Genetic deletion of fibroblast growth factor 14 recapitulates phenotypic alterations underlying cognitive impairment associated with schizophrenia

Cognitive processing is highly dependent on the functional integrity of gamma-amino-butyric acid (GABA) interneurons in the brain. These cells regulate excitability and synaptic plasticity of principal neurons balancing the excitatory/inhibitory tone of cortical networks. Reduced function of parvalbumin (PV) interneurons and disruption of GABAergic synapses in the cortical circuitry result in desynchronized network activity associated with cognitive impairment across many psychiatric disorders, including schizophrenia. However, the mechanisms underlying these complex phenotypes are still poorly understood. Here we show that in animal models, genetic deletion of fibroblast growth factor 14 (Fgf14), a regulator of neuronal excitability and synaptic transmission, leads to loss of PV interneurons in the CA1 hippocampal region, a critical area for cognitive function. Strikingly, this cellular phenotype associates with decreased expression of glutamic acid decarboxylase 67 (GAD67) and vesicular GABA transporter (VGAT) and also coincides with disrupted CA1 inhibitory circuitry, reduced in vivo gamma frequency oscillations and impaired working memory. Bioinformatics analysis of schizophrenia transcriptomics revealed functional co-clustering of FGF14 and genes enriched within the GABAergic pathway along with correlatively decreased expression of FGF14, PVALB, GAD67 and VGAT in the disease context. These results indicate that Fgf14(-/-) mice recapitulate salient molecular, cellular, functional and behavioral features associated with human cognitive impairment, and FGF14 loss of function might be associated with the biology of complex brain disorders such as schizophrenia

Sedimentology and stratigraphic architecture of a fluvial to shallow-marine succession: The Jurassic Dhruma Formation, Saudi Arabia

The interaction of fluvial, tidal, and wave processes in coastal and paralic environments gives rise to sedimentary successions with highly varied styles of facies architecture; these are determined by the morphology and evolutionary behavior of the range of coastal sub-environments, which may be difficult to diagnose in subsurface sedimentary successions with limited well control. This study presents depositional models to account for stratigraphic complexity in a subsurface fluvial to shallow-marine succession, the Middle Jurassic Dhruma Formation, Saudi Arabia. The study achieves the following: i) it examines and demonstrates sedimentary relationships between various fluvial, nearshore, and shallow-marine deposits, ii) it develops depositional models to account for the stratigraphic complexity inherent in fluvial to shallow-marine successions, and iii) it documents the sedimentology and the stratigraphic evolutionary patterns of the lower Dhruma Formation in the studied area of Saudi Arabia. The dataset comprises facies descriptions of 570 m of core from 14 wells, 77 representative core thin sections, 14 gamma-ray logs, and FMI image logs from 4 wells. These data are integrated with quantitative information from > 50 analogous systems from a wide range of modern and ancient settings, stored in a relational database. Stratigraphic correlations reveal the internal anatomy of the succession. Facies associations are representative of fluvial channels, intertidal flats, pedogenically modified supratidal flats or floodplains, river-influenced tidal bars, weakly storm-affected shoreface and offshore-transition zones, storm-dominated delta-front and prodelta settings, and an open-marine carbonate-dominated shelf. These sub-environments interacted in a complex way through space and time. The vertical succession of the studied interval records an overall transition from coastal-plain deposits at the base to marine deposits at the top. As such, the succession records a long-term transgressive, deepening-upward trend. However, this general trend is punctuated by repeated progradational events whereby coastal sand bodies of fluvial, wave, and tidal origin prograded basinward during stillstands to fill bays along a coastline. The nature of juxtaposition of neighboring sub-environments has resulted in a sedimentary record that is highly complex compared to that generated by morphologically simple shoreface systems that accumulate more regularly ordered stratal packages

Partial Purification and Characterization of Exo-Polygalacturonase Produced by Penicillium oxalicum AUMC 4153

Pectinase enzymes are important industrial enzymes having considerable applications in several industries, especially in food processing. Pectinases contribute 25% of global food enzyme sales. Therefore, the demand for a commercial enzyme with desirable characteristics and low production costs has become one of the great targets. Hence, this study aims to produce exo-polygalacturonase (exo-PG) using local fungal isolate Penicillium oxalicum AUMC 4153 by utilizing sugar beet manufacturing waste (sugar beet pulp) as a sole raw carbon source under shaken submerged fermentation, which is purified and characterized to optimize enzyme biochemical properties for industrial application. The purity of the obtained exo-PG was increased by about 28-fold, and the final enzyme yield was 57%. The partially purified enzyme was active at a broad range of temperatures (30–60 °C). The optimum temperature and pH for the purified exo-PG activity were 50 °C and pH 5. The enzyme was stable at a range of pH 3 to 6 and temperature 30–50 °C for 210 min. The values for Km and Vmax were 0.67 mg/mL, with polygalacturonic acid as substrate and 6.13 µmole galacturonic acid/min/mg protein, respectively. It can be concluded that purified exo-PG production by P. oxalicum grown on sugar beet waste is a promising effective method for useful applications.</jats:p

Improving the Melting Duration of a PV/PCM System Integrated with Different Metal Foam Configurations for Thermal Energy Management

Data Availability Statement: Not applicable.Copyright: © 2022 by the authors. The melting duration in the photovoltaic/phase-change material (PV/PCM) system is a crucial parameter for thermal energy management such that its improvement can realize better energy management in respect to thermal storage capabilities, thermal conditions, and the lifespan of PV modules. An innovative and efficient technique for improving the melting duration is the inclusion of an exterior metal foam layer in the PV/PCM system. For detailed investigations of utilizing different metal foam configurations in terms of their convective heat transfer coefficients, the present paper proposes a newly developed mathematical model for the PV/PCM–metal foam assembly that can readily be implemented with a wide range of operating conditions. Both computational fluid dynamic (CFD) and experimental validations proved the good accuracy of the proposed model for further applications. The present research found that the average PV cell temperature can be reduced by about 12 °C with a corresponding improvement in PCM melting duration of 127%. The addition of the metal foam is more effective at low solar radiation, ambient temperatures far below the PCM solidus temperature, and high wind speeds in nonlinear extension. With increasing of tilt angle, the PCM melting duration is linearly decreased by an average value of (13.4–25.0)% when the metal foam convective heat transfer coefficient is changed in the range of (0.5–20) W/m2.K. The present research also shows that the PCM thickness has a positive linear effect on the PCM melting duration, however, modifying the metal foam configuration from 0.5 to 20 W/m2.K has an effect on the PCM melting duration in such a way that the average PCM melting duration is doubled. This confirms the effectiveness of the inclusion of metal foam in the PV/PCM system.Funding: This research received no external funding

Environmental enrichment and social isolation mediate neuroplasticity of medium spiny neurons through the GSK3 pathway

Resilience and vulnerability to neuropsychiatric disorders are linked to molecular changes underlying excitability that are still poorly understood. Here, we identify glycogen-synthase kinase 3b (GSK3b) and voltage-gated Na+ channel Nav1.6 as regulators of neuroplasticity induced by environmentally enriched (EC) or isolated (IC) conditions\u2014models for resilience and vulnerability. Transcriptomic studies in the nucleus accumbens from EC and IC rats predicted low levels of GSK3b and SCN8A mRNA as a protective phenotype associated with reduced excitability in medium spiny neurons (MSNs). In vivo genetic manipulations demonstrate that GSK3b and Nav1.6 are molecular determinants of MSN excitability and that silencing of GSK3b prevents maladaptive plasticity of IC MSNs. In vitro studies reveal direct interaction of GSK3b with Nav1.6 and phosphorylation at Nav1.6T1936 by GSK3b. A GSK3b-Nav1.6T1936 competing peptide reduces MSNs excitability in IC, but not EC rats. These results identify GSK3b regulation of Nav1.6 as a biosignature ofMSNs maladaptive plasticity

Genetic and phenotypic characterization of NKX6‐2‐related spastic ataxia and hypomyelination

Background and purpose Hypomyelinating leukodystrophies are a heterogeneous group of genetic disorders with a wide spectrum of phenotypes and a high rate of genetically unsolved cases. Bi‐allelic mutations in NKX6‐2 were recently linked to spastic ataxia 8 with hypomyelinating leukodystrophy. Methods Using a combination of homozygosity mapping, exome sequencing, and detailed clinical and neuroimaging assessment a series of new NKX6‐2 mutations in a multicentre setting is described. Then, all reported NKX6‐2 mutations and those identified in this study were combined and an in‐depth analysis of NKX6‐2‐related disease spectrum was provided. Results Eleven new cases from eight families of different ethnic backgrounds carrying compound heterozygous and homozygous pathogenic variants in NKX6‐2 were identified, evidencing a high NKX6‐2 mutation burden in the hypomyelinating leukodystrophy disease spectrum. Our data reveal a phenotype spectrum with neonatal onset, global psychomotor delay and worse prognosis at the severe end and a childhood onset with mainly motor phenotype at the milder end. The phenotypic and neuroimaging expression in NKX6‐2 is described and it is shown that phenotypes with epilepsy in the absence of overt hypomyelination and diffuse hypomyelination without seizures can occur. Conclusions NKX6‐2 mutations should be considered in patients with autosomal recessive, very early onset of nystagmus, cerebellar ataxia with hypotonia that rapidly progresses to spasticity, particularly when associated with neuroimaging signs of hypomyelination. Therefore, it is recommended that NXK6‐2 should be included in hypomyelinating leukodystrophy and spastic ataxia diagnostic panels

Contextualising adverse events of special interest to characterise the baseline incidence rates in 24 million patients with COVID-19 across 26 databases: a multinational retrospective cohort study

BACKGROUND: Adverse events of special interest (AESIs) were pre-specified to be monitored for the COVID-19 vaccines. Some AESIs are not only associated with the vaccines, but with COVID-19. Our aim was to characterise the incidence rates of AESIs following SARS-CoV-2 infection in patients and compare these to historical rates in the general population. METHODS: A multi-national cohort study with data from primary care, electronic health records, and insurance claims mapped to a common data model. This study's evidence was collected between Jan 1, 2017 and the conclusion of each database (which ranged from Jul 2020 to May 2022). The 16 pre-specified prevalent AESIs were: acute myocardial infarction, anaphylaxis, appendicitis, Bell's palsy, deep vein thrombosis, disseminated intravascular coagulation, encephalomyelitis, Guillain- Barré syndrome, haemorrhagic stroke, non-haemorrhagic stroke, immune thrombocytopenia, myocarditis/pericarditis, narcolepsy, pulmonary embolism, transverse myelitis, and thrombosis with thrombocytopenia. Age-sex standardised incidence rate ratios (SIR) were estimated to compare post-COVID-19 to pre-pandemic rates in each of the databases. FINDINGS: Substantial heterogeneity by age was seen for AESI rates, with some clearly increasing with age but others following the opposite trend. Similarly, differences were also observed across databases for same health outcome and age-sex strata. All studied AESIs appeared consistently more common in the post-COVID-19 compared to the historical cohorts, with related meta-analytic SIRs ranging from 1.32 (1.05 to 1.66) for narcolepsy to 11.70 (10.10 to 13.70) for pulmonary embolism. INTERPRETATION: Our findings suggest all AESIs are more common after COVID-19 than in the general population. Thromboembolic events were particularly common, and over 10-fold more so. More research is needed to contextualise post-COVID-19 complications in the longer term. FUNDING: None

Socializing One Health: an innovative strategy to investigate social and behavioral risks of emerging viral threats

In an effort to strengthen global capacity to prevent, detect, and control infectious diseases in animals and people, the United States Agency for International Development’s (USAID) Emerging Pandemic Threats (EPT) PREDICT project funded development of regional, national, and local One Health capacities for early disease detection, rapid response, disease control, and risk reduction. From the outset, the EPT approach was inclusive of social science research methods designed to understand the contexts and behaviors of communities living and working at human-animal-environment interfaces considered high-risk for virus emergence. Using qualitative and quantitative approaches, PREDICT behavioral research aimed to identify and assess a range of socio-cultural behaviors that could be influential in zoonotic disease emergence, amplification, and transmission. This broad approach to behavioral risk characterization enabled us to identify and characterize human activities that could be linked to the transmission dynamics of new and emerging viruses. This paper provides a discussion of implementation of a social science approach within a zoonotic surveillance framework. We conducted in-depth ethnographic interviews and focus groups to better understand the individual- and community-level knowledge, attitudes, and practices that potentially put participants at risk for zoonotic disease transmission from the animals they live and work with, across 6 interface domains. When we asked highly-exposed individuals (ie. bushmeat hunters, wildlife or guano farmers) about the risk they perceived in their occupational activities, most did not perceive it to be risky, whether because it was normalized by years (or generations) of doing such an activity, or due to lack of information about potential risks. Integrating the social sciences allows investigations of the specific human activities that are hypothesized to drive disease emergence, amplification, and transmission, in order to better substantiate behavioral disease drivers, along with the social dimensions of infection and transmission dynamics. Understanding these dynamics is critical to achieving health security--the protection from threats to health-- which requires investments in both collective and individual health security. Involving behavioral sciences into zoonotic disease surveillance allowed us to push toward fuller community integration and engagement and toward dialogue and implementation of recommendations for disease prevention and improved health security