Large-scale genome-wide association studies (GWASs) have associated intronic variants in PDE4B, encoding cAMP-specific phosphodiesterase-4B (PDE4B), with increased risk for post-traumatic stress disorder (PTSD), as well as schizophrenia and substance use disorders that are often comorbid with it. However, the pathophysiological mechanisms of genetic risk involving PDE4B are poorly understood. To examine the effects of PDE4B variation on phenotypes with translational relevance to psychiatric disorders, we focused on PDE4B missense variant M220T, which is present in the human genome as rare coding variant rs775201287. When expressed in HEK-293 cells, PDE4B1-M220T exhibited an attenuated response to a forskolin-elicited increase in the intracellular cAMP concentration. In behavioral tests, homozygous Pde4b^M220T male mice with a C57BL/6JJcl background exhibited increased reactivity to novel environments, startle hyperreactivity, prepulse inhibition deficits, altered cued fear conditioning, and enhanced spatial memory, accompanied by an increase in cAMP signaling pathway-regulated expression of BDNF in the hippocampus. In response to a traumatic event (10 tone–shock pairings), neuronal activity was decreased in the cortex but enhanced in the amygdala and hippocampus of Pde4b^M220T mice. At 24 h post-trauma, Pde4b^M220T mice exhibited increased startle hyperreactivity and decreased plasma corticosterone levels, similar to phenotypes exhibited by PTSD patients. Trauma-exposed Pde4b^M220T mice also exhibited a slower decay in freezing at 15 and 30 d post-trauma, demonstrating enhanced persistence of traumatic memories, similar to that exhibited by PTSD patients. These findings provide substantive mouse model evidence linking PDE4B variation to PTSD-relevant phenotypes and thus highlight how genetic variation of PDE4B may contribute to PTSD risk.

Getting vaccinated and boosted when you are eligible remains one of the key ways to Stay One Step Ahead of COVID-19 in our state.

The Delaware Public Health Laboratory (DPHL) has identified a case of SARS-CoV-2 lineage BA.2.86 from a specimen provided to the laboratory for testing. This is the first case of BA.2.86 detected in Delaware, currently classified as a Variant Being Monitored (VBM) by the SARS-CoV-2 Interagency Group (SIG). The case was detected in a Pennsylvania resident seen at a Delaware Hospital. The […]

Title: Delta Variant Has Americans' Stress Levels Rising Again: Poll
Category: Health News
Created: 8/20/2021 12:00:00 AM
Last Editorial Review: 8/23/2021 12:00:00 AM

Title: 'Dream Vaccine' for All COVID Variants
Category: Health News
Created: 8/23/2021 12:00:00 AM
Last Editorial Review: 8/24/2021 12:00:00 AM

Title: COVID Incubation Shorter With Each New Variant
Category: Health News
Created: 8/23/2022 12:00:00 AM
Last Editorial Review: 8/23/2022 12:00:00 AM

Title: COVID Boosters Targeted to Latest Variants Could Be Ready After Labor Day
Category: Health News
Created: 8/24/2022 12:00:00 AM
Last Editorial Review: 8/24/2022 12:00:00 AM

The transcription factor (TF) cone-rod homeobox (CRX) is essential for the differentiation and maintenance of photoreceptor cell identity. Several human CRX variants cause degenerative retinopathies, but most are variants of uncertain significance. We performed a deep mutational scan (DMS) of nearly all possible single amino acid substitutions in CRX using a cell-based transcriptional reporter assay, curating a high-confidence list of nearly 2000 variants with altered transcriptional activity. In the structured homeodomain, activity scores closely aligned to a predicted structure and demonstrated position-specific constraints on amino acid substitution. In contrast, the intrinsically disordered transcriptional effector domain displayed a qualitatively different pattern of substitution effects, following compositional constraints without specific residue position requirements in the peptide chain. These compositional constraints were consistent with the acidic exposure model of transcriptional activation. We evaluated the performance of the DMS assay as a clinical variant classification tool using gold-standard classified human variants from ClinVar, identifying pathogenic variants with high specificity and moderate sensitivity. That this performance could be achieved using a synthetic reporter assay in a foreign cell type, even for a highly cell type-specific TF like CRX, suggests that this approach shows promise for DMS of other TFs that function in cell types that are not easily accessible. Together, the results of the CRX DMS identify molecular features of the CRX effector domain and demonstrate utility for integration into the clinical variant classification pipeline.

The diagnosis of maturity-onset diabetes of the young (MODY), a monogenic form of diabetes mellitus caused by a mutation in a single gene, is often uncertain until genetic testing is performed. We report a 13-yr-old Korean boy who was initially diagnosed with type 2 diabetes (T2DM). MODY was suspected because of his nonobese body habitus and family history of multiple affected members. Targeted panel sequencing of all MODY-related genes was performed using the NextSeq 550Dx platform (Illumina). Sanger sequencing was performed using blood samples from the parents, siblings, and other relatives. A frameshift variant in the 3' region of the last exon of PDX1 was detected in the patient and his family members with diabetes. PP1_Moderate criterion was applied and this variant was confirmed to be the genetic cause of diabetes in the family and classified as likely pathogenic. The study highlights the importance of genetic testing for nonobese, early-onset diabetic patients with multiple affected family members. Increased awareness and aggressive genetic testing for MODY are needed.

Electron transport chain (ETC) disorders are a group of rare, multisystem diseases caused by impaired oxidative phosphorylation and energy production. Deficiencies in complex III (CIII), also known as ubiquinol–cytochrome c reductase, are particularly rare in humans. Ubiquinol–cytochrome c reductase core protein 2 (UQCRC2) encodes a subunit of CIII that plays a crucial role in dimerization. Several pathogenic UQCRC2 variants have been identified in patients presenting with metabolic abnormalities that include lactic acidosis, hyperammonemia, hypoglycemia, and organic aciduria. Almost all previously reported UQCRC2-deficient patients exhibited neurodevelopmental involvement, including developmental delays and structural brain anomalies. Here, we describe a girl who presented at 3 yr of age with lactic acidosis, hyperammonemia, and hypoglycemia but has not shown any evidence of neurodevelopmental dysfunction by age 15. Whole-exome sequencing revealed compound heterozygosity for two novel variants in UQCRC2: c.1189G>A; p.Gly397Arg and c.437T>C; p.Phe146Ser. Here, we discuss the patient's clinical presentation and the likely pathogenicity of these two missense variants.

Anorectal malformations (ARMs) constitute a group of congenital defects of the gastrointestinal and urogenital systems. They affect males and females, with an estimated worldwide prevalence of 1 in 5000 live births. These malformations are clinically heterogeneous and can be part of a syndromic presentation (syndromic ARM) or as a nonsyndromic entity (nonsyndromic ARM). Despite the well-recognized heritability of nonsyndromic ARM, the genetic etiology in most patients is unknown. In this study, we describe three siblings with diverse congenital anomalies of the genitourinary system, anemia, delayed milestones, and skeletal anomalies. Genome sequencing identified a novel, paternally inherited heterozygous Caudal type Homeobox 2 (CDX2) variant (c.722A > G (p.Glu241Gly)), that was present in all three affected siblings. The variant identified in this family is absent from population databases and predicted to be damaging by most in silico pathogenicity tools. So far, only two other reports implicate variants in CDX2 with ARMs. Remarkably, the individuals described in these studies had similar clinical phenotypes and genetic alterations in CDX2. CDX2 encodes a transcription factor and is considered the master regulator of gastrointestinal development. This variant maps to the homeobox domain of the encoded protein, which is critical for interaction with DNA targets. Our finding provides a potential molecular diagnosis for this family's condition and supports the role of CDX2 in anorectal anomalies. It also highlights the clinical heterogeneity and variable penetrance of ARM predisposition variants, another well-documented phenomenon. Finally, it underscores the diagnostic utility of genomic profiling of ARMs to identify the genetic etiology of these defects.

We identified a de novo heterozygous transient receptor potential cation channel subfamily M (melastatin) member 3 (TRPM3) missense variant, p.(Asn1126Asp), in a patient with developmental delay and manifestations of cerebral palsy (CP) using phenotype-driven prioritization analysis of whole-genome sequencing data with Exomiser. The variant is localized in the functionally important ion transport domain of the TRPM3 protein and predicted to impact the protein structure. Our report adds TRPM3 to the list of Mendelian disease–associated genes that can be associated with CP and provides further evidence for the pathogenicity of the variant p.(Asn1126Asp).

Here, we highlight the case of a 31-yr-old man who had clinical features of primary hypertrophic osteoarthropathy (PHOAR) and harbored a homozygous variant (c.38C > A, p.Ala13Glu) in the HPGD gene, as indicated by whole-exome sequencing (WES). This variant has been previously classified by our laboratory as a variant of uncertain significance (VUS). However, another patient with the same phenotype and the same homozygous variant in HPGD was subsequently reported. In reassessing the variant, the absence of this variant in the gnomAD population database, supporting computational predictions, observation in homozygosity in two probands, and specificity of the phenotype for HPGD, all provide sufficient evidence to reclassify the HPGD c.38C > A, p.Ala13Glu variant as likely pathogenic.

TP53 plays a critical role as a tumor suppressor by controlling cell cycle progression, DNA repair, and apoptosis. Post-translational modifications such as acetylation of specific lysine residues in the DNA binding and carboxy-terminus regulatory domains modulate its tumor suppressor activities. In this study, we addressed the functional consequences of the germline TP53 p.K164E (NM_000546.5: c.490A>G) variant identified in a patient with early-onset breast cancer and a significant family history of cancer. K164 is a conserved residue located in the L2 loop of the p53 DNA binding domain that is post-translationally modified by acetylation. In silico, in vitro, and in vivo analyses demonstrated that the glutamate substitution at K164 marginally destabilizes the p53 protein structure but significantly impairs sequence-specific DNA binding, transactivation, and tumor cell growth inhibition. Although p.K164E is currently considered a variant of unknown significance by different clinical genetic testing laboratories, the clinical and laboratory-based findings presented here provide strong evidence to reclassify TP53 p.K164E as a likely pathogenic variant.

T-lymphoblastic lymphoma (T-LLy) is the most common lymphoblastic lymphoma in children and often presents with a mediastinal mass. Lymphomatous suprarenal masses are possible but rare. Here, we discuss the case of a previously healthy 3-yr-old male who presented with mediastinal T-LLy with bilateral suprarenal masses. Following initial treatment, surgical biopsy of persisting adrenal masses revealed bilateral neuroblastoma (NBL). A clinical genetics panel for germline cancer predisposition did not identify any pathogenic variants. Combination large panel (864 genes) profiling analysis in the context of a precision oncology study revealed two novel likely pathogenic heterozygous variants: SMARCA4 c.1420-1G > T p.? and EZH2 c.1943G > C p.(Ile631Phefs*44). Somatic analysis revealed potential second hits/somatic variants in EZH2 (in the T-LLy) and a segmental loss in Chromosome 19p encompassing SMARCA4 (in the NBL). Synchronous cancers, especially at a young age, warrant genetic evaluation for cancer predisposition; enrollment in a precision oncology program assessing germline and tumor DNA can fulfill that purpose, particularly when standard first-line genetic testing is negative and in the setting of tumors that are not classic for common cancer predisposition syndromes.

A new covid-19 variant called XEC may spread more easily than past variants, but current vaccines are still effective against it

In Uttar Pradesh the DEN-2 variant of dengue is increasingly common among people who have tested positive for this mosquito-transmitted disease (!--ref1--).

Researchers from the National Institutes of Health (NIH), US have identified over 275 million medlinkgenetic variants/medlink that were not previously reported.

Accessory conduction pathways in the heart, associated with medlinkWolff-Parkinson-White syndrome/medlink, can lead to rhythm disturbances uncovered

A growing number of studies indicate Omicron is more resistant to current vaccines than previous Covid variants, though boosters seem to help. WSJ’s Daniela Hernandez gets an exclusive look inside a lab testing how antibodies interact with Omicron. Photo illustration: Tom Grillo

The Omicron variant caused more than 70% of new coronavirus cases in the U.S. registered the week ending Dec. 18, according to the Centers for Disease Control and Prevention. The surge comes as the holidays approach and some people reconsider travel plans. Photo: Jeenah Moon/Bloomberg

Scientists are using automation, real-time analysis and pooling data from around the world to rapidly identify and understand new coronavirus variants before the next one spreads widely. Photo Illustration: Sharon Shi

Apple is gearing up for a significant update across its Mac computer range, focusing on the integration of artificial intelligence (AI) capabilities through its upcoming M4 chipset. The tech giant, headquartered in Cupertino, California, has already introduced its M3 chip in

Maruti has introduced the latest version of the Dzire in India, starting at Rs 6.79 lakh (introductory ex-showroom price) until 31 December. The car is available in four trims, with two engine choices and two transmission options. The Dzire's pricing begins

Maruti Suzuki launched the fourth-generation Dzire in India on the 11th of November, revealing the nation's most popular sedan in its newest avatar. The new 2024 Maruti Suzuki Dzire is offered in four distinct variant levels - LXI, VXI, ZXI and

Basel ; Boston : Birkhauser, 2007

The number of hospitalisations in 20 days since the Omicron variant was discovered was relatively lower than the pace observed during the Delta wave in Gauteng in South Africa

Short α-synuclein peptide affects uptake of dopamine rather than forming typical clumps in the brain

The Honda SP125 competitor comes with an optional front disc brake but the drum version accords a better price point.

Bajaj Platina 110 H-Gear sees a considerable price hike with the launch of the BS6 model. Here is how much more you need to pay now and what all has changed!

The Indian FTR Carbon only recently made its global debut and it has been advertised on the company’s India region website suggesting its arrival to our market soon.

The Hero Xpulse T is supposed to be a road going tourer version but here is the catch behind this motorcycle.

Olfactomedins are a family of modular proteins found in multicellular organisms that all contain five-bladed β-propeller olfactomedin (OLF) domains. In support of differential functions for the OLF propeller, the available crystal structures reveal that only some OLF domains harbor an internal calcium-binding site with ligands derived from a triad of residues. For the myocilin OLF domain (myoc-OLF), ablation of the ion-binding site (triad Asp, Asn, Asp) by altering the coordinating residues affects the stability and overall structure, in one case leading to misfolding and glaucoma. Bioinformatics analysis reveals a variety of triads with possible ion-binding characteristics lurking in OLF domains in invertebrate chordates such as Arthropoda (Asp–Glu–Ser), Nematoda (Asp–Asp–His) and Echinodermata (Asp–Glu–Lys). To test ion binding and to extend the observed connection between ion binding and distal structural rearrangements, consensus triads from these phyla were installed in the myoc-OLF. All three protein variants exhibit wild-type-like or better stability, but their calcium-binding properties differ, concomitant with new structural deviations from wild-type myoc-OLF. Taken together, the results indicate that calcium binding is not intrinsically destabilizing to myoc-OLF or required to observe a well ordered side helix, and that ion binding is a differential feature that may underlie the largely elusive biological function of OLF propellers.

Appendices B4 and B5 of Cayron [Acta Cryst. (2019), A75, 411–437] contain equations involving the point group and the metric tensor in which the equality symbol should be substituted by the inclusion symbol.

Researchers isolate a gene mutation that might give a strong indication on whether or not a person will develop type 2 diabetes.

North Korea-linked hacking group Lazarus has been leveraging a Mac variant of the Dacls Remote Access Trojan (RAT), Malwarebytes reports.

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In this article, we characterize nearly invariant subspaces of finite defect for the backward shift operator acting on the vector-valued Hardy space which is a vectorial generalization of a result of Chalendar-Gallardo-Partington (C-G-P). Using this characterization of nearly invariant subspace under the backward shift we completely describe the almost invariant subspaces for the shift and its adjoint acting on the vector valued Hardy space.

We study an equivariant extension of the Batalin-Vilkovisky formalism for quantizing gauge theories. Namely, we introduce a general framework to encompass failures of the quantum master equation, and we apply it to the natural equivariant extension of AKSZ solutions of the classical master equation (CME). As examples of the construction, we recover the equivariant extension of supersymmetric Yang-Mills in 2d and of Donaldson-Witten theory.

The characterization of phase dynamics in coupled oscillators offers insights into fundamental phenomena in complex systems. To describe the collective dynamics in the oscillatory system, order parameters are often used but are insufficient for identifying more specific behaviors. We therefore propose a topological approach that constructs quantitative features describing the phase evolution of oscillators. Here, the phase data are mapped into a high-dimensional space at each time point, and topological features describing the shape of the data are subsequently extracted from the mapped points. We extend these features to time-variant topological features by considering the evolution time, which serves as an additional dimension in the topological-feature space. The resulting time-variant features provide crucial insights into the time evolution of phase dynamics. We combine these features with the machine learning kernel method to characterize the multicluster synchronized dynamics at a very early stage of the evolution. Furthermore, we demonstrate the usefulness of our method for qualitatively explaining chimera states, which are states of stably coexisting coherent and incoherent groups in systems of identical phase oscillators. The experimental results show that our method is generally better than those using order parameters, especially if only data on the early-stage dynamics are available.

We introduce a Gaussian measure formally preserved by the 2-dimensional Primitive Equations driven by additive Gaussian noise. Under such measure the stochastic equations under consideration are singular: we propose a solution theory based on the techniques developed by Gubinelli and Jara in cite{GuJa13} for a hyperviscous version of the equations.

In this paper we construct an equivariant embedding of the affine space $mathbb{A}^n$ with the translation group action into a complete non-projective algebraic variety $X$ for all $n geq 3$. The theory of toric varieties is used as the main tool for this construction. In the case of $n = 3$ we describe the orbit structure on the variety $X$.

In learning-to-rank for information retrieval, a ranking model is automatically learned from the data and then utilized to rank the sets of retrieved documents. Therefore, an ideal ranking model would be a mapping from a document set to a permutation on the set, and should satisfy two critical requirements: (1)~it should have the ability to model cross-document interactions so as to capture local context information in a query; (2)~it should be permutation-invariant, which means that any permutation of the inputted documents would not change the output ranking. Previous studies on learning-to-rank either design uni-variate scoring functions that score each document separately, and thus failed to model the cross-document interactions; or construct multivariate scoring functions that score documents sequentially, which inevitably sacrifice the permutation invariance requirement. In this paper, we propose a neural learning-to-rank model called SetRank which directly learns a permutation-invariant ranking model defined on document sets of any size. SetRank employs a stack of (induced) multi-head self attention blocks as its key component for learning the embeddings for all of the retrieved documents jointly. The self-attention mechanism not only helps SetRank to capture the local context information from cross-document interactions, but also to learn permutation-equivariant representations for the inputted documents, which therefore achieving a permutation-invariant ranking model. Experimental results on three large scale benchmarks showed that the SetRank significantly outperformed the baselines include the traditional learning-to-rank models and state-of-the-art Neural IR models.

Multimodal Sentiment Analysis is an active area of research that leverages multimodal signals for affective understanding of user-generated videos. The predominant approach, addressing this task, has been to develop sophisticated fusion techniques. However, the heterogeneous nature of the signals creates distributional modality gaps that pose significant challenges. In this paper, we aim to learn effective modality representations to aid the process of fusion. We propose a novel framework, MISA, which projects each modality to two distinct subspaces. The first subspace is modality invariant, where the representations across modalities learn their commonalities and reduce the modality gap. The second subspace is modality-specific, which is private to each modality and captures their characteristic features. These representations provide a holistic view of the multimodal data, which is used for fusion that leads to task predictions. Our experiments on popular sentiment analysis benchmarks, MOSI and MOSEI, demonstrate significant gains over state-of-the-art models. We also consider the task of Multimodal Humor Detection and experiment on the recently proposed UR_FUNNY dataset. Here too, our model fares better than strong baselines, establishing MISA as a useful multimodal framework.

We show that the traveling salesman problem (TSP) and its many variants may be modeled as functional optimization problems over a graph. In this formulation, all vertices and arcs of the graph are functionals; i.e., a mapping from a space of measurable functions to the field of real numbers. Many variants of the TSP, such as those with neighborhoods, with forbidden neighborhoods, with time-windows and with profits, can all be framed under this construct. In sharp contrast to their discrete-optimization counterparts, the modeling constructs presented in this paper represent a fundamentally new domain of analysis and computation for TSPs and their variants. Beyond its apparent mathematical unification of a class of problems in graph theory, the main advantage of the new approach is that it facilitates the modeling of certain application-specific problems in their home space of measurable functions. Consequently, certain elements of economic system theory such as dynamical models and continuous-time cost/profit functionals can be directly incorporated in the new optimization problem formulation. Furthermore, subtour elimination constraints, prevalent in discrete optimization formulations, are naturally enforced through continuity requirements. The price for the new modeling framework is nonsmooth functionals. Although a number of theoretical issues remain open in the proposed mathematical framework, we demonstrate the computational viability of the new modeling constructs over a sample set of problems to illustrate the rapid production of end-to-end TSP solutions to extensively-constrained practical problems.

A modeling framework for evaluating the impact of weather conditions on farming and harvest operations applies real-time, field-level weather data and forecasts of meteorological and climatological conditions together with user-provided and/or observed feedback of a present state of a harvest-related condition to agronomic models and to generate a plurality of harvest advisory outputs for precision agriculture. A harvest advisory model simulates and predicts the impacts of this weather information and user-provided and/or observed feedback in one or more physical, empirical, or artificial intelligence models of precision agriculture to analyze crops, plants, soils, and resulting agricultural commodities, and provides harvest advisory outputs to a diagnostic support tool for users to enhance farming and harvest decision-making, whether by providing pre-, post-, or in situ-harvest operations and crop analyzes.

The invention relates to improved variants of the anti-serum albumin immunoglobulin single variable domain DOM7h-11, as well as ligands and drug conjugates comprising such variants, compositions, nucleic acids, vectors and hosts.

Variant factor H binding proteins that can elicit antibodies that are bactericidal for at least one strain of Neisseria meningitidis, compositions comprising such proteins, and methods of use of such proteins, are provided.