Unveiling the Ro60-Ro52 complex.

The coexistence within a subcellular complex of inter-cellular proteins Ro60, responsible for preserving ncRNA quality, and Ro52, involved in intracellular proteolysis, has been a subject of ongoing debate. Employing molecular docking in tandem with experimental methods like Quartz Crystal Microbalance with Dissipation (QCM-D), Proximity Ligation Assay (PLA), and Indirect Immunofluorescence (IIF), we reveal the presence of Ro60 associating with Ro52 within the cytoplasm. This result unveils the formation of a weak transient complex with a Ka ≈ (3.7 ± 0.3) x 106 M-1, where the toroid-shaped Ro60 structure interacts with the Ro52's Fc receptor, aligning horizontally within the PRY-SPRY domains of the Ro52's homodimer. The stability of this complex relies on the interaction between Ro52 chain A and specific Ro60 residues, such as K133, W177, or L185, vital in the Ro60-YRNA bond. These findings bridge the role of Ro60 in YRNA management with Ro52's function in intracellular proteolysis, emphasizing the potential impact of transient complexes on cellular pathways. See also the graphical abstract(Fig. 1).

Potential climate change effects on the distribution of urban and sylvatic dengue and yellow fever vectors.

Climate change may increase the risk of dengue and yellow fever transmission by urban and sylvatic mosquito vectors. Previous research primarily focused on Aedes aegypti and Aedes albopictus. However, dengue and yellow fever have a complex transmission cycle involving sylvatic vectors. Our aim was to analyze how the distribution of areas favorable to both urban and sylvatic vectors could be modified as a consequence of climate change. We projected, to future scenarios, baseline distribution models already published for these vectors based on the favorability function, and mapped the areas where mosquitoes' favorability could increase, decrease or remain stable in the near (2041-2060) and distant (2061-2080) future. Favorable areas for the presence of dengue and yellow fever vectors show little differences in the future compared to the baseline models, with changes being perceptible only at regional scales. The model projections predict dengue vectors expanding in West and Central Africa and in South-East Asia, reaching Borneo. Yellow fever vectors could spread in West and Central Africa and in the Amazon. In some locations of Europe, the models suggest a reestablishment of Ae. aegypti, while Ae. albopictus will continue to find new favorable areas. The results underline the need to focus more on vectors Ae. vittatus, Ae. luteocephalus and Ae. africanus in West and Central sub-Saharan Africa, especially Cameroon, Central Africa Republic, and northern Democratic Republic of Congo; and underscore the importance of enhancing entomological monitoring in areas where populations of often overlooked vectors may thrive as a result of climate changes.

Real-world evaluation of a QCM-based biosensor for exhaled air.

The biosensor, named "virusmeter" in this study, integrates quartz crystal microbalance technology with an immune-functionalized chip to distinguish between symptomatic patients with respiratory diseases and healthy individuals by analyzing exhaled air samples. Renowned for its compact design, rapidity, and noninvasive nature, this device yields results within a 5-min timeframe. Evaluated under controlled conditions with 54 hospitalized symptomatic COVID-19 patients and 128 control subjects, the biosensor demonstrated good overall sensitivity (98.15%, 95% CI 90.1-100.0) and specificity (96.87%, 95% CI 92.2-99.1). This proof-of-concept presents an innovative approach with significant potential for leveraging piezoelectric sensors to diagnose respiratory diseases.

Time-dependent ligand-receptor binding kinetics and functionality in a heterodimeric receptor model.

GPCRs heteromerize both in CNS and non-CNS regions. The cell uses receptor heteromerization to modulate receptor functionality and to provide fine tuning of receptor signaling. In order for pharmacologists to explore these mechanisms for therapeutic purposes, quantitative receptor models are needed. We have developed a time-dependent model of the binding kinetics and functionality of a preformed heterodimeric receptor involving two drugs. Two cases were considered: both or only one of the drugs are in excess with respect to the total concentration of the receptor. The latter case can be applied to those situations in which a drug causes unwanted side effects that need to be reduced by decreasing its concentration. The required efficacy can be maintained by the allosteric effects mutually exerted by the two drugs in the two-drug combination system. We discuss this concept assuming that the drug causing unwanted side effects is an opioid and that analgesia is the therapeutic effect. As additional points, allosteric modulation by endogenous compounds and synthetic bivalent ligands was included in the study. Receptor heteromerization offers a mechanistic understanding and quantification of the pharmacological effects elicited by combinations of two drugs at different doses and with different efficacies and cooperativity effects, thus providing a conceptual framework for drug combination therapy.

In silico model development and optimization of in vitro lung cell population growth.

Tissue engineering predominantly relies on trial and error in vitro and ex vivo experiments to develop protocols and bioreactors to generate functional tissues. As an alternative, in silico methods have the potential to significantly reduce the timelines and costs of experimental programs for tissue engineering. In this paper, we propose a methodology to formulate, select, calibrate, and test mathematical models to predict cell population growth as a function of the biochemical environment and to design optimal experimental protocols for model inference of in silico model parameters. We systematically combine methods from the experimental design, mathematical statistics, and optimization literature to develop unique and explainable mathematical models for cell population dynamics. The proposed methodology is applied to the development of this first published model for a population of the airway-relevant bronchio-alveolar epithelial (BEAS-2B) cell line as a function of the concentration of metabolic-related biochemical substrates. The resulting model is a system of ordinary differential equations that predict the temporal dynamics of BEAS-2B cell populations as a function of the initial seeded cell population and the glucose, oxygen, and lactate concentrations in the growth media, using seven parameters rigorously inferred from optimally designed in vitro experiments.

Employing digital PCR for enhanced detection of perinatal Toxoplasma gondii infection: A cross-sectional surveillance and maternal-infant outcomes study in El Salvador.

Toxoplasma gondii is a parasitic infection that can be transmitted in utero, resulting in fetal chorioretinitis and other long-term neurological outcomes. If diagnosed early, pregnancy-safe chemotherapeutics can prevent vertical transmission. Unfortunately, diagnosis of acute, primary infection among pregnant women remains neglected, particularly in low-and-middle-income countries. Clinically actionable diagnosis is complex due to the commonality of infection during childhood and early adulthood which spawn long-last antibody titers and historically unreliable direct molecular diagnostics. The current study employed a cross-sectional T. gondii perinatal surveillance study using digital PCR, a next generation molecular diagnostic platform, and a maternal-fetal outcomes survey to ascertain the risk of vertical toxoplasmosis transmission in the Western Region of El Salvador. Of 198 enrolled mothers at the time of childbirth, 6.6% had evidence of recent T. gondii infection-85% of these cases were identified using digital PCR. Neonates born to these acutely infected mothers were significantly more likely to meconium aspiration syndrome and mothers were more likely to experience labor and delivery complications. Multivariable logistic regression found higher maternal T. gondii infection odds were associated with the presence of pet cats, the definitive T. gondii host. In closing, this study provides evidence of maternal T. gondii infection, vertical transmission and deleterious fetal outcomes in a vulnerable population near the El Salvador-Guatemala border. Further, this is the first published study to show clinical utility potential of digital PCR for accurate diagnosis of congenital toxoplasmosis cases.

Perinatal dengue and Zika virus cross-sectional seroprevalence and maternal-fetal outcomes among El Salvadoran women presenting for labor-and-delivery.

BACKGROUND: Despite maternal flavivirus infections' linkage to severe maternal and fetal outcomes, surveillance during pregnancy remains limited globally. Further complicating maternal screening for these potentially teratogenic pathogens is the overwhelming subclinical nature of acute infection. This study aimed to understand perinatal and neonatal risk for poor health outcomes associated with flaviviral infection during pregnancy in El Salvador. METHODS: Banked serologic samples and clinical results obtained from women presenting for labor and delivery at a national referent hospital in western El Salvador March to September 2022 were used for this study. 198 samples were screened for dengue and Zika virus IgM, and statistical analyses analyzed demographic and clinical outcome associations with IgM positivity. RESULTS: This serosurvey revealed a high rate of maternal flavivirus infection-24.2% of women presenting for labor and delivery were dengue or Zika virus IgM positive, suggesting potential infection within pregnancy. Specifically, 20.2% were Zika virus IgM positive, 1.5% were dengue virus IgM positive, and 2.5% were both dengue and Zika virus IgM positive. Women whose home had received mosquito abatement assistance within the last year by the ministry of health were 70% less likely to test IgM positive (aOR = 0.30, 95%CI: 0.10, 0.83). Further, statistical geospatial clustering revealed transmission foci in six primary municipalities. Pregnancy complications and poor birth outcomes were noted among the dengue and/or Zika virus maternal infection group, although these outcomes were not statistically different than the seronegative group. None of the resulting neonates born during this study were diagnosed with congenital Zika syndrome. CONCLUSIONS: The high rate of Zika virus detected among pregnant women and the lack of Zika-specific neonatal outcomes monitoring during a non-outbreak year highlights the need for continued surveillance in Central America and among immigrant mothers presenting for childbirth from these countries. As changing climatic conditions continue to expand the range of the disease vector, asymptomatic screening programs could be vital to early identification of outbreaks and clinical management of cases.

Ab initio study of the vibrational spectra of amorphous boron nitride.

Boron Nitride (BN) is an interesting polymorphic insulator that is commonly found in four different crystalline structures, each one with different electrical and mechanical properties which makes it an attractive material for technological and industrial applications. Seeking to improve its features, several experimental and simulational works have studied the amorphous phase (a-BN) focusing on electronic and structural properties, pressure-induced phase transformations, and a hydrogenated form of a-BN. By means of ab initio Molecular Dynamics and our well-proven amorphization process known as the undermelt-quench approach, herein three amorphous supercells were computationally generated, two with 216 atoms (densities of 2.04 and 2.80 g cm-3) and a third one with 254 atoms (density of 3.48 g cm-3). The topology, the vibrational density of states and some thermodynamic properties of the three samples are reported and compared with existing experiments and with other computational results.

Prevalent role of homologous recombination in the repair of specific double-strand breaks in Rhizobium etli.

Double-strand breaks (DSBs) are the most dangerous injuries for a genome. When unrepaired, death quickly ensues. In most bacterial systems, DSBs are repaired through homologous recombination. Nearly one-quarter of bacterial species harbor a second system, allowing direct ligation of broken ends, known as Non-Homologous End Joining (NHEJ). The relative role of both systems in DSBs repair in bacteria has been explored only in a few cases. To evaluate this in the bacterium Rhizobium etli, we used a modified version of the symbiotic plasmid (264 kb), containing a single copy of the nifH gene. In this plasmid, we inserted an integrative plasmid harboring a modified nifH gene fragment containing an I-SceI site. DSBs were easily inflicted in vivo by conjugating a small, replicative plasmid that expresses the I-SceI nuclease into the appropriate strains. Repair of a DSB may be achieved through homologous recombination (either between adjacent or distant repeats) or NHEJ. Characterization of the derivatives that repaired DSB in different configurations, revealed that in most cases (74%), homologous recombination was the prevalent mechanism responsible for repair, with a relatively minor contribution of NHEJ (23%). Inactivation of the I-SceI gene was detected in 3% of the cases. Sequence analysis of repaired derivatives showed the operation of NHEJ. To enhance the number of derivatives repaired through NHEJ, we repeated these experiments in a recA mutant background. Derivatives showing NHEJ were readily obtained when the DSB occurred on a small, artificial plasmid in a recA mutant. However, attempts to deliver a DSB on the symbiotic plasmid in a recA background failed, due to the accumulation of mutations that inactivated the I-SceI gene. This result, coupled with the absence of derivatives that lost the nonessential symbiotic plasmid, may be due to an unusual stability of the symbiotic plasmid, possibly caused by the presence of multiple toxin-antitoxin modules.

Epigenetic and transcriptional regulation of cytokine production by Plasmodium falciparum-exposed monocytes.

Plasmodium falciparum infection causes the most severe form of malaria, where excessive production of proinflammatory cytokines can drive the pathogenesis of the disease. Monocytes play key roles in host defense against malaria through cytokine production and phagocytosis; however, they are also implicated in pathogenesis through excessive proinflammatory cytokine production. Understanding the underlying molecular mechanisms that contribute to inflammatory cytokine production in P. falciparum-exposed monocytes is key towards developing better treatments. Here, we provide molecular evidence that histone 3 lysine 4 (H3K4) methylation is key for inflammatory cytokine production in P. falciparum-exposed monocytes. In an established in vitro system that mimics blood stage infection, elevated proinflammatory TNF and IL-6 cytokine production is correlated with increased mono- and tri-methylated H3K4 levels. Significantly, we demonstrate through utilizing a pharmacological inhibitor of H3K4 methylation that TNF and IL-6 expression can be suppressed in P. falciparum-exposed monocytes. This elucidated epigenetic regulatory mechanism, controlling inflammatory cytokine production, potentially provides new therapeutic options for future malaria treatment.

PbS Quantum Dots Ink with Months-Long Shelf-Lifetime Enabling Scalable and Efficient Short-Wavelength Infrared Photodetectors.

The phase-transfer ligand exchange of PbS quantum dots (QDs) has substantially simplified device fabrication giving hope for future industrial exploitation. However, this technique when applied to QDs of large size (>4 nm) gives rise to inks with poor colloidal stability, thus hindering the development of QDs photodetectors in short-wavelength infrared range. Here, it is demonstrated that methylammonium lead iodide ligands can provide sufficient passivation of PbS QDs of size up to 6.7 nm, enabling inks with a minimum of ten-week shelf-life time, as proven by optical absorption and solution-small angle X-ray scattering. Furthermore, the maximum linear electron mobility of 4.7 × 10-2 cm2 V-1 s-1 is measured in field-effect transistors fabricated with fresh inks, while transistors fabricated with the same solution after ten-week storage retain 74% of the average starting electron mobility, demonstrating the outstanding quality both of the fresh and aged inks. Finally, photodetectors fabricated via blade-coating exhibit 76% external quantum efficiency at 1300 nm and 1.8 × 1012 Jones specific detectivity, values comparable with devices fabricated using ink with lower stability and wasteful methods such as spin-coating.

Neuromyelitis optica associated with the use of Atezolizumab in a patient with advanced lung adenocarcinoma.

Immune checkpoint inhibitors (ICIs) are a pharmacological group increasingly used in Oncology and Hematology. These treatments can lead to autoimmune complications, with neurological conditions, especially central nervous system (CNS) involvement, being rare. We describe a case of seropositive neuromyelitis optica in a patient with locally advanced lung adenocarcinoma treated with Atezolizumab.

Using fuzzy logic to compare species distribution models developed on the basis of expert knowledge and sampling records : Expert knowledge versus sampling in species distribution modelling.

BACKGROUND: Experts use knowledge to infer the distribution of species based on fuzzy logical assumptions about the relationship between species and the environment. Thus, expert knowledge is amenable to fuzzy logic modelling, which give to propositions a continuous truth value between 0 and 1. In species distribution modelling, fuzzy logic may also be used to model, from a number of records, the degree to which conditions are favourable to the occurrence of a species. Therefore, fuzzy logic operations can be used to compare and combine models based on expert knowledge and species records. Here, we applied fuzzy logic modelling to the distribution of amphibians in Uruguay as inferred from expert knowledge and from observed records to infer favourable locations, with favourability being the commensurable unit for both kinds of data sources. We compared the results for threatened species, species considered by experts to be ubiquitous, and non-threatened, non-ubiquitous species. We calculated the fuzzy intersection of models based on both knowledge sources to obtain a unified prediction of favourable locations. RESULTS: Models based on expert knowledge involved a larger number of variables and were less affected by sampling bias. Models based on experts had the same overprediction rate for the three types of species, whereas models based on species records had a lower prediction rate for ubiquitous species. Models based on expert knowledge performed equally as well or better than corresponding models based on species records for threatened species, even when they had to discriminate and classify the same set of records used to build the models based on species records. For threatened species, expert models predicted more restrictive favourable territories than those predicted based on records. Observed records generated the best-fitted models for non-threatened non-ubiquitous species, and ubiquitous species. CONCLUSIONS: Fuzzy modelling permitted the objective comparison of the potential of expert knowledge and incomplete distribution records to infer the territories favourable for different species. Distribution of threatened species was able to be better explained by subjective expert knowledge, while for generalist species models based on observed data were more accurate. These results have implications for the correct use of expert knowledge in conservation planning.

TANK-Binding Kinase 1 Mutation as a Rare Cause of Frontotemporal Dementia in a Mexican Patient: The First Case Report in a Tertiary Referral Hospital in Mexico.

Frontotemporal dementia (FTD) is a heterogeneous condition characterized by changes in behavior, personality, and language resulting from degeneration of the frontal and/or temporal lobes. A wide spectrum of clinical syndromes and an overlap with different motor disorders make this entity challenging for clinicians, both in achieving a correct diagnosis and providing proper treatment. Despite the majority of cases being sporadic, FTD has a hereditary component, and more than 10 disease-causing genes have been identified. We present the case of a Mexican patient with a positive family history of neurocognitive disorders who developed early-onset behavioral symptoms, cognitive alterations, and motor disturbances. After a comprehensive study and multiple assessments by various medical services, a molecular diagnosis was achieved by documenting a loss-of-function mutation in the TANK-binding kinase 1 (TBK1) gene, an extremely rare cause of FTD. Genetic diagnosis is crucial in these situations, as this mutation has been associated with rapid disease progression and the potential development of motor syndromes during its course. Our case underscores the challenges involved in reaching an accurate diagnosis, highlighting the importance of molecular testing. A thorough family history, past medical records, and a detailed description of symptom onset and progression are imperative, as they can significantly influence both treatment approaches and prognosis. Diagnostic errors, combined with their subsequent inappropriate treatment, can further deteriorate patients' quality of life.

Prediction of bird-beak configuration in thoracic endovascular aortic repair preoperatively using patient-specific finite element simulations.

Objectives: Formation of bird-beak configuration in thoracic endovascular aortic repair (TEVAR) has been shown to be correlated with the risk of complications such as type Ia endoleaks, stent graft migration, and collapse. The aim of this study was to use patient-specific computational simulations of TEVAR to predict the formation of bird-beak configuration preoperatively. Methods: Patient-specific TEVAR computational simulations are developed using a retrospective cohort of patients treated for thoracic aortic aneurysm. The preoperative computed tomography images were segmented to develop three-dimensional geometry of the thoracic aorta. These geometries were used in finite element simulations of stent graft deployment during TEVAR. Simulated results were compared against the postoperative computed tomography images to assess the accuracy of simulations in predicting the proximal position of a deployed stent graft and presence of bird-beak. In cases with a bird-beak configuration, the length and angle of the bird-beak were measured and compared between the simulated and postoperative results. Results: Twelve TEVAR patient cases were simulated. Computational simulations were able to accurately predict whether the proximal stent graft was fully apposed, proximal bare stents were protruded, or bird-beak configuration was present. In three cases with bird-beak configuration, simulations predicted the length and angle of the bird-beak with less than 10% and 24% error, respectively. Other factors such as a small aortic arch angle, small oversizing value, and landing zones close to the arch apex may have played a role in formation of bird-beak in these patients. Conclusions: Computational simulations of TEVAR accurately predicted the proximal position of a deployed stent graft and the presence of bird-beak preoperatively. The computational models were able to predict the length and angle of bird-beak configurations with good accuracy. These simulations can provide insight into the surgical planning process with the goal of minimizing bird-beak occurrence.

Osteosynthesis of a patellar fracture with repair of the knee extensor mechanism: Case report.

Patella fractures correspond to 1 % of all fractures. In recent decades, the role of the patella in increasing the lever arm of the quadriceps has been well defined. Surgical treatment is indicated for open fractures, those that compromise the function of the extensor mechanism, those with a joint gap >5 mm and/or joint incongruity >3 mm, a group that corresponds to around 30 % of the total. Anatomical reduction and stabilization with various types of modified tension bands is the most frequently used procedure. Biomechanical studies have shown that stabilization through the use of a tension band replacing the Kirchner wires with cannulated screws presents adequate resistance to fracture displacement and provides greater stability than the classic configuration, maintaining the theoretical principle of converting the forces of anterior tension of the patella generated by the quadriceps in compression at the level of the articular surface. A case of a patient who required reduction and osteosynthesis of an exposed patella fracture, associated with an extensor mechanism lesion, is presented. Clinical and radiographic characteristics of the patient and the resolution of the case are described.

Retinal thickness as a biomarker of cognitive impairment in manifest Huntington's disease.

BACKGROUND: Cognitive decline has been reported in premanifest and manifest Huntington's disease but reliable biomarkers are lacking. Inner retinal layer thickness seems to be a good biomarker of cognition in other neurodegenerative diseases. OBJECTIVE: To explore the relationship between optical coherence tomography-derived metrics and global cognition in Huntington's Disease. METHODS: Thirty-six patients with Huntington's disease (16 premanifest and 20 manifest) and 36 controls matched by age, sex, smoking status, and hypertension status underwent macular volumetric and peripapillary optical coherence tomography scans. Disease duration, motor status, global cognition and CAG repeats were recorded in patients. Group differences in imaging parameters and their association with clinical outcomes were analyzed using linear mixed-effect models. RESULTS: Premanifest and manifest Huntington's disease patients presented thinner retinal external limiting membrane-Bruch's membrane complex, and manifest patients had thinner temporal peripapillary retinal nerve fiber layer compared to controls. In manifest Huntington's disease, macular thickness was significantly associated with MoCA scores, inner nuclear layer showing the largest regression coefficients. This relationship was consistent after adjusting for age, sex, and education and p-value correction with False Discovery Rate. None of the retinal variables were related to Unified Huntington's Disease Rating Scale score, disease duration, or disease burden. Premanifest patients did not show a significant association between OCT-derived parameters and clinical outcomes in corrected models. CONCLUSIONS: In line with other neurodegenerative diseases, OCT is a potential biomarker of cognitive status in manifest HD. Future prospective studies are needed to evaluate OCT as a potential surrogate marker of cognitive decline in HD.

Understanding the Geographic Patterns of Closely-Related Species of Paspalum (Poaceae) Using Distribution Modelling and Seed Germination Traits.

The sexual species of the Dilatata complex (Paspalum dasypleurum, P. flavescens, P. plurinerve, P. vacarianum, and P. urvillei) are closely related phylogenetically and show allopatric distributions, except P. urvillei. These species show microhabitat similarities and differences in germination traits. We integrated species distribution models (SDMs) and seed germination assays to determine whether germination divergences explain their biogeographic pattern. We trained SDMs in South America using species' presence-absence data and environmental variables. Additionally, populations sampled from highly favourable areas in the SDMs of these species were grown together, and their seeds germinated at different temperatures and dormancy-breaking conditions. Differences among species in seed dormancy and germination niche breadth were tested, and linear regressions between seed dormancy and climatic variables were explored. SDMs correctly classified both the observed presences and absences. Spatial factors and anthropogenic activities were the main factors explaining these distributions. Both SDMs and germination analyses confirmed that the niche of P. urvillei was broader than the other species which showed restricted distributions, narrower germination niches, and high correlations between seed dormancy and precipitation regimes. Both approaches provided evidence about the generalist-specialist status of each species. Divergences in seed dormancy between the specialist species could explain these allopatric distributions.