Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms

The phenotypic variability associated with pathogenic variants in Lysine Acetyltransferase 6B (KAT6B, a.k.a. MORF, MYST4) results in several interrelated syndromes including Say-Barber-Biesecker-Young-Simpson Syndrome and Genitopatellar Syndrome. Here we present 20 new cases representing 10 novel KAT6B variants. These patients exhibit a range of clinical phenotypes including intellectual disability, mobility and language difficulties, craniofacial dysmorphology, and skeletal anomalies. Given the range of features previously described for KAT6B-related syndromes, we have identified additional phenotypes including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported. We surveyed clinicians to qualitatively assess the ways families engage with genetic counselors upon diagnosis. We found that 56% (10/18) of individuals receive diagnoses before the age of 2 years (median age = 1.96 years), making it challenging to address future complications with limited accessible information and vast phenotypic severity. We used CRISPR to introduce truncating variants into the KAT6B gene in model cell lines and performed chromatin accessibility and transcriptome sequencing to identify key dysregulated pathways. This study expands the clinical spectrum and addresses the challenges to management and genetic counseling for patients with KAT6B-related disorders

Base eletrônica de dados clínicos e cirúrgicos em tromboembolismo venoso

Resumo: A criação de protocolos eletrônicos para auxílio na pesquisa científica acompanha a constante evolução médica. A criação de um banco de dados com capacidade de armazenamento de informações de pacientes e posterior recuperação das mesmas resultaria em uma produção científica de alta qualidade e confiabilidade.Objetivos: a) criar uma base de dados clínicos cirúrgicos em doenças vasculares e a partir desta base, criar uma nova base de dados clínicos e cirúrgicos em tromboembolismo venoso, b) informatizar esta base sob forma de um protocolo eletrônico, c) incorporar este protocolo eletrônico ao SINPE© (Sistema Integrado de Protocolos Eletrônicos) e d) realizar um projeto piloto para testar a funcionalidade do módulo analisador do SINPE©. Material e Método: Inicialmente, criou-se um banco de dados clínicos sobre as doenças vasculares, gerando-se o protocolo mestre. Utilizando-se a base teórica do protocolo mestre foi selecionada a base a ser utilizada no protocolo específico do tromboembolismo venoso. Depois, realizou-se a informatização e o armazenamento destes dados na forma de um software que viabiliza a transformação da base teórica de dados clínicos em sistema computadorizado para coleta de dados denominado SINPE©. Efetuou-se um estudo com a interpretação das informações obtidas através de estatísticas e gráficos pelo módulo SINPE© Analisador. Resultados: Os dados clínicos e cirúrgicos sobre tromboembolismo venoso puderam ser armazenados e posteriormente utilizados para a produção de um estudo científico. Estes dados puderam ser resgatados e itens específicos selecionados para pesquisa, a qual mostrou o número de coletas que satisfazem os parâmetros escolhidos e informações estatísticas sobre a mesma. Os 47 pacientes que foram incluídos no protocolo específico demonstraram a eficácia do método empregado. Conclusões: Foi possível criar, informatizar e armazenar uma base de dados sobre o tromboembolismo venoso, incorporando-a ao SINPE© . Conseguiu-se gerar um meio para coletar os dados de pacientes e realizar um estudo com os resultados armazenados

A Tweak for a PRF Mode of a Compression Function and Its Applications

We discuss a tweak for the domain extension called Merkle-Damgård with Permutation (MDP), which was presented at ASIACRYPT 2007. We first show that MDP may produce multiple independent pseudorandom functions (PRFs) using a single secret key and multiple permutations if the underlying compression function is a PRF against related-key attacks with respect to the permutations. Using this result, we then construct a hash-function-based MAC function, which we call FMAC, using a compression function as its underlying primitive. We also present a scheme to extend FMAC so as to take as input a vector of strings

Immuno-surgical management of pancreatic cancer with analysis of cancer exosomes

Exosomes (EXs), a type of extracellular vesicles secreted from various cells and especially cancer cells, mesenchymal cells, macrophages and other cells in the tumor microenvironment (TME), are involved in biologically malignant behaviors of cancers. Recent studies have revealed that EXs contain microRNAs on their inside and express proteins and glycolipids on their outsides, every component of which plays a role in the transmission of genetic and/or epigenetic information in cell-to-cell communications. It is also known that miRNAs are involved in the signal transduction. Thus, EXs may be useful for monitoring the TME of tumor tissues and the invasion and metastasis, processes that are associated with patient survival. Because several solid tumors secrete immune checkpoint proteins, including programmed cell death-ligand 1, the EX-mediated mechanisms are suggested to be potent targets for monitoring patients. Therefore, a companion therapeutic approach against cancer metastasis to distant organs is proposed when surgical removal of the primary tumor is performed. However, EXs and immune checkpoint mechanisms in pancreatic cancer are not fully understood, we provide an update on the recent advances in this field and evidence that EXs will be useful for maximizing patient benefit in precision medicine

Search for extraterrestrial antineutrino sources with the KamLAND detector

We present the results of a search for extraterrestrial electron antineutrinos ($\bar{\nu}_{e}$'s) in the energy range $8.3 MeV < E_{\bar{\nu}_{e}} < 31.8 MeV$ using the KamLAND detector. In an exposure of 4.53 kton-year, we identify 25 candidate events. All of the candidate events can be attributed to background, most importantly neutral current atmospheric neutrino interactions, setting an upper limit on the probability of $^{8}$B solar $\nu_{e}$'s converting into $\bar{\nu}_{e}$'s at $5.3 \times 10^{-5}$ (90% C.L.), if we assume an undistorted $\bar{\nu}_{e}$ shape. This limit corresponds to a solar $\bar{\nu}_{e}$ flux of $93 cm^{-2} s^{-1}$ or an event rate of $1.6 events (kton-year)^{-1}$ above the energy threshold $(E_{\bar{\nu}_{e}} > 8.3 MeV)$. The present data also allows us to set more stringent limits on the diffuse supernova neutrino flux and on the annihilation rates for light dark matter particles.Comment: 22 pages, 6 figure

Measurement of the 8B Solar Neutrino Flux with the KamLAND Liquid Scintillator Detector

We report a measurement of the neutrino-electron elastic scattering rate from 8B solar neutrinos based on a 123 kton-day exposure of KamLAND. The background-subtracted electron recoil rate, above a 5.5 MeV analysis threshold is 1.49+/-0.14(stat)+/-0.17(syst) events per kton-day. Interpreted as due to a pure electron flavor flux with a 8B neutrino spectrum, this corresponds to a spectrum integrated flux of 2.77+/-0.26(stat)+/-0.32(syst) x 10^6 cm^-2s^-1. The analysis threshold is driven by 208Tl present in the liquid scintillator, and the main source of systematic uncertainty is due to background from cosmogenic 11Be. The measured rate is consistent with existing measurements and with Standard Solar Model predictions which include matter enhanced neutrino oscillation.Comment: 6 pages, 3 figure

Wild grape alleviates nasal symptoms.

As expression level of allergic disease-sensitive genes are correlated with allergic symptom severity, suppression of these gene expressions could be good therapeutics. We have demonstrated that PKCδ signaling and NFAT signaling, involve in histamine H1 receptor (H1R) and IL-9 gene expressions, respectively, are responsible for the pathogenesis of allergic rhinitis. We explore anti-allergic compounds that suppress these signaling pathways and found that wild grape (WG) contains such compounds. Here, we investigated the effect of WG hot water extract (WGE) on the signaling pathways for PKCδ-mediated H1R and NFAT-mediated IL-9 gene expressions. WGE suppressed histamine/PMA-induced H1R gene up-regulation in HeLa cells. Toluene-2,4-diisocyanate (TDI)-induced H1R mRNA elevation in TDI-sensitized rats was also suppressed by WGE treatment. Treatment with WGE in combination with Awa-tea, suppresses NFAT signaling-mediated IL-9 gene, markedly alleviated nasal symptoms. Furthermore, WGE suppressed PMA-induced IL-33 gene up-regulation in Swiss 3T3 cells. Data suggest that combination of WGE, suppresses PKCδ signaling with Awa-tea, suppresses NFAT signaling would have distinct clinical and therapeutic advantages as a substitute for anti-allergic drugs. In addition, as the expression level of IL-33 mRNA was correlated with the blood eosinophils number in patients with pollinosis, WG could alleviate eosinophilic inflammation through the suppression of IL-33 gene expression

Optical sectioning in multi-foci Raman hyperspectral imaging

In this study, we compared the depth-discrimination and speed performance of multi-foci Raman hyperspectral imaging with the reference standard of a single laser point confocal Raman mapping. A liquid crystal spatial light modulator (LC-SLM) was employed for the generation of multi-foci laser beams, and a digital micromirror device (DMD) was used as a software-configurable reflective pinhole array. The patterns of the laser-foci and pinhole array can be rapidly changed without requiring any hardware alterations. Confocal patterns with different distance-to-size ratios were tested and compared. After optimisation of the laser foci pattern, we demonstrated the feasibility of multi-foci Raman hyperspectral microscopy for recording depth-resolved molecular maps of biological cells (Acanthamoeba castellanii trophozoites). Micrometric depth-discrimination and short acquisition times (20 minutes for single plane confocal image) was achieved