopía, espectroscopía y difracción de rayos X, a la variabilidad histológica y mineral del tejido óseo en el transcurso de la ontogenia y así, poder realizar una extrapolación que permita comprender mejor el implante de materiales biodegradables. Respecto a la variabilidad histológica, se han observado diferentes tipos de tejidos en la cortical del hueso en las distintas edades, siendo el hueso fibrolaminar principal en etapas tempranas de la vida, y el hueso secundario o haversiano en etapas adultas. Los análisis de espectroscopía Raman e infrarroja indican un aumento en la cristalinidad de la parte inorgánica del hueso a lo largo del ciclo vital. Por último, el estudio del tejido óseo mediante difracción de rayos X muestra la presencia de β-fosfato de calcio e hidroxiapatito como componentes minerales principales del hueso.

In recent years, attention has focused on addressing the environmental problems caused by the use of construction materials, proposing to develop new environmentally friendly concrete; One of the alternatives that has emerged is to replace cement or aggregates with agricultural waste because its treatment is expensive and not very sustainable; This is the case of rice husk ash (RHA), the main agricultural residue resulting from this cereal, which represents an abundant production worldwide. Marine reinforced concrete structures are in constant exposure to the marine environment, so that their structural capacity and useful life are affected by the breakdown of aggregates, which cause a greater amount of free CaO and MgO in concrete mixtures, and the penetration of chloride ions, which destroy the passive layer of steel and produce cracks in the concrete that cause loss of load and structural damage. In this investigation, cylindrical specimens of conventional concrete and sustainable concrete with cement replacement percentages of 5%, 10% and 15% RHA have been developed. The results show that for a 5% RHA replacement, the compressive strength is greater than conventional concrete at an early age; the disintegration of the aggregates decreases, being for the fine of 9.86% and for the coarse aggregate of 4.34%, the penetrability of sulfate ions decreases as the percentage of RHA replacement increases, the permeability of conventional concrete is much greater with respect to RHA replacement concrete and, finally, the unit cost analysis per cubic meter of RHA concrete is less than conventional concrete

Resumen: El cine puede ser un instrumento de análisis y reflexión acerca de la ocupación humana y de los aspectos que hacen emergerla y mantenerla.Objetivo y método: Análisis descriptivo-interpretativo del rol ocupacional del protagonista de la película “El hijo de la Novia” desde la visión fenomenológica del Modelo de Ocupación Humana.Conclusiones: “El hijo de la novia” demuestra la elección de roles ocupacionales motivados por los valores propios de la persona, sus intereses y su sentido de eficacia e influenciados por el ambiente.AbstractCinema may be a good tool for the analysis and reflection about human occupation and the aspects which make its emergency and maintenance.Objective and Method: Descriptive-interpretative analysis of the occupational roles of the film characters in "Son of the bride" from the phenomenologic viewpoint of Model of Human Occupation.Conclusions: The film of "Son of the bride" shows the choice of occupational roles run by the individual's values, and their interests, and efficiency influenced by environment.

Introduction: Digital contact-tracing smartphone apps have the potential to slow the spread of disease but are not widely used. We tested whether messages describing how a COVID-19 digital contact-tracing app protects users’ privacy led to increased or decreased intentions to download the app by either calming privacy concerns or increasing their saliency. Design: Randomized controlled trial. Setting/participants: We recruited adult smartphone owners in the U.S. (oversampled for younger adults aged 18–34 years) in November 2020 through an online panel. Intervention: Survey software randomly assigned 860 participants to 1 of 2 parallel messaging conditions (n=430 privacy assured, n=430 no privacy described). Main outcome measures: 4-point scale of intention to use the app “if public health officials released a COVID Exposure Notification app in their state” that averaged likelihood to (1) download and install the app on their phone; (2) keep the app active on their phone; and (3) keep Bluetooth active on their phone (needed for the app to work). Results: After removing incompletes, those who failed the manipulation checks, or those who had already downloaded a COVID-19 digital contact-tracing app, we analyzed 671 participants (n=330 privacy, n=341 no privacy) in 2021. There was no relationship between privacy condition and download intention (meanprivacy=2.69, meannoprivacy=2.69, b=0.01, 95% CI= –0.13, 0.15, p=0.922) but also no evidence that describing the app's security increased context-dependent privacy concerns (measured 3 ways). Instead, we found increased endorsement of data security in the privacy condition using a scale of beliefs about the app keeping privacy secure (meanprivacy=2.74, meannoprivacy=2.58, b=0.16, 95% CI=0.04, 0.28, p=0.009, small effect ω2=0.009). Conclusions: This study provides some evidence that people developing contact-tracing messaging campaigns do not need to worry that describing a digital contact-tracing app's privacy protections will backfire. Future mixed methods testing of messages about who has access to information—and for how long—may uncover new communication strategies to increase public trust in contact-tracing apps. Trial registration: This study is registered with AsPredicted#51826

Copyright © 2020 Harris. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Castor bean (Ricinus communis) is cultivated agriculturally for oil and ornamentally for its bright foliage and seed. Ornamental castor bean has naturalized in many areas of the world, including the state of Sinaloa, Mexico, where it is not planted commercially. In a survey conducted in 2019 in Sinaloa, wild castor bean was found widely affected by a foliar blight with symptoms similar to Alternaria ricini previously described in the United States (Stevenson 1945) and in the state of Chiapas, Mexico (López-Guillén et al. 2015). Sampling was conducted from February to April along roadsides and irrigation canals at 10 sites that were 10-12 km apart. Symptoms consisted of dark lesions < 2 cm dia with occasional concentric rings and coalescing with age. Incidence of disease among sites ranged from 20 to 60%. The severity of disease was greater in the lower canopy where the foliage area diseased (FAD) ranged from 15 to 35%. Ten symptomatic leaves were collected from each site and leaf fragments were plated on potato dextrose agar (PDA) using standard microbiological techniques for fungal recovery. Isolates of long-beaked Alternaria were recovered from 60 to 70% of fragments from each site and representative isolates (1/site) were selected for further studies. Isolates were transferred to Petri dishes containing PDA for characterization of the colony and V8 juice agar (V8A) for examination of the conidia (Simmons 2007). On PDA, colonies were dark olive brown, cottony, subsurface microsclerotia production abundant, and no production of pigments in the medium. On V8A, conidia were produced singly, darkly pigmented, and broadly ellipsoidal. The length and width of mature conidia ranged 70 to 100 µm (avg 88 µm) and 17 to 26 µm (avg 22 µm), respectively, with 2 to 4 transepta and 1 to 3 longisepta. The apical beak length ranged 10 to 125 um (avg 72 µm). Morphological characteristics were consistent with those of A. ricini from commercial castor bean (Simmons 2007). DNA was extracted from each isolate and the GAPDH and calmodulin genes were sequenced using protocol previously described (Lawrence et al. 2013). For each locus, sequences were identical among fungal isolates and representative sequences were deposited in GenBank (accessions OQ868796 and OQ868803, respectively). When compared to the NCBI database by BLASTn, the sequences had 100% identities to A. ricini GAPDH JQ646331 (576/576 bp) and A. ricini calmodulin JQ646230 (772/772 bp). To confirm pathogenicity of recovered Alternaria, all ten isolates were tested on the commercial castor bean cultivar Chinatan in two independent greenhouse trials. Seed was sown one per pot and four plants per isolate were tested. Spore solutions were prepared from V8A plates and spore densities were adjusted to 4 x 104 conidia/ml. At 4 to 5 leaves stage, plants were sprayed with spore solution until runoff, placed in clear polyethylene bags for 48 hr. After 14 dpi, the percentage of FAD ranged from 19 to 80% with significant differences among fungal isolates. Control plants sprayed with water remained healthy. To fulfill Koch´s postulates, the fungus was re-isolated from representative inoculated plants and its identity was confirmed using morphological characteristics. This is the first report of A. ricini causing foliar blight of castor bean in the state of Sinaloa, Mexico. Strategies for managing inoculum from wild castor bean should be developed in advance of increasing commercial castor production in Sinaloa.

Polarizable force fields crucially enhance the modeling of macromolecules in polar media. Here, we present new parameters to model six common monosaccharides with the polarizable AMOEBA force field. These parameters yield a thinner, but denser, hydration layer than that previously reported. This denser hydration layer results in eliminating non-physical aggregation of glucose in water-an issue that has plagued molecular dynamics simulations of carbohydrates for decades.

Utilizing waxes to gel oils presents a viable approach for diminishing trans and saturated fat levels in commercial fats such as margarines. This technique ensures that oleogels mimic traditional fats in terms of rheological properties, oil-binding capacity, and overall structure. Our study employed cooling-shear rates to finely adjust physical characteristics, evaluating rheology via SAOS-LAOS, oil retention, and crystal structure of wax oleogels, compared against commercial margarines as benchmarks. Findings indicate that wax oleogels, under specific cooling/shear conditions, exhibit softer yet more ductile-like behavior, akin to margarine, while retaining oil effectively. This similarity is evidenced through Lissajous curves and plastic dissipation ratio during yielding, reflecting a ductile yielding response characterized by square-like Lissajous curves and a plastic dissipation ratio index approximating one. Although these crystallization conditions influence the mechanical properties of wax oleogels, they do not alter oil losses or wax characteristics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background and Objectives: Nucleic acid-amplification testing (NAT) is used for screening blood donations/donors for blood-borne viruses. We reviewed global viral NAT characteristics and NAT-yield confirmatory testing used by blood operators., Materials and Methods: NAT characteristics and NAT-yield confirmatory testing used during 2019 was surveyed internationally by the International Society of Blood Transfusion Working Party Transfusion-Transmitted Infectious Diseases. Reported characteristics are presented herein., Results: NAT was mainly performed under government mandate. Human immunodeficiency virus (HIV), hepatitis C virus (HCV) and hepatitis B virus (HBV) NAT was performed on all donors and donation types, while selective testing was reported for West Nile virus, hepatitis E virus (HEV), and Zika virus. Individual donation NAT was used for HIV, HCV and HBV by ~50% of responders, while HEV was screened in mini-pools by 83% of responders performing HEV NAT. Confirmatory testing for NAT-yield samples was generally performed by NAT on a sample from the same donation or by NAT and serology on samples from the same donation and a follow-up sample., Conclusion: In the last decade, there has been a trend towards use of smaller pool sizes or individual donation NAT. We captured characteristics of NAT internationally in 2019 and provide insights into confirmatory testing approaches used for NAT-yields, potentially benefitting blood operators seeking to implement NAT., (© 2024 The Authors. Vox Sanguinis published by John Wiley & Sons Ltd on behalf of International Society of Blood Transfusion.)

Cordycepin, or 3'-deoxyadenosine, is an adenosine analog with a broad spectrum of biological activity. The key structural difference between cordycepin and adenosine lies in the absence of a hydroxyl group at the 3' position of the ribose ring. Upon administration, cordycepin can undergo an enzymatic transformation in specific tissues, forming cordycepin triphosphate. In this study, we conducted a comprehensive analysis of the structural features of cordycepin and its derivatives, contrasting them with endogenous purine-based metabolites using chemoinformatics and bioinformatics tools in addition to molecular dynamics simulations. We tested the hypothesis that cordycepin triphosphate could bind to the active site of the adenylate cyclase enzyme. The outcomes of our molecular dynamics simulations revealed scores that are comparable to, and superior to, those of adenosine triphosphate (ATP), the endogenous ligand. This interaction could reduce the production of cyclic adenosine monophosphate (cAMP) by acting as a pseudo-ATP that lacks a hydroxyl group at the 3' position, essential to carry out nucleotide cyclization. We discuss the implications in the context of the plasticity of cancer and other cells within the tumor microenvironment, such as cancer-associated fibroblast, endothelial, and immune cells. This interaction could awaken antitumor immunity by preventing phenotypic changes in the immune cells driven by sustained cAMP signaling. The last could be an unreported molecular mechanism that helps to explain more details about cordycepin's mechanism of action., Competing Interests: The authors declare no conflicts of interest.

Gels composed of multicomponent building blocks offer promising opportunities for the development of novel soft materials with unique and useful structures. While interpenetrating polymer networks have been extensively studied and applied in the creation of these gels, equivalent strategies utilizing colloidal particles have received limited scientific and technological attention. This study presents a novel class of thermo-responsive apolar double gels from interpenetrating networks of attractive colloidal silica and lipid particles. These double gels are easily assembled and suitable for the fabrication of 3D-printed edible soft constructs. Emphasis is focused on the rheological properties and structure emerging on the dilute regime ( ϕ ≲ 0.1). Rheological investigations demonstrate that double gels exhibit greater stiffness and resilience to yielding compared to their single lipid gel counterparts. The scaling behavior of the oscillatory linear shear moduli and the critical strain for yielding with volume fraction remain comparable between single and double gels. Creep yielding in double gels exhibits two exponential decay regimes, suggesting the presence of thicker gel strands undergoing flow. Visualization and quantification of the quiescent microstructure confirms the existence of such denser aggregates devoid of larger clusters due to steric hindrance of interpenetrating networks in double gels. This is in stark contrast to lipid single gels where aggregates grow unrestrictedly into larger clusters. Our study constitutes the first demonstration on the assembly of apolar double gel networks as a promising avenue for the design of novel soft materials and foods with tailored structure and mechanics.

Background and Objectives: Nucleic acid amplification testing (NAT), in blood services context, is used for the detection of viral and parasite nucleic acids to reduce transfusion-transmitted infections. This project reviewed NAT for screening blood donations globally., Materials and Methods: A survey on NAT usage, developed by the International Society of Blood Transfusion Working Party on Transfusion-transmitted Infectious Diseases (ISBT WP-TTID), was distributed through ISBT WP-TTID members. Data were analysed using descriptive statistics., Results: Forty-three responses were received from 32 countries. Increased adoption of blood donation viral screening by NAT was observed over the past decade. NAT-positive donations were detected for all viruses tested in 2019 (proportion of donations positive by NAT were 0.0099% for human immunodeficiency virus [HIV], 0.0063% for hepatitis C virus [HCV], 0.0247% for hepatitis B virus [HBV], 0.0323% for hepatitis E virus [HEV], 0.0014% for West Nile virus [WNV] and 0.00005% for Zika virus [ZIKV]). Globally, over 3100 NAT-positive donations were identified as NAT yield or solely by NAT in 2019 and over 22,000 since the introduction of NAT, with HBV accounting for over half. NAT-positivity rate was higher in first-time donors for all viruses tested except WNV. During 2019, a small number of participants performed NAT for parasites (Trypanosoma cruzi, Babesia spp., Plasmodium spp.)., Conclusion: This survey captures current use of blood donation NAT globally. There has been increased NAT usage over the last decade. It is clear that NAT contributes to improving blood transfusion safety globally; however, there is a need to overcome economic barriers for regions/countries not performing NAT., (© 2024 The Authors. Vox Sanguinis published by John Wiley & Sons Ltd on behalf of International Society of Blood Transfusion.)

Background: In Cuba, little is known regarding the prevalence of Chlamydia trachomatis (CT) infection in adolescents and young people. We study the frequency of CT infection in these populations, and its association with clinical-epidemiological variables., Methods: A total of 496 individuals aged 12 to 24 were recruited from November 2018 to November 2019. Of them, 302 were patients attending at sexually transmitted infections (STI) services and 194 were young volunteers. CT detections were carried out by real-time PCR and IgG serology., Results: The prevalence of CT using PCR was 9.1% (45/496); 12.3% (37/302) for subjects attending STI service and 4.1% (8/194) for young volunteers, being significantly higher in the first group (OR=3.25; p =.001). CT IgG antibodies was detected in 38.6% (81/210). Individuals from 12 to 17 years old were more likely infected with CT (OR=2.21; p =.010). Infection was associated with the early onset of sexual intercourse, the frequent changing of sexual partners and black ethnicity., Conclusions: The results suggest that Cuban adolescents and young populations are at highest risk of acquiring CT infection and developing reproductive complications. The data obtained advise the needs of implementation of a routine CT screening strategy, for timely diagnosis, detection and treatment at the earliest ages., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

One of the main challenges in the fight against coronavirus disease 2019 (COVID-19) stems from the ongoing evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into multiple variants. To address this hurdle, research groups around the world have independently developed protocols to isolate these variants from clinical samples. These isolates are then used in translational and basic research-for example, in vaccine development, drug screening or characterizing SARS-CoV-2 biology and pathogenesis. However, over the course of the COVID-19 pandemic, we have learned that the introduction of artefacts during both in vitro isolation and subsequent propagation to virus stocks can lessen the validity and reproducibility of data. We propose a rigorous pipeline for the generation of high-quality SARS-CoV-2 variant clonal isolates that minimizes the acquisition of mutations and introduces stringent controls to detect them. Overall, the process includes eight stages: (i) cell maintenance, (ii) isolation of SARS-CoV-2 from clinical specimens, (iii) determination of infectious virus titers by plaque assay, (iv) clonal isolation by plaque purification, (v) whole-virus-genome deep-sequencing, (vi and vii) amplification of selected virus clones to master and working stocks and (viii) sucrose purification. This comprehensive protocol will enable researchers to generate reliable SARS-CoV-2 variant inoculates for in vitro and in vivo experimentation and will facilitate comparisons and collaborative work. Quality-controlled working stocks for most applications can be generated from acquired biorepository virus within 1 month. An additional 5-8 d are required when virus is isolated from clinical swab material, and another 6-7 d is needed for sucrose-purifying the stocks., (© 2023. Springer Nature Limited.)

Chikungunya virus (CHIKV) infection has been associated with severe cardiac manifestations, yet, how CHIKV infection leads to heart disease remains unknown. Here, we leveraged both mouse models and human primary cardiac cells to define the mechanisms of CHIKV heart infection. Using an immunocompetent mouse model of CHIKV infection as well as human primary cardiac cells, we demonstrate that CHIKV directly infects and actively replicates in cardiac fibroblasts. In immunocompetent mice, CHIKV is cleared from cardiac tissue without significant damage through the induction of a local type I interferon response from both infected and non-infected cardiac cells. Using mice deficient in major innate immunity signaling components, we found that signaling through the mitochondrial antiviral-signaling protein (MAVS) is required for viral clearance from the heart. In the absence of MAVS signaling, persistent infection leads to focal myocarditis and vasculitis of the large vessels attached to the base of the heart. Large vessel vasculitis was observed for up to 60 days post infection, suggesting CHIKV can lead to vascular inflammation and potential long-lasting cardiovascular complications. This study provides a model of CHIKV cardiac infection and mechanistic insight into CHIKV-induced heart disease, underscoring the importance of monitoring cardiac function in patients with CHIKV infections., (© 2023. Springer Nature Limited.)

Small animal models have been a challenge for the study of SARS-CoV-2 transmission, with most investigators using golden hamsters or ferrets. Mice have the advantages of low cost, wide availability, less regulatory and husbandry challenges, and the existence of a versatile reagent and genetic toolbox. However, adult mice do not robustly transmit SARS-CoV-2. Here we establish a model based on neonatal mice that allows for transmission of clinical SARS-CoV-2 isolates. We characterize tropism, respiratory tract replication and transmission of ancestral WA-1 compared to variants Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Omicron BA.1 and Omicron BQ.1.1. We identify inter-variant differences in timing and magnitude of infectious particle shedding from index mice, both of which shape transmission to contact mice. Furthermore, we characterize two recombinant SARS-CoV-2 lacking either the ORF6 or ORF8 host antagonists. The removal of ORF8 shifts viral replication towards the lower respiratory tract, resulting in significantly delayed and reduced transmission in our model. Our results demonstrate the potential of our neonatal mouse model to characterize viral and host determinants of SARS-CoV-2 transmission, while revealing a role for an accessory protein in this context., (© 2023. The Author(s).)

Metabolic reprogramming in cancer is considered to be one of the most important hallmarks to drive proliferation, angiogenesis, and invasion. AMP-activated protein kinase activation is one of the established mechanisms for metformin's anti-cancer actions. However, it has been suggested that metformin may exert antitumoral effects by the modulation of other master regulators of cellular energy. Here, based on structural and physicochemical criteria, we tested the hypothesis that metformin may act as an antagonist of L-arginine metabolism and other related metabolic pathways. First, we created a database containing different L-arginine-related metabolites and biguanides. After that, comparisons of structural and physicochemical properties were performed employing different cheminformatic tools. Finally, we performed molecular docking simulations using AutoDock 4.2 to compare the affinities and binding modes of biguanides and L-arginine-related metabolites against their corresponding targets. Our results showed that biguanides, especially metformin and buformin, exhibited a moderate-to-high similarity to the metabolites belonging to the urea cycle, polyamine metabolism, and creatine biosynthesis. The predicted affinities and binding modes for biguanides displayed good concordance with those obtained for some L-arginine-related metabolites, including L-arginine and creatine. In conclusion, metabolic reprogramming in cancer cells by metformin and biguanides may be also driven by metabolic disruption of L-arginine and structurally related compounds.

Many therapies have been developed against COVID-19 since it first appeared in December 2019. Antivirals, antimalarials, cephalosporins, colchicine, anticoagulants, and corticosteroids, among others, have been evaluated as protecting agents against antibacterial complications due to their anti-inflammatory and immunomodulatory effects against thrombosis and cell death caused by infection with SARS-CoV-2. Nevertheless, the overall balance in their application has not been found to be satisfactory. On the other hand, developing and applying several vaccines against this virus have marked an important watershed in preventive and prophylactic medicine in the new millennium. However, given the regular efficacy reported of some of them, the still scarce affordability, and the emergency of new strains for which no drug has been evaluated, the search for new pharmacological therapy alternatives still represents an essential component in the clinical management of COVID-19, and the rapid identification of drugs with potential antiviral and/or immunomodulatory properties is needed. In the present review, a potential therapeutic effect of metformin and other antidiabetic therapies for the management of COVID-19 are proposed and discussed from the viewpoint of their in vitro and in vivo immunomodulatory effects. Given that acute inflammation is an important component of COVID-19, antidiabetic therapies could be promising alternatives in its management and reducing the disease's severity. In order to understand how metformin and other antidiabetic therapies could work in the context of COVID-19, here we review the possible mechanisms of action through a detailed description of cellular and molecular events., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Epidemic RNA viruses seem to arise year after year leading to countless infections and devastating disease. SARS-CoV-2 is the most recent of these viruses, but there will undoubtedly be more to come. While effective SARS-CoV-2 vaccines are being deployed, one approach that is still missing is effective antivirals that can be used at the onset of infections and therefore prevent pandemics. Here, we screened FDA-approved compounds against SARS-CoV-2. We found that atovaquone, a pyrimidine biosynthesis inhibitor, is able to reduce SARS-CoV-2 infection in human lung cells. In addition, we found that berberine chloride, a plant-based compound used in holistic medicine, was able to inhibit SARS-CoV-2 infection in cells through direct interaction with the virion. Taken together, these studies highlight potential avenues of antiviral development to block emerging viruses. Such proactive approaches, conducted well before the next pandemic, will be essential to have drugs ready for when the next emerging virus hits.

Background/aim: To identify the best of three isatin-based scaffolds in terms of anticancer activity., Materials and Methods: Synthesis of isatin-based scaffolds was performed through a reaction to form Schiff bases. In silico analyses consisted of a target prediction with the Swiss Target Prediction tool and a molecular docking by AutoDock Vina. Anticancer activity and cytotoxicity were determined using the WST1 viability assay., Results: Three scaffolds (IA, IB, and IC) were synthesized and confirmed with good reaction yields. The Swiss Target Prediction tool showed a trend towards kinases. Molecular docking assays demonstrated higher affinity of IC towards CDK2. Anticancer activity assays identified IC as the most active against the cancer cell lines. Cytotoxicity results in non-cancer cells suggested a lack of selectivity., Conclusion: The scaffold IC was identified as the best in terms of anticancer activity and these effects may be due to inhibition of CDK2, as evidenced by molecular docking., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Understanding antibody responses to SARS-CoV-2 is indispensable for the development of containment measures to overcome the current COVID-19 pandemic. Recent studies showed that serum from convalescent patients can display variable neutralization capacities. Still, it remains unclear whether there are specific signatures that can be used to predict neutralization. Here, we performed a detailed analysis of sera from a cohort of 101 recovered healthcare workers and we addressed their SARS-CoV-2 antibody response by ELISA against SARS-CoV-2 Spike receptor binding domain and nucleoprotein. Both ELISA methods detected sustained levels of serum IgG against both antigens. Yet, the majority of individuals from our cohort generated antibodies with low neutralization capacity and only 6% showed high neutralizing titers against both authentic SARS-CoV-2 virus and the Spike pseudotyped virus. Interestingly, higher neutralizing sera correlate with detection of -IgG, IgM and IgA antibodies against both antigens, while individuals with positive IgG alone showed poor neutralization response. These results suggest that having a broader repertoire of antibodies may contribute to more potent SARS-CoV-2 neutralization. Altogether, our work provides a cross sectional snapshot of the SARS-CoV-2 neutralizing antibody response in recovered healthcare workers and provides preliminary evidence that possessing multiple antibody isotypes can play an important role in predicting SARS-CoV-2 neutralization.

Although circular RNAs (circRNAs) are enriched in the mammalian brain, very little is known about their potential involvement in brain function and psychiatric disease. Here, we show that circHomer1a, a neuronal-enriched circRNA abundantly expressed in the frontal cortex, derived from Homer protein homolog 1 (HOMER1), is significantly reduced in both the prefrontal cortex (PFC) and induced pluripotent stem cell-derived neuronal cultures from patients with schizophrenia (SCZ) and bipolar disorder (BD). Moreover, alterations in circHomer1a were positively associated with the age of onset of SCZ in both the dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC). No correlations between the age of onset of SCZ and linear HOMER1 mRNA were observed, whose expression was mostly unaltered in BD and SCZ postmortem brain. Using in vivo circRNA-specific knockdown of circHomer1a in mouse PFC, we show that it modulates the expression of numerous alternative mRNA transcripts from genes involved in synaptic plasticity and psychiatric disease. Intriguingly, in vivo circHomer1a knockdown in mouse OFC resulted in specific deficits in OFC-mediated cognitive flexibility. Lastly, we demonstrate that the neuronal RNA-binding protein HuD binds to circHomer1a and can influence its synaptic expression in the frontal cortex. Collectively, our data uncover a novel psychiatric disease-associated circRNA that regulates synaptic gene expression and cognitive flexibility.

Cryo-electron microscopy (cryo-EM) has revolutionized structural biology by providing 3D density maps of biomolecules at near-atomic resolution. However, map validation is still an open issue. Despite several efforts from the community, it is possible to overfit 3D maps to noisy data. Here, we develop a novel methodology that uses a small independent particle set (not used during the 3D refinement) to validate the maps. The main idea is to monitor how the map probability evolves over the control set during the 3D refinement. The method is complementary to the gold-standard procedure, which generates two reconstructions at each iteration. We low-pass filter the two reconstructions for different frequency cutoffs, and we calculate the probability of each filtered map given the control set. For high-quality maps, the probability should increase as a function of the frequency cutoff and the refinement iteration. We also compute the similarity between the densities of probability distributions of the two reconstructions. As higher frequencies are included, the distributions become more dissimilar. We optimized the BioEM package to perform these calculations, and tested it over systems ranging from quality data to pure noise. Our results show that with our methodology, it possible to discriminate datasets that are constructed from noise particles. We conclude that validation against a control particle set provides a powerful tool to assess the quality of cryo-EM maps., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 Published by Elsevier Inc.)

The ability of small secretory microvesicles known as exosomes to influence neuronal and glial function via their microRNA (miRNA) cargo has positioned them as a novel and effective method of cell-to-cell communication. However, little is known about the role of exosome-secreted miRNAs in the regulation of glutamate receptor gene expression and their relevance for schizophrenia (SCZ) and bipolar disorder (BD). Using mature miRNA profiling and quantitative real-time PCR (qRT-PCR) in the orbitofrontal cortex (OFC) of SCZ (N = 29; 20 male and 9 female), BD (N = 26; 12 male and 14 female), and unaffected control (N = 25; 21 male and 4 female) subjects, we uncovered that miR-223, an exosome-secreted miRNA that targets glutamate receptors, was increased at the mature miRNA level in the OFC of SCZ and BD patients with positive history of psychosis at the time of death and was inversely associated with deficits in the expression of its targets glutamate ionotropic receptor NMDA-type subunit 2B (GRIN2B) and glutamate ionotropic receptor AMPA-type subunit 2 (GRIA2). Furthermore, changes in miR-223 levels in the OFC were positively and negatively correlated with inflammatory and GABAergic gene expression, respectively. Moreover, miR-223 was found to be enriched in astrocytes and secreted via exosomes, and antipsychotics were shown to control its cellular and exosomal localization in a cell-specific manner. Furthermore, addition of astrocytic exosomes in neuronal cultures resulted in a significant increase in miR-223 expression and a notable reduction in Grin2b and Gria2 mRNA levels, which was strongly inversely associated with miR-223 expression. Lastly, inhibition of astrocytic miR-223 abrogated the exosomal-mediated reduction in neuronal Grin2b expression. Taken together, our results demonstrate that the exosomal secretion of a psychosis-altered and glial-enriched miRNA that controls neuronal gene expression is regulated by antipsychotics.

Understanding the fundamental mechanisms of arbovirus transmission and pathogenesis is essential to develop strategies for treatment and prevention. We previously took an in vivo evolution-based approach and identified the chikungunya virus E1 glycoprotein residue 80 to play a critical role in viral transmission and pathogenesis. In this study, we address the genetic conservation and function of position 80 and demonstrate that this residue is a key determinant in alphavirus infectivity and dissemination through modulation of viral fusion and cholesterol dependence. In addition, in studying the evolution of position 80, we identified a network of glycoprotein residues, including epidemic determinants, that regulate virus dissemination and infectivity. These studies underscore the importance of taking evolution-based approaches to not only identify key viral determinants driving arbovirus transmission and pathogenesis but also to uncover fundamental aspects of arbovirus biology., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Addition of 1% (w/w) soy lecithin increased the shear moduli 10-fold and gel hardness 20-fold for 10% ethylcellulose (EC) oleogels. Higher lecithin addition levels or addition to gels with a higher EC concentration caused smaller increases. Similar trends were observed in the penetration force of the gels. Gels displayed thermal reversibility and a high temperature plateau at T≈120-130 °C. Large amplitude oscillatory shear rheology demonstrated similar solid-to-fluid transitions indicating that the polymer drives elastic softening and failure of the network. However, EC oleogels differed in their resistance to flow: the addition of unsaturated lecithin promoted a more gradual thickening response compared to gels containing saturated lecithin or only EC (the last two types of gels display strong intra-cycle thickening and thinning, more indicative of brittle failure). The thickening response of EC oleogels containing unsaturated lecithin, resembles more closely that of a model edible fat (lard)., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

This study tested a psychosocial model of suicide risk in a sample of 156 Latino college students. Specifically, depression and loneliness were hypothesized to be important predictors of suicide risk (namely, hopelessness and suicidal behaviors) in Latino students. Results of conducting regression analyses indicated that, independent of age and gender, depression and loneliness were significant predictors of both indices of suicide risk examined in the present study. It is noteworthy that within the psychosocial predictor set of depression and loneliness, depression was consistently found to be nearly twice as strong a predictor than was loneliness. Moreover, we found evidence for a significant depression-loneliness interaction effect in predicting suicide risk. That is, the highest level of suicide risk was found among dysphoric Latino students who were also socially isolated. Our findings indicate that depression and loneliness are important factors to consider in understanding suicide risk among Latino college students.

An increase in the average herd size on Australian dairy farms has also increased the labor and animal management pressure on farmers, thus potentially encouraging the adoption of precision technologies for enhanced management control. A survey was undertaken in 2015 in Australia to identify the relationship between herd size, current precision technology adoption, and perception of the future of precision technologies. Additionally, differences between farmers and service providers in relation to perception of future precision technology adoption were also investigated. Responses from 199 dairy farmers, and 102 service providers, were collected between May and August 2015 via an anonymous Internet-based questionnaire. Of the 199 dairy farmer responses, 10.4% corresponded to farms that had fewer than 150 cows, 37.7% had 151 to 300 cows, 35.5% had 301 to 500 cows; 6.0% had 501 to 700 cows, and 10.4% had more than 701 cows. The results showed that farmers with more than 500 cows adopted between 2 and 5 times more specific precision technologies, such as automatic cup removers, automatic milk plant wash systems, electronic cow identification systems and herd management software, when compared with smaller farms. Only minor differences were detected in perception of the future of precision technologies between either herd size or farmers and service providers. In particular, service providers expected a higher adoption of automatic milking and walk over weighing systems than farmers. Currently, the adoption of precision technology has mostly been of the type that reduces labor needs; however, respondents indicated that by 2025 adoption of data capturing technology for monitoring farm system parameters would be increased., (Copyright © 2018 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Rett syndrome (RTT) is an X-linked, neurodevelopmental disorder caused primarily by mutations in the methyl-CpG-binding protein 2 (MECP2) gene, which encodes a multifunctional epigenetic regulator with known links to a wide spectrum of neuropsychiatric disorders. Although postnatal functions of MeCP2 have been thoroughly investigated, its role in prenatal brain development remains poorly understood. Given the well-established importance of microRNAs (miRNAs) in neurogenesis, we employed isogenic human RTT patient-derived induced pluripotent stem cell (iPSC) and MeCP2 short hairpin RNA knockdown approaches to identify novel MeCP2-regulated miRNAs enriched during early human neuronal development. Focusing on the most dysregulated miRNAs, we found miR-199 and miR-214 to be increased during early brain development and to differentially regulate extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase and protein kinase B (PKB/AKT) signaling. In parallel, we characterized the effects on human neurogenesis and neuronal differentiation brought about by MeCP2 deficiency using both monolayer and three-dimensional (cerebral organoid) patient-derived and MeCP2-deficient neuronal culture models. Inhibiting miR-199 or miR-214 expression in iPSC-derived neural progenitors deficient in MeCP2 restored AKT and ERK activation, respectively, and ameliorated the observed alterations in neuronal differentiation. Moreover, overexpression of miR-199 or miR-214 in the wild-type mouse embryonic brains was sufficient to disturb neurogenesis and neuronal migration in a similar manner to Mecp2 knockdown. Taken together, our data support a novel miRNA-mediated pathway downstream of MeCP2 that influences neurogenesis via interactions with central molecular hubs linked to autism spectrum disorders.

Fats are ubiquitous in biological membranes, foods, and many other commercial products. In these, they play essential roles in biological, nutritional, and physical functions. In this review, we focus on physical mechanical functions. The rheology of fats arises from the crystal network, which displays hierarchical structural levels from the molecular to the mesoscopic. Under linear deformations, the crystal network behaves as a viscoelastic solid with elasticity dictated by particle concentration and microstructural features as represented in fractal rheo-mechanical models. Under nonlinear deformations, the crystal network yields, showing a variety of nonlinear phenomena, i.e., softening, stiffening, thixotropy. These features largely contribute to functionality or performance as essentially all processing and end-uses of fatty materials involve large nonlinear deformations. Early work on rheology of fats gave hints of their nonlinear mechanical behavior, although in many cases the measured properties were empirical. In contrast, recent efforts from our group measured fundamental rheological functions using large amplitude oscillatory shear rheology. We demonstrate the ability of this technique to discern among the bulk functionality of bakery fats (all-purpose and lamination shortenings) based on well-defined rheological signatures that also relate to the fat structure. This technique has the potential to provide similar insights on other fatty systems and novel ideas for reformulation and design of alternative lipid-structuring materials.

The rise in Multidrug-resistant (MDR) infections has become a significant problem in both the developing countries and in the United States (U.S.). Specifically, MDR gram-negative infections are emerging, affecting not only adults but children as well. The specific gram-negative organisms that have been most concerning within the pediatric population include MDR P. aeruginosa, Enterobacteriaceae, and Acinetobacter spp. The increase in antimicrobial resistance rates is associated with various mechanisms with one of the most common being the production of beta-lactamases. Both Ceftazidime/Avibactam (CZA) and Ceftolozane/Tazobactam (C/T) are two recently approved antibiotics in the U.S. While both of these agents are inhibitors of beta-lactamase enzymes, there are differences between them that are important to understand. At this time, the data in children for these agents are extremely limited. The aim of this review is to describe the characteristics of these agents and their potential uses in pediatric patients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

To characterize susceptibility to HIV infection, we phenotyped infected tonsillar T cells by single-cell mass cytometry and created comprehensive maps to identify which subsets of CD4+ T cells support HIV fusion and productive infection. By comparing HIV-fused and HIV-infected cells through dimensionality reduction, clustering, and statistical approaches to account for viral perturbations, we identified a subset of memory CD4+ T cells that support HIV entry but not viral gene expression. These cells express high levels of CD127, the IL-7 receptor, and are believed to be long-lived lymphocytes. In HIV-infected patients, CD127-expressing cells preferentially localize to extrafollicular lymphoid regions with limited viral replication. Thus, CyTOF-based phenotyping, combined with analytical approaches to distinguish between selective infection and receptor modulation by viruses, can be used as a discovery tool., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

Mutations in DNA methyltransferase 3A (DNMT3A) are common in acute myeloid leukemia and portend a poor prognosis; thus, new therapeutic strategies are needed. The likely mechanism by which DNMT3A loss contributes to leukemogenesis is altered DNA methylation and the attendant gene expression changes; however, our current understanding is incomplete. We observed that murine hematopoietic stem cells (HSCs) in which Dnmt3a had been conditionally deleted markedly overexpress the histone 3 lysine 79 (H3K79) methyltransferase, Dot1l. We demonstrate that Dnmt3a(-/-) HSCs have increased H3K79 methylation relative to wild-type (WT) HSCs, with the greatest increases noted at DNA methylation canyons, which are regions highly enriched for genes dysregulated in leukemia and prone to DNA methylation loss with Dnmt3a deletion. These findings led us to explore DOT1L as a therapeutic target for the treatment of DNMT3A-mutant AML. We show that pharmacologic inhibition of DOT1L resulted in decreased expression of oncogenic canyon-associated genes and led to dose- and time-dependent inhibition of proliferation, induction of apoptosis, cell-cycle arrest, and terminal differentiation in DNMT3A-mutant cell lines in vitro. We show in vivo efficacy of the DOT1L inhibitor EPZ5676 in a nude rat xenograft model of DNMT3A-mutant AML. DOT1L inhibition was also effective against primary patient DNMT3A-mutant AML samples, reducing colony-forming capacity (CFC) and inducing terminal differentiation in vitro. These studies suggest that DOT1L may play a critical role in DNMT3A-mutant leukemia. With pharmacologic inhibitors of DOT1L already in clinical trials, DOT1L could be an immediately actionable therapeutic target for the treatment of this poor prognosis disease., (© 2016 by The American Society of Hematology.)

Hematopoietic stem cells (HSCs) possess unique gene expression programs that enforce their identity and regulate lineage commitment. Long non-coding RNAs (lncRNAs) have emerged as important regulators of gene expression and cell fate decisions, although their functions in HSCs are unclear. Here we profiled the transcriptome of purified HSCs by deep sequencing and identified 323 unannotated lncRNAs. Comparing their expression in differentiated lineages revealed 159 lncRNAs enriched in HSCs, some of which are likely HSC specific (LncHSCs). These lncRNA genes share epigenetic features with protein-coding genes, including regulated expression via DNA methylation, and knocking down two LncHSCs revealed distinct effects on HSC self-renewal and lineage commitment. We mapped the genomic binding sites of one of these candidates and found enrichment for key hematopoietic transcription factor binding sites, especially E2A. Together, these results demonstrate that lncRNAs play important roles in regulating HSCs, providing an additional layer to the genetic circuitry controlling HSC function., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Propionic acid (PA) is a short-chain fatty acid with wide industrial application including uses in pharmaceuticals, herbicides, cosmetics, and food preservatives. As a three-carbon building block, PA also has potential as a precursor for high-volume commodity chemicals such as propylene. Currently, most PA is manufactured through petrochemical routes, which can be tied to increasing prices and volatility due to difficulty in demand forecasting and feedstock availability. Herein described are research advancements to develop an industrially feasible, renewable route to PA. Seventeen Propionibacterium strains were screened using glucose and sucrose as the carbon source to identify the best platform strain. Propionibacterium acidipropionici ATCC 4875 was selected as the platform strain and subsequent fermentation optimization studies were performed to maximize productivity and yield. Fermentation productivity was improved three-fold to exceed 2 g/l/h by densifying the inoculum source. Byproduct levels, particularly lactic and succinic acid, were reduced by optimizing fermentor headspace pressure and shear. Following achievement of commercially viable productivities, the lab-grade medium components were replaced with industrial counterparts to further reduce fermentation costs. A pure enzymatically treated corn mash (ECM) medium improved the apparent PA yield to 0.6 g/g (PA produced/glucose consumed), but it came at the cost of reduced productivity. Supplementation of ECM with cyanocobalamin restored productivity to near lab-grade media levels. The optimized ECM recipe achieved a productivity of 0.5 g/l/h with an apparent PA yield of 0.60 g/g corresponding to a media cost <1 USD/kg of PA. These improvements significantly narrow the gap between the fermentation and incumbent petrochemical processes, which is estimated to have a manufacturing cost of 0.82 USD/kg in 2017.