Viral infections and implications for male reproductive health

Viral infections have haunted humankind since times immemorial.Overpopulation,globalization,and extensive deforestation have created an ideal environment for a ...     

Tracheal and laryngotracheal resections and reconstructions—a single-centre experience

BackgroundSurgical resection has proven to be the most effective long-term treatment in managing airway stenoses and has shown to decrease the risk of tumor recurrence and mortality in patients with tumor infiltration to the airways. However, there are only a few Nordic reports on the results of a tracheal resection (TR) and cricotracheal resection (CTR). This study aimed to evaluate the volume and short-term outcome of TR and CTR at our institution.MethodsRetrospective review of patients who underwent TR or CTR between 2004 and 2019 at the Helsinki University Hospital (Helsinki, Finland).ResultsForty-four patients were included, of which 21 (47.7%) underwent surgery for a tumor, whereas 23 (52.3%) were operated for a benign stenosis. The most common tumor type was thyroid carcinoma with tracheal invasion (15.9%). The distance between the upper margin of the stenosis or tumor infiltration and the vocal cords was in median 3 [interquartile range (IQR), 2–5] cm and the median length of resection 2.5 (IQR, 2–3.5) cm. Overall success rate was 75% (no need for reoperation or postoperative intervention). Complications occurred in 20 (45.5%) patients, of which 10 patients were operated for a tumor, and 10 for a benign stenosis.ConclusionsTracheal and CTRs were effective in treating tracheal and subglottic stenoses with variable etiology. However, complications were common especially following cricotracheal tumor resections. These procedures show a clear need for further centralization due to their complex nature and should therefore be performed primarily at institutes with highly experienced multi-professional teams.     

Multi-population generalizability of a deep learning-based chest radiograph severity score for COVID-19

To tune and test the generalizability of a deep learning-based model for assessment of COVID-19 lung disease severity on chest radiographs (CXRs) from different patient populations.A published convolutional Siamese neural network-based model previously trained on hospitalized patients with COVID-19 was tuned using 250 outpatient CXRs. This model produces a quantitative measure of COVID-19 lung disease severity (pulmonary x-ray severity (PXS) score). The model was evaluated on CXRs from 4 test sets, including 3 from the United States (patients hospitalized at an academic medical center (N = 154), patients hospitalized at a community hospital (N = 113), and outpatients (N = 108)) and 1 from Brazil (patients at an academic medical center emergency department (N = 303)). Radiologists from both countries independently assigned reference standard CXR severity scores, which were correlated with the PXS scores as a measure of model performance (Pearson R). The Uniform Manifold Approximation and Projection (UMAP) technique was used to visualize the neural network results.Tuning the deep learning model with outpatient data showed high model performance in 2 United States hospitalized patient datasets (R = 0.88 and R = 0.90, compared to baseline R = 0.86). Model performance was similar, though slightly lower, when tested on the United States outpatient and Brazil emergency department datasets (R = 0.86 and R = 0.85, respectively). UMAP showed that the model learned disease severity information that generalized across test sets.A deep learning model that extracts a COVID-19 severity score on CXRs showed generalizable performance across multiple populations from 2 continents, including outpatients and hospitalized patients.     

Prediction of shoulder dystocia using multivariate analysis

We evaluated the use of multivariate analysis in the prediction of shoulder dystocia (SD). One hundred consecutive cases with SD were matched with 100 controls without dystocia. All patients had term, vaginal delivery. Multivariate analysis was used to identify independent variables significantly related to shoulder dystocia. The regression coefficients for the identified factors were used to calculate a composite score from which receiver operating characteristics (ROC) curves were derived. Birthweight (BW), 1-hour Glucola (GLU), operative vaginal delivery (OVD), and height of fundus (HOF) were related independently to SD. The sensitivity and specificity reached 84 and 80%, respectively, with BW + GLU + OVD. Significant associations persisted when HOF and carbohydrate intolerance were substituted for BW and GLU, respectively. SD is independently associated with BW, GLU, and OVD, and may be predicted with clinically acceptable accuracy using multiple variables. This model may be useful in the design of prospective studies for managing suspected macrosomia.     

Agar Biopolymer Films for Biodegradable Packaging: A Reference Dataset for Exploring the Limits of Mechanical Performance

This article focuses on agar biopolymer films that offer promise for developing biodegradable packaging, an important solution for reducing plastics pollution. At present there is a lack of data on the mechanical performance of agar biopolymer films using a simple plasticizer. This study takes a Design of Experiments approach to analyze how agar-glycerin biopolymer films perform across a range of ingredients concentrations in terms of their strength, elasticity, and ductility. Our results demonstrate that by systematically varying the quantity of agar and glycerin, tensile properties can be achieved that are comparable to agar-based materials with more complex formulations. Not only does our study significantly broaden the amount of data available on the range of mechanical performance that can be achieved with simple agar biopolymer films, but the data can also be used to guide further optimization efforts that start with a basic formulation that performs well on certain property dimensions. We also find that select formulations have similar tensile properties to thermoplastic starch (TPS), acrylonitrile butadiene styrene (ABS), and polypropylene (PP), indicating potential suitability for select packaging applications. We use our experimental dataset to train a neural network regression model that predicts the Young’s modulus, ultimate tensile strength, and elongation at break of agar biopolymer films given their composition. Our findings support the development of further data-driven design and fabrication workflows.     

Mechanism of voltage sensing in Ca2+- and voltage-activated K+ (BK) channels

In neurosecretion, allosteric communication between voltage sensors and Ca²⁺ binding in BK channels is crucially involved in damping excitatory stimuli. Nevertheless, the voltage-sensing mechanism of BK channels is still under debate. Here, based on gating current measurements, we demonstrate that two arginines in the transmembrane segment S4 (R210 and R213) function as the BK gating charges. Significantly, the energy landscape of the gating particles is electrostatically tuned by a network of salt bridges contained in the voltage sensor domain (VSD). Molecular dynamics simulations and proton transport experiments in the hyperpolarization-activated R210H mutant suggest that the electric field drops off within a narrow septum whose boundaries are defined by the gating charges. Unlike Kv channels, the charge movement in BK appears to be limited to a small displacement of the guanidinium moieties of R210 and R213, without significant movement of the S4.

Excitable tissues accomplish their signaling functions thanks in part to the interplay of several voltage-sensitive ion channels (1–6). Hence, to understand these processes, it is crucial to establish how voltage-sensitive ion channels sense changes in the electric field across the membrane, an issue that has been a matter of extensive study and intense debate for decades. The most widely accepted mechanism proposes the existence of voltage-sensor domains (VSDs), modules that undergo two or more discrete conformational states in response to changes in the membrane voltage. The simplest model considers two states: active (A), which promotes pore opening, and resting (R), which promotes channel closing. To accomplish its function, VSDs contain voltage-sensitive particles, which move in response to changes in the electric field. This movement triggers the interconversion between the two discrete conformational states. These voltage-sensing particles are typically the guanidine groups of arginine residues within the S4 transmembrane segment, which undergo a combination of rotational, translational, and tilting movement in response to changes in membrane voltage (7–14).The large-conductance Ca²⁺- and voltage-activated K⁺ (BK) channels have a wide distribution in mammalian tissues (15–18), where they participate in a diversity of physiological processes. Their malfunction is often related to diverse pathological conditions (19, 20). BK channel open probability is independently regulated by membrane depolarization and intracellular Ca²⁺ concentration (21, 22), each stimulus being detected by specialized modules. Like other voltage-sensitive K⁺ (Kv) channels, BK is an homotetramer in which each of its α subunits consists of a pore domain (PD; S5-S6 transmembrane segments), a voltage-sensing domain (VSD; S1–S4 transmembrane segments) containing a positively charged S4, and a cytosolic C-terminal regulatory domain, which contains the Ca²⁺-binding sites (23, 24). Also, like some members of other K⁺ channel families (25, 26), the VSD and PD of BK are non–domain swapped (23, 24). BK channels display some distinctive structural and functional features: Despite sharing the selectivity filter sequence with Kv channels, BK unitary conductance and selectivity are exquisitely high (27–30). The BK α subunit has an additional transmembrane segment S0 [therefore, its N terminus faces the extracellular medium (31)], and the voltage sensitivity in BK channels is significantly lower than that of Kv channels, presumably because of their lower number of gating charges (32).Although thoroughly studied, research into BK VSD and its voltage dependence has faced several technical obstacles. The relatively small gating charge per channel (32) and the large conductance of the BK pore makes isolating of the gating currents from the ionic currents a tough experimental challenge. In addition, because mutations of VSD residues can produce very large shifts in both the gating charge-voltage (Q(V)) and the conductance-voltage G(V)) relationships (33), it is necessary to use extreme voltages to accurately measure the voltage dependence of some mutants. Consequently, the identification of BK gating charges has been addressed by using indirect approaches (33, 34). The combination of electrophysiology measurements and kinetic modeling suggests a decentralized VSD in the BK channel, where four charged residues (D153 and R167 in S2, D186 in S3, and R213 in S4) act as voltage sensor particles (33). A recent report of the atomistic cryo-electron microscopy (cryo-EM) structures of the human BK channel and its homolog in Aplysia californica (AcSlo) revealed minor structural differences between the VSD in both the Ca²⁺-bound (open pore) and the Ca²⁺-unbound (closed pore) conformations (23, 24, 35). This result can be explained if the conformational changes of the BK VSD upon activation are small compared to those that occur during the activation of other channels, such as HCN channels (12–14).In this study, we identified voltage-sensing particles in the BK channel by using a direct functional approach, involving gating of current measurements and analysis of the Q(V) curves spanning 800 mV in the voltage axis. Systematic neutralization of the individual charged residues in the VSD (S1–S4) revealed that only the neutralization of two arginines in S4 (R210 and R213) changed the voltage dependence of the Q(V) curves. Neutralization of other VSD charges point to roles in tuning of the half-activation voltage of the VSD and its allosteric coupling with the PD. Molecular dynamics (MD) simulations based on the cryo-EM structures of the human BK channel (35) as templates suggested that R210 and R213 lie in a very narrow septum separating intra- and extracellular water-filled vestibules. This interpretation is consistent with the robust hyperpolarization-activated proton currents generated when R210 is mutated to the protonable amino acid histidine. Overall, our results point to a unique and distinctive mode of activation in BK: In contrast to Kv channels, where positive charges move one by one through a charge transfer center (absent in BK channels) that spans the entire electric field (36, 37), charge movement in BK channels is limited to the small displacement of R210 and R213, which itself constitutes a narrow septum where the electric field drops.     

Cocktails of Mycotoxins,Phytoestrogens, and Other Secondary Metabolites in Diets of Dairy Cows in Austria: Inferences from Diet Composition and Geo-Climatic Factors

Dairy production is a pivotal economic sector of Austrian and European agriculture. Dietary toxins and endocrine disruptors of natural origin such as mycotoxins and phytoestrogens can affect animal health, reproduction, and productivity. This study characterized the profile of a wide spectrum of fungal, plant, and unspecific secondary metabolites, including regulated, emerging, and modified mycotoxins, phytoestrogens, and cyanogenic glucosides, in complete diets of lactating cows from 100 Austrian dairy farms. To achieve this, a validated multi-metabolite liquid chromatography/electrospray ionization–tandem mass spectrometric (LC/ESI–MS/MS) method was employed, detecting 155 of >800 tested metabolites. Additionally, the most influential dietary and geo-climatic factors related to the dietary mycotoxin contamination of Austrian dairy cattle were recognized. We evidenced that the diets of Austrian dairy cows presented ubiquitous contamination with mixtures of mycotoxins and phytoestrogens. Metabolites derived from Fusarium spp. presented the highest concentrations, were the most recurrent, and had the highest diversity among the detected fungal compounds. Zearalenone, deoxynivalenol, and fumonisin B1 were the most frequently occurring mycotoxins considered in the EU legislation, with detection frequencies >70%. Among the investigated dietary factors, inclusion of maize silage (MS) and straw in the diets was the most influential factor in contamination with Fusarium-derived and other fungal toxins and metabolites, and temperature was the most influential among the geo-climatic factors.