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Abstract Aquaporin-1 (Aqp1), a water channel, has garnered significant interest for cell-based medicine and in vivo synthetic biology due to its ability to be genetically encoded to produce magnetic resonance signals by increasing the rate of water diffusion in cells. However, concerns regarding the effects of Aqp1 overexpression and increased membrane diffusivity on cell physiology have limited its widespread use as a deep-tissue reporter. In this study, we present evidence that Aqp1 generates strong diffusion-based magnetic resonance signals without adversely affecting cell viability or morphology in diverse cell lines derived from mice and humans. Our findings indicate that Aqp1 overexpression does not induce ER stress, which is frequently associated with heterologous expression of membrane proteins. Furthermore, we observed that Aqp1 expression had no detrimental effects on native biological activities, such as phagocytosis, immune response, insulin secretion, and tumor cell migration in the analyzed cell lines. These findings should serve to alleviate any lingering safety concerns regarding the utilization of Aqp1 as a genetic reporter and should foster its broader application as a noninvasive reporter for in vivo studies.

Abstract These analyses characterized tofacitinib pharmacokinetics (PKs) in children and adolescents with juvenile idiopathic arthritis (JIA). Data were pooled from phase I (NCT01513902), phase III (NCT02592434), and open‐label, long‐term extension (NCT01500551) studies of tofacitinib tablet/solution (weight‐based doses administered twice daily [b.i.d.]) in patients with JIA aged 2 to less than 18 years. Population PK modeling used a nonlinear mixed‐effects approach, with covariates identified using stepwise forward‐inclusion backward‐deletion procedures. Simulations were performed to derive dosing recommendations for children and adolescents with JIA. Two hundred forty‐six pediatric patients were included in the population PK model. A one‐compartment model with first‐order elimination and absorption with body weight as a covariate for oral clearance and apparent volume of distribution sufficiently described the data. Oral solution was associated with comparable average concentration (Cavg) and slightly higher (113.9%) maximum concentration (Cmax) versus tablet, which was confirmed by a subsequent randomized, open‐label, bioavailability study conducted in healthy adult participants (n = 12) by demonstrating adjusted geometric mean ratios (90% confidence interval) between oral solution and tablet of 1.04 (1.00–1.09) and 1.10 (1.00–1.21) for area under the curve extrapolated to infinity and Cmax, respectively (NCT04111614). A dosing regimen of 3.2 mg b.i.d. solution in patients 10 to less than 20 kg, 4 mg b.i.d. solution in patients 20 to less than 40 kg, and 5 mg b.i.d. tablet/solution in patients greater than or equal to 40 kg, irrespective of age, was proposed to achieve constant Cavg across weight groups. In summary, population PK characterization informed a simplified tofacitinib dosing regimen that has been implemented in pediatric patients with JIA.

Abstract VISTA, an inhibitory myeloid-T-cell checkpoint, holds promise as a target for cancer immunotherapy. However, its effective targeting has been impeded by issues such as rapid clearance and cytokine release syndrome observed with previous VISTA antibodies. Here we demonstrate that SNS-101, a newly developed pH-selective VISTA antibody, addresses these challenges. Structural and biochemical analyses confirmed the pH-selectivity and unique epitope targeted by SNS-101. These properties confer favorable pharmacokinetic and safety profiles on SNS-101. In syngeneic tumor models utilizing human VISTA knock-in mice, SNS-101 shows in vivo efficacy when combined with a PD-1 inhibitor, modulates cytokine and chemokine signaling, and alters the tumor microenvironment. In summary, SNS-101, currently in Phase I clinical trials, emerges as a promising therapeutic biologic for a wide range of patients whose cancer is refractory to current immunotherapy regimens.

ObjectivesDespite their efficacy, some immunotherapies have been shown to induce immune-related adverse events, including the potentially life-threatening cytokine release syndrome (CRS), calling for reliable and translational preclinical models to predict potential safety issues and investigate their rescue. Here, we tested the reliability of humanized BRGSF mice for the assessment of therapeutics-induced CRS features in preclinical settings.MethodsBRGSF mice reconstituted with human umbilical cord blood CD34+ cells (BRGSF-CBC) were injected with anti-CD3 antibody (OKT3), anti-CD3/CD19 bispecific T-cell engager Blinatumomab, or VISTA-targeting antibody. Human myeloid and dendritic cells’ contribution was investigated in hFlt3L-boosted BRGSF-CBC mice. OKT3 treatment was also tested in human PBMC-reconstituted BRGSF mice (BRGSF-PBMC). Cytokine release, immune cell distribution, and clinical signs were followed.ResultsOKT3 injection in BRGSF-CBC mice induced hallmark features of CRS, specifically inflammatory cytokines release, modifications of immune cell distribution and activation, body weight loss, and temperature drop. hFlt3L-boosted BRGSF-CBC mice displayed enhanced CRS features, revealing a significant role of myeloid and dendritic cells in this process. Clinical CRS-managing treatment Infliximab efficiently attenuated OKT3-induced toxicity. Comparison of OKT3 treatment’s effect on BRGSF-CBC and BRGSF-PBMC mice showed broadened CRS features in BRGSF-CBC mice. CRS-associated features were also observed in hFlt3L-boosted BRGSF-CBC mice upon treatment with other T-cell or myeloid-targeting compounds.ConclusionsThese data show that BRGSF-CBC mice represent a relevant model for the preclinical assessment of CRS and CRS-managing therapies. They also confirm a significant role of myeloid and dendritic cells in CRS development and exhibit the versatility of this model for therapeutics-induced safety assessment.

Abstract Because of extraordinary optoelectronic properties, two-dimensional (2D) materials are the subject of intense study in recent times. Hence, we investigate sub-wavelength dipole cavities (hole array) as a sensing platform for the detection of 2D reduced graphene oxide (r-GO) using terahertz time-domain spectroscopy (THz-TDS). The r-GO is obtained by reducing graphene oxide (GO) via Hummer's method. Its structural characteristics are verified using X-ray diffraction (XRD) and Raman spectroscopy. We also assessed the morphology and chemistry of r-GO nanosheets by scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDAX), and Fourier Transformed Infrared (FTIR) spectroscopy. Further, we studied the surface plasmon resonance (SPR) characteristics of r-GO nanosheets hybridized dipole cavities using THz-TDS by varying the r-GO thickness on top of the dipole cavities, since these cavities are well known for sustaining strong SPRs. Based on these, we experimentally obtained a sensitivity of 12 GHz/µm for the porous r-GO film. Thus, a modification in SPR characteristics can be employed towards the identification and quantification of r-GO by suitably embedding it on an array of dipole cavities. Moreover, we have adopted a generic approach that can be expanded to sense other 2D materials like Boron Nitride (BN), phosphorene, MoS2, etc., leading to the development of novel THz nanophotonic sensing devices.

Background: The application of classsification methods through multivariate and machine learning techniques has enormous significance in agricultural sector. It is vital to classify various types of seeds as well as identify the quality of seeds which has a great impact on the production of crops. There is a wide range of genetic variations in dry beans all over the world. Many studies have been conducted previously on various dataset to indentify the sorts of dry beans, however most of them focused on machine learning techniques with binary classification. Objective: The aim of this study is to investigate a reliable classifier which has the lowest noise implications and establish an algorithm for dry bean classification effectively. This paper focuses on outlier removals, oversampling with Adaptive Synthetic (ADASYN) algorithm and finding the best classifier to guarantee the highest possible accuracy. Methods: The raw dataset for this study was accessed from UCI Machine Learning Repository. The dataset contained grains having 16 features, 12 dimensions, and 4 distinct shapes. For the purpose of eliminating missing values from the dataset, interquartile range (IQR) with python programming was utilized. Eight most popular classifiers were used in this study which are Logistic Regression (LR), Naïve Bayes (NB), k-Nearest Neighbor (KNN), Decision Tree (DT), Random Forest (RF), Extreme Gradient Boosting (XGB), Support Vector Machine (SVM), and Multilayer Perception (MLP) with balanced and imbalanced classes. The authors utilized frequency tables, bar diagrams, boxplots, analysis of variance for descriptive analysis as well as data preprocessing. Results: The XGB classifier preferably outperformed than other classifiers with balanced and imbalanced distribution of dry beans within each class. It has acquired accuracy (ACC) 93.0% and 95.4% in imbalanced and balanced classes respectively. In case of balanced dataset, after application of ADASYN algorithm both KNN and RF techniques also performed well regarding the Classification Accuracy (ACC), Sensitivity (SE), Specificity (SP) and Cohen's kappa coefficient (Kappa) etc. The most important attributes for classifying the dry beans were found ShapeFactor2, Minor Axis Length, and ShapeFactor1 along with EquivDiameter, Roundness and ConvexArea. Conclusions: For classification of dry seeds, the XGB classifier had performed well when the dataset contained both balanced and imbalanced distribution in classes. Also, it is the primary approach of identifying the classes of seeds/beans with balanced or not. If the classes of the target variable are balanced well, then the KNN and RF algorithms may be applied along with XGB technique for more accurate classification.

Abstract We introduce a new model of relativistic quantum analogue of the classical Otto engine in the presence of a perfectly reflecting boundary. A single qubit acts as the working substance interacting with a massless quantum scalar field, with the boundary obeying the Dirichlet condition. The quantum vacuum serves as a thermal bath through the Unruh effect. We observe that the response function of the qubit gets significantly modified by the presence of the reflecting boundary. From the structure of the correlation function, we find that three different cases emerge, namely, the intermediate boundary regime, the near boundary regime, and the far boundary regime. As expected, the correlation in the far boundary regime approaches that of the Unruh quantum Otto engine (UQOE) when the reflecting boundary goes to infinity. The effect of the reflecting boundary is manifested through the reduction of the critical excitation probability of the qubit and the work output of the engine. Inspite of the reduced work output, the efficiency of the engine remains unaltered even in the presence of the boundary.

There is high prevalence of psychological distress in patients diagnosed with neurological disorders. A cross-sectional study was done among inpatients from the department of neurology in a tertiary care centre in South India to assess prevalence of anxiety, depression, and barriers to mental health-care utilization. Anxiety and depression were estimated using the Hospital Anxiety and Depression Scale (HADS). There is a high prevalence of psychological distress among the study participants. Proactive inquiry and screening of distress by the treating team may help identify psychological distress. Patients are more conforming and open to treating doctor. Barriers to mental health-care utilization included stigma, patient perception regarding treating doctor's attitude, patients' perception regarding distress, and doctor's perception regarding patient distress. There is a need for measures to alleviate stigma.

We use the notion of the gauge/string duality and discuss the Liouvillian (non) integrability criteria for string sigma models in the context of recently proposed Arutyunov-Bassi-Lacroix (ABL) model in Arutyunov et al. (2021) [31]. Our analysis complements those previous results due to numerical analysis as well as Lax pair formulation. We consider a winding string ansatz for the deformed torus Tk(λ1,λ2,λ) which can be interpreted as a system of coupled pendulums. Our analysis reveals the Liouvillian nonintegrability of the associated sigma model. We also obtain the generalized decoupling limit and confirm the analytic integrability for the decoupled sector.

Background: Indian society is considered to have conservative attitudes regarding sex and is ambivalent about the concept of sex education. Previous reports suggest that a considerable proportion of Indian youth have inadequate sexual knowledge and hold a variety of sexual misconceptions. Methodological flaws limit the generalizability of some earlier studies. Aims: This study assessed knowledge and attitude toward sexual health and common sexual practices among college students in Tamil Nadu. Methodology: A total of 952 students from seven randomly selected colleges in Vellore district of Tamil Nadu participated in the survey. The survey questionnaire contained 51 questions on knowledge and attitude toward sexual health and common sexual practices and incorporated items from standardized questionnaires and additional questions suggested by a multidisciplinary group who work in the field. Results: Two hundred seventy-five students among those who completed the survey were women. Higher knowledge scores were associated with older age, male gender, being from a rural background, pursuing non-science streams, and being in postgraduate courses. Nonconservative attitudes were associated with older age, male gender, enrollment in non-science disciplines, discomfort with the family environment, and a religious family background. Conclusions: Sexual knowledge is inadequate and sexual misconceptions were widely prevalent in the population studied. School-based comprehensive sex education programs, which have been demonstrated to be effective in improving sexual health, could be used to deal with these lacunae in sexual health knowledge and attitudes.

Magnetic resonance imaging combined with molecular reporters can visualise cellular functions in intact organisms. Here Mukherjeeet al. present a cellular imaging approach based on intracellular changes in water diffusion using human aquaporin 1 gene as a genetically encoded reporter for MRI.

Ewing′s sarcoma (ES) is a rare malignancy primarily affecting skeletal system and it is commonly diagnosed in children and young adults. It seldom occurs in the head and neck region. ES has poor prognosis because of uncontrolled metastatic potential making early diagnosis and intervention critical for survival of the patient. This paper reports a rare case of ES involving mandible in an 8-year-old girl with clinical, radiological, histopathological and immunohistochemical features.

Fluorescent reporter proteins based on flavin-binding photosensors were recently developed as a new class of genetically encoded probes characterized by small size and oxygen-independent maturation of fluorescence. Flavin-based fluorescent proteins (FbFPs) address two major limitations associated with existing fluorescent reporters derived from the green fluorescent protein (GFP)-namely, the overall large size and oxygen-dependent maturation of fluorescence of GFP. However, FbFPs are at a nascent stage of development and have been utilized in only a handful of biological studies. Importantly, a full understanding of the performance and properties of FbFPs as a practical set of biological probes is lacking. In this work, we extensively characterize three FbFPs isolated from Pseudomonas putida, Bacillus subtilis, and Arabidopsis thaliana, using in vitro studies to assess probe brightness, oligomeric state, maturation time, fraction of fluorescent holoprotein, pH tolerance, redox sensitivity, and thermal stability. Furthermore, we validate FbFPs as stable molecular tags using in vivo studies by constructing a series of FbFP-based transcriptional constructs to probe promoter activity in Escherichia coli. Overall, FbFPs show key advantages as broad-spectrum biological reporters including robust pH tolerance (4-11), thermal stability (up to 60°C), and rapid maturation of fluorescence (