Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM.

Multiple sclerosis (MS) is a heterogenous autoimmune disease in which autoreactive lymphocytes attack the myelin sheath of the central nervous system. B lymphocytes in the cerebrospinal fluid (CSF) of patients with MS contribute to inflammation and secrete oligoclonal immunoglobulins1,2. Epstein-Barr virus (EBV) infection has been epidemiologically linked to MS, but its pathological role remains unclear3. Here we demonstrate high-affinity molecular mimicry between the EBV transcription factor EBV nuclear antigen 1 (EBNA1) and the central nervous system protein glial cell adhesion molecule (GlialCAM) and provide structural and in vivo functional evidence for its relevance. A cross-reactive CSF-derived antibody was initially identified by single-cell sequencing of the paired-chain B cell repertoire of MS blood and CSF, followed by protein microarray-based testing of recombinantly expressed CSF-derived antibodies against MS-associated viruses. Sequence analysis, affinity measurements and the crystal structure of the EBNA1-peptide epitope in complex with the autoreactive Fab fragment enabled tracking of the development of the naive EBNA1-restricted antibody to a mature EBNA1-GlialCAM cross-reactive antibody. Molecular mimicry is facilitated by a post-translational modification of GlialCAM. EBNA1 immunization exacerbates disease in a mouse model of MS, and anti-EBNA1 and anti-GlialCAM antibodies are prevalent in patients with MS. Our results provide a mechanistic link for the association between MS and EBV and could guide the development of new MS therapies.

Wiring Between Close Nodes in Molecular Networks Evolves More Quickly Than Between Distant Nodes.

As species diverge, a wide range of evolutionary processes lead to changes in protein-protein interaction (PPI) networks and metabolic networks. The rate at which molecular networks evolve is an important question in evolutionary biology. Previous empirical work has focused on interactomes from model organisms to calculate rewiring rates, but this is limited by the relatively small number of species and sparse nature of network data across species. We present a proxy for variation in network topology: variation in drug-drug interactions (DDIs), obtained by studying drug combinations (DCs) across taxa. Here, we propose the rate at which DDIs change across species as an estimate of the rate at which the underlying molecular network changes as species diverge. We computed the evolutionary rates of DDIs using previously published data from a high-throughput study in gram-negative bacteria. Using phylogenetic comparative methods, we found that DDIs diverge rapidly over short evolutionary time periods, but that divergence saturates over longer time periods. In parallel, we mapped drugs with known targets in PPI and cofunctional networks. We found that the targets of synergistic DDIs are closer in these networks than other types of DCs and that synergistic interactions have a higher evolutionary rate, meaning that nodes that are closer evolve at a faster rate. Future studies of network evolution may use DC data to gain larger-scale perspectives on the details of network evolution within and between species.

Constraints on Neutrino Natal Kicks from Black-Hole Binary VFTS 243.

The recently reported observation of VFTS 243 is the first example of a massive black-hole binary system with negligible binary interaction following black-hole formation. The black-hole mass (≈10M_{⊙}) and near-circular orbit (e≈0.02) of VFTS 243 suggest that the progenitor star experienced complete collapse, with energy-momentum being lost predominantly through neutrinos. VFTS 243 enables us to constrain the natal kick and neutrino-emission asymmetry during black-hole formation. At 68% confidence level, the natal kick velocity (mass decrement) is ≲10 km/s (≲1.0M_{⊙}), with a full probability distribution that peaks when ≈0.3M_{⊙} were ejected, presumably in neutrinos, and the black hole experienced a natal kick of 4 km/s. The neutrino-emission asymmetry is ≲4%, with best fit values of ∼0-0.2%. Such a small neutrino natal kick accompanying black-hole formation is in agreement with theoretical predictions.

Management of the axial modulation of the illumination pattern in structured illumination microscopy using an extended illumination source.

We have designed and implemented an approach for three-dimensional (3D) structured illumination (SI) microscopy (SIM) based on a quasi-monochromatic extended source illuminating a Wollaston prism to improve robustness, light efficiency and flexibility over our previous design. We show through analytical and experimental verification of the presented theoretical framework for our proposed tunable structured illumination microscopy (TSIM) system, that a simple and accurate determination of the axial modulation of the SI pattern is achieved, enabling a realistic characterization of the system's effective optical transfer function (OTF). System performance as a function of the extended source size is investigated with simulations. Results from a comparative performance analysis of the proposed TSIM system and traditional SIM systems show some advantages over the traditional two-wave and three-wave interference SIM systems. We show that by controlling the source size and thereby the axial modulation of the 3D SI pattern, the TSIM scheme offers increased OTF compact support and improved optical sectioning capability, quantified by the integrated intensity, under certain conditions, which may be desirable when imaging optically thick samples. The additional tunability of the 3D SI pattern, provides a unique opportunity for OTF engineering in our TSIM system.

Piperazine-derived small molecules as potential Flaviviridae NS3 protease inhibitors. In vitro antiviral activity evaluation against Zika and Dengue viruses.

Since 2011 Direct Acting antivirals (DAAs) drugs targeting different non-structural (NS) viral proteins (NS3, NS5A or NS5B inhibitors) have been approved for clinical use in HCV therapies. However, currently there are not licensed therapeutics to treat Flavivirus infections and the only licensed DENV vaccine, Dengvaxia, is restricted to patients with preexisting DENV immunity. Similarly to NS5 polymerase, the NS3 catalytic region is evolutionarily conserved among the Flaviviridae family sharing strong structural similarity with other proteases belonging to this family and therefore is an attractive target for the development of pan-flavivirus therapeutics. In this work we present a library of 34 piperazine-derived small molecules as potential Flaviviridae NS3 protease inhibitors. The library was developed through a privileged structures-based design and then biologically screened using a live virus phenotypic assay to determine the half-maximal inhibitor concentration (IC50) of each compound against ZIKV and DENV. Two lead compounds, 42 and 44, with promising broad-spectrum activity against ZIKV (IC50 6.6 µM and 1.9 µM respectively) and DENV (IC50 6.7 µM and 1.4 µM respectively) and a good security profile were identified. Besides, molecular docking calculations were performed to provide insights about key interactions with residues in NS3 proteases' active sites.

Determinants of COVID-19 vaccine hesitancy among pregnant persons.

BACKGROUND: Vaccines reduce the risk of contracting and developing complications from coronavirus disease 2019 (COVID-19). Pregnant people are at increased risk of disease-related complications but have a higher prevalence of vaccine hesitancy (VH) than their nonpregnant counterparts. OBJECTIVE: This study aimed to describe risk factors and COVID-19- and vaccine-related perspectives that lead to VH among pregnant people in Mexico to target strategies to increase vaccine acceptance in this population. METHODS: A cross-sectional survey-based study to evaluate risk factors and COVID-19- and vaccine-related perspectives associated with VH among pregnant people was conducted. Respondents were pregnant people of all ages attending a regular follow-up visit or admitted to labor and delivery in a third-level maternity hospital in Mexico. VH was defined as not having received a COVID-19 vaccine and either declining or being undecided to accept a vaccine during their pregnancy. We used bivariate and multivariable logistic regression models to estimate assess the relationship among demographic factors, COVID-19- and vaccine-related perspectives, and VH. RESULTS: A total of 1475 respondents completed the questionnaire; 216 (18%) were under the age of 18 years, and 860 (58%) had received at least one dose of a COVID-19 vaccine. In this sample, 264 (18%) were classified as vaccine hesitant. Key factors associated with VH were adolescence, having family as a primary source of information, first pregnancy, and history of vaccines in previous pregnancies. COVID-19 perspectives were also strongly associated with VH. CONCLUSIONS: Among pregnant people in Mexico, VH is associated with demographic factors, vaccination history, sources of information, and perceived risks to the fetus. This information is relevant to policy makers and health care professionals to identify those more likely to be hesitant and to inform strategies to increase vaccine uptake among pregnant people.

MitraClip as bridge to mitral valve replacement in the setting of ischemic cardiogenic shock and papillary muscle rupture.

MitraClip implantation has been reported in severe mitral regurgitation following ischemic papillary muscle rupture in surgically high-risk patients with cardiogenic shock. Here we present a case of a 68-year-old female patient who suffered an ischemic papillary muscle rupture resulting in severe mitral prolapse and had a MitraClip implanted. Three months later, due to progressive symptoms, she was taken to surgery and had an elective minimally invasive mitral valve replacement. Informed consent was given and ethics board approval was obtained.

Bench bioprosthetic aortic valve replacement in a donor heart before transplantation.

Critical donor shortages have impulsed the need to expand donor heart eligibility through the use of marginal hearts in cardiac transplantation. Donor valvular disease has been considered as an absolute contraindication for transplant. A 39-year-old male patient with end-stage non-compaction cardiomyopathy, an INTERMACS II heart failure, and a left ventricular ejection fraction of 8% was taken to an orthotopic heart transplantation. During donor bench graft examination, a congenital bicuspid and calcified aortic valve was found. The native bicuspid valve was removed and the annular calcification debrided; a #21 bioprosthetic aortic valve was then implanted.

Pllans-II Induces Cell Death in Cervical Cancer Squamous Epithelial Cells via Unfolded Protein Accumulation and Endoplasmic Reticulum Stress.

Due to the lack of chemotherapeutic drugs that selectively affect cervical cancer cells, natural sources such as snake venom are currently being investigated for molecules with antitumor potential. Pllans-II, a phospholipase A2 type-Asp49 from Porthidium lansbergii lansbergii snake venom, induced cell death in a cervical cancer cell line-Ca Ski-related to dysfunction in the ability to resolve endoplasmic reticulum stress, evidenced by sub-expression of genes such as PERK, ERO1 PDIs, HSP70, and CHOP. Western blot analysis validated the last two genes' sub-expression at the protein level. In addition, Pllans-II presented a dose-dependent cytotoxic effect on cancer cells and an insignificant effect on healthy endothelial cells (HUVEC). Additionally, Pllans-II inhibited cancer cells' adhesion and migration capacity, induced cell cycle arrest in the G2/M phase, and induced apoptosis stimulated possibly by the extrinsic route. These results demonstrate for the first time that Pllans-II has an antitumor effect on a squamous epithelial cervical cancer cell line and represents a possible biotechnological tool for designing a prominent antitumor agent.

MitraClip as bridge to mitral valve replacement in the setting of ischemic cardiogenic shock and papillary muscle rupture.

MitraClip implantation has been reported in severe mitral regurgitation following ischemic papillary muscle rupture in surgically high-risk patients with cardiogenic shock. Here we present a case of a 68-year-old female patient who suffered an ischemic papillary muscle rupture resulting in severe mitral prolapse and had a MitraClip implanted. Three months later, due to progressive symptoms, she was taken to surgery and had an elective minimally invasive mitral valve replacement. Informed consent was given and ethics board approval was obtained.

Peri-operative nutrition in cardiovascular surgery: current pitfalls and future directions.

In the field of cardiovascular surgery, many areas are frequently evaluated to improve patient outcomes. Even though cardiac surgery has advanced significantly, peri-operative nutrition remains an area needing special attention and is under-considered in patient results. The three portions of cardiac surgical nutrition optimization are pre-operative, intra-operative and post-operative. All these, merit important clinical intervention which when done properly can significantly improve patient recovery and reduce morbidity and mortality. Here we provide a narrative review and recommendations for peri-operative nutritional optimization in cardiac surgery.

Incidence of COVID-19 in 902 Patients With Immunomediated Inflammatory Diseases Treated With Biologics and Targeted Synthetic Disease-Modifying Antirheumatic Drugs-Findings From the BIOCOVID Study.

OBJECTIVES: The aim of this study was to examine the incidence of coronavirus disease 2019 (COVID-19) among patients with immunomediated inflammatory diseases (IMIDs) treated with biologic or targeted synthetic disease-modifying antirheumatic drugs (bDMARDs and tsDMARDs) and to evaluate the influence of either IMIDs or related therapies on the incidence and evolution of COVID-19. METHODS: This observational, cross-sectional study was conducted from January 31, 2020, to May 15, 2020. Data of 902 patients were obtained from clinical records in hospitals, primary care units, and community pharmacies. Inclusion criteria were adults with IMIDs treated with bDMARDs or tsDMARDs who started therapy 3 months prior to study commencement. Patients with poor adherence to treatments were excluded. COVID-19 was classified as "definitive" (severe acute respiratory syndrome coronavirus 2 polymerase chain reaction [PCR]-positive), "possible" (characteristic symptoms and negative PCR), and "suspected" (characteristic symptoms but PCR not performed). RESULTS: COVID-19 was diagnosed in 70 patients (11 definitive, 19 possible, and 40 suspected). The cumulative incidence of definitive COVID-19 was 1.2%. When considering all cases, the incidence was 7.8%. Patients on biosimilars tumor necrosis factor blockers were more likely to have a diagnosis of COVID-19 (odds ratio, 2.308; p < 0.001). Patients on anti-B-cell therapies had a lower incidence of infections (p = 0.046). Low rates of hospitalization (14.3%), pneumonia (14.3%), death (2.9%), or thrombosis (2.9%) were observed, and 94.3% of patients recovered. CONCLUSIONS: The cumulative incidence of confirmed cases of COVID-19 was similar to the general population, with generally low hospitalization, intensive care management, and mortality rates. COVID-19 incidence was less frequent in patients with more severe immunosuppression.

The Predicament of Surgical Correction of Tetralogy of Fallot.

Surgery for tetralogy of Fallot has a long history, which may be described as both a success story and a failure story. It is a success story because prognosis without surgery is very poor, but surgery makes it possible for affected babies to reach adulthood and lead productive lives. It is a failure story, however, since we still cannot cure this condition; we can only palliate it as illustrated in the sobering long-term outcome of affected patients. In this review article, we aim to explore the reason for this failure. This may be summed up in terms of the nature of the obstruction to the right ventricular outflow tract, which characterizes this malformation and must be relieved. This obstruction has several possible components, but none may be eliminated without harming the ventricle. There seems to be no 'extra' muscle band in tetralogy of Fallot that may be dispensed with without undermining ventricular function; every muscle band that is there should be there, just like in the normal heart, except that these are thicker than normal and somewhat displaced in tetralogy of Fallot, thus narrowing the right ventricular outflow tract. Consequently, ventricular function deteriorates with every muscle band that is cut, just like in the normal heart. We have to harm the heart in order to repair it. Every repaired Fallot is inevitably a damaged heart. Consequently, repair of this condition cannot be curative at present; it is palliative surgery.

Prospective observational study on the characteristics of eosinophilic esophagitis in southeast Spain.

INTRODUCTION: Eosinophilic esophagitis (EoE) is a chronic esophageal atopic disease because sensitization to aeroallergens and foods allergens is very common. OBJECTIVES: This study is the first work that studies multiple characteristics of EoE in the southeast of Spain to know whether EoE in the patients of this region is similar to that of other regions of Spain in terms of demography, symptoms, and atopic characteristics. METHOD: It is an observational prospective study of patients diagnosed with EoE at Granada (Spain). We recorded demographic data (age, sex, and personal history of atopy), clinical data (impaction and dysphagia), allergologic data (prick test and specific immunoglobulin E) to foods, aeroallergen, and pan-allergens, and other endoscopic-histologic data and comorbidities. RESULTS: The demographic, allergologic, and endoscopic characteristics of patients with EoE in Granada were similar to the rest of Spain, except the higher frequency of sensitization to olive pollen, food allergy, and anaphylaxis reactions. CONCLUSIONS: The higher frequency of sensitization to olive pollen and food allergy with severe clinical manifestations (anaphylaxis) in patients with EoE in Granada could have a negative impact on patients' quality of life.

A Comparative Analysis of Aerosol Optical Coefficients and Their Associated Errors Retrieved from Pure-Rotational and Vibro-Rotational Raman Lidar Signals.

This paper aims to quantify the improvement obtained with a purely rotational Raman (PRR) channel over a vibro-rotational Raman (VRR) channel, used in an aerosol lidar with elastic and Raman channels, in terms of signal-to-noise ratio (SNR), effective vertical resolution, and absolute and relative uncertainties associated to the retrieved aerosol optical (extinction and backscatter) coefficients. Measurements were made with the European Aerosol Research Lidar Network/Universitat Politècnica de Catalunya (EARLINET/UPC) multi-wavelength lidar system enabling a PRR channel at 353.9 nm, together with an already existing VRR (386.7 nm) and an elastic (354.7 nm) channels. Inversions were performed with the EARLINET Single Calculus Chain (SCC). When using PRR instead of VRR, the measurements show a gain in SNR of a factor 2.8 and about 7.6 for 3-h nighttime and daytime measurements, respectively. For 3-h nighttime (daytime) measurements the effective vertical resolution is reduced by 17% (20%), the absolute uncertainty (associated to the extinction) is divided by 2 (10) and the relative uncertainty is divided by 3 (7). During daytime, VRR extinction coefficient is retrieved in a limited height range (<2.2 km) preventing the SCC from finding a suitable calibration range in the search height range. So the advantage of using PRR instead of VRR is particularly evidenced in daytime conditions. For nighttime measurements, decreasing the time resolution from 3 to 1 h has nearly no effect on the relative performances of PRR vs. VRR.

The p24 Complex Contributes to Specify Arf1 for COPI Coat Selection.

Golgi trafficking depends on the small GTPase Arf1 which, upon activation, drives the assembly of different coats onto budding vesicles. Two related types of guanine nucleotide exchange factors (GEFs) activate Arf1 at different Golgi sites. In yeast, Gea1 in the cis-Golgi and Gea2 in the medial-Golgi activate Arf1 to form COPI-coated vesicles for retrograde cargo sorting, whereas Sec7 generates clathrin/adaptor-coated vesicles at the trans-Golgi network (TGN) for forward cargo transport. A central question is how the same activated Arf1 protein manages to assemble different coats depending on the donor Golgi compartment. A previous study has postulated that the interaction between Gea1 and COPI would channel Arf1 activation for COPI vesicle budding. Here, we found that the p24 complex, a major COPI vesicle cargo, promotes the binding of Gea1 with COPI by increasing the COPI association to the membrane independently of Arf1 activation. Furthermore, the p24 complex also facilitates the interaction of Arf1 with its COPI effector. Therefore, our study supports a mechanism by which the p24 complex contributes to program Arf1 activation by Gea1 for selective COPI coat assembly at the cis-Golgi compartment.

Cervical cancer and potential pharmacological treatment with snake venoms.

Cervical cancer is the fourth most common cancer worldwide in women. Apoptosis reactivation has become the main strategy for decreasing cancer proliferation. There is a need to extend the search for new drugs to implement more effective and less toxic strategies for cervical cancer treatment. Research has been carried out to find new drugs that have minimal side effects and that focus on the tumor microenvironment, particularly in the induction of cellular apoptosis and cell migration and the inhibition of angiogenesis. Potent toxins from snake venoms have shown potential as sources for the synthesis of new drugs with such characteristics. The present work aimed to describe cervical cancer characteristics, associated risk factors, current treatments and to highlight the effects of toxins isolated from the venom of snakes of the Viperidae family on cervical cancer cell lines.

Calculation of the Overlap Function and Associated Error of an Elastic Lidar or a Ceilometer: Cross-Comparison with a Cooperative Overlap-Corrected System.

This paper establishes the relationship between the signal of a lidar system corrected for the incomplete overlap effect and the signal of another lidar system or a ceilometer for which the overlap function is unknown. Simple mathematical relationships permit the estimation of the overlap function of the second system as well as the associated error. Several overlap functions have been retrieved with this method over a period of 1.5 years with two lidar systems of the Universitat Politècnica de Catalunya, Barcelona, Spain. The error when the overlap function reaches 1 is usually less than 7%. The temporal variability estimated over a period of 1.5 years is less than 11% in the first 1.5 km from the surface and peaks at 18% at heights between 1.7 and 2.4 km. The use of a non-appropriate overlap function in the retrieval of the backscatter coefficient yield errors up to 60% in the first 0.5 km and up to 20% above.

Increase in phenolic compounds of Coriandrum sativum L. after the application of a Bacillus halotolerans biofertilizer.

BACKGROUND: There is an urgent need for a new sustainable way of satisfying the increasing demand for food worldwide. One of the main challenges is replacing chemical fertilizers with biofertilizers, which include plant root-associated beneficial microorganisms. The present study reports, for the first time, the effects of SCCPVE07 bacterial strain with respect to improving not only plant development, but also the nutritional content and bioactive compounds content of Coriandrum sativum L., one of the most economically important crops, even for plant growth under salinity stress. RESULTS: Innoculated coriander plants (C. sativum L.) showed an increase in potassium, carbon, calcium and iron content. A significant improvement in phenolic compounds contents was also observed. The contents of 5-O-caffeoylquinic acid, cinnamic acid, 4-methoxy-cinnamic acid hexoside, K-3-O rutinoside, Q-3-O-rutinoside, Q-3-O-glucoside and Q-3-O-glucuronide were significantly enhanced. Moreover, an efficient bacterial root colonization and a noted growth promotion were demonstrated. Bacterial genome was sequenced and analysed. Gene coding related to Plant growth promotion (PGP) mechanisms and proteins involved in plant defence from salinity or in the metabolism of phenolic compounds, such as quercetin 2,3-dioxygenase and phenolic acid decarboxylase, were identified. CONCLUSION: The results obtained in the present study show, for the first time, the beneficial effects of the inoculation of a bacterial Bacillus halotolerans biofertilizer on coriander crops with respect to increasing the content in bioactive compounds and plant development. © 2020 Society of Chemical Industry.

Genetic Diversity, Population Structure, and Migration Scenarios of the Marsupial "Monito del Monte" in South-Central Chile.

In this study, we quantified the 3 pivotal genetic processes (i.e., genetic diversity, spatial genetic structuring, and migration) necessary for a better biological understanding and management of the singular "living-fossil" and near-threatened mouse opossum marsupial Dromiciops gliroides, the "Monito del Monte," in south-central Chile. We used 11 microsatellite loci to genotype 47 individuals distributed on the mainland and northern Chiloé Island. Allelic richness, observed and expected heterozygosity, inbreeding coefficient, and levels of genetic differentiation were estimated. The genetic structure was assessed based on Bayesian clustering methods. In addition, potential migration scenarios were evaluated based on a coalescent theory framework and Bayesian approach to parameter estimations. Microsatellites revealed moderate to high levels of genetic diversity across sampled localities. Moreover, such molecular markers suggested that at least 2 consistent genetic clusters could be identified along the D. gliroides distribution ("Northern" and "Southern" cluster). However, general levels of genetic differentiation observed among localities and between the 2 genetic clusters were relatively low. Migration analyses showed that the most likely routes of migration of D. gliroides occurred 1) from the Southern cluster to the Northern cluster and 2) from the Mainland to Chiloé Island. Our results could represent critical information for future conservation programs and for a recent proposal about the taxonomic status of this unique mouse opossum marsupial.