SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of ...dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability-more than 1 in 50-warrant its consideration for mutation screening in clinical practice.
The study of the genetic and selective landscape of immunity genes across primates can provide insight into the existing differences in susceptibility to infection observed between human and ...non-human primates. Here, we explored how selection has driven the evolution of a key family of innate immunity receptors, the Toll-like receptors (TLRs), in African great ape species. We sequenced the 10 TLRs in various populations of chimpanzees and gorillas, and analysed these data jointly with a human data set. We found that purifying selection has been more pervasive in great apes than in humans. Furthermore, in chimpanzees and gorillas, purifying selection has targeted TLRs irrespectively of whether they are endosomal or cell surface, in contrast to humans where strong selective constraints are restricted to endosomal TLRs. These observations suggest important differences in the relative importance of TLR-mediated pathogen sensing, such as that of recognition of flagellated bacteria by TLR5, between humans and great apes. Lastly, we used a population genetics-phylogenetics method that jointly analyses polymorphism and divergence data to detect fine-scale variation in selection pressures at specific codons within TLR genes. We identified different codons at different TLRs as being under positive selection in each species, highlighting that functional variation at these genes has conferred a selective advantage in immunity to infection to specific primate species. Overall, this study showed that the degree of selection driving the evolution of TLRs has largely differed between human and non-human primates, increasing our knowledge on their respective biological contribution to host defence in the natural setting.
SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of ...dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ~1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability--more than 1 in 50--warrant its consideration for mutation screening in clinical practice.
SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of ...dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability-more than 1 in 50-warrant its consideration for mutation screening in clinical practice.
SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of ...dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability-more than 1 in 50-warrant its consideration for mutation screening in clinical practice.
Despite decades of effort in understanding pancreatic ductal adenocarcinoma (PDAC), there is still a lack of innovative targeted therapies for this devastating disease. Herein, we report the ...expression of apelin and its receptor, APJ, in human pancreatic adenocarcinoma and its protumoral function. Apelin and APJ protein expression in tumor tissues from patients with PDAC and their spatiotemporal pattern of expression in engineered mouse models of PDAC were investigated by immunohistochemistry. Apelin signaling function in tumor cells was characterized in pancreatic tumor cell lines by Western blot as well as proliferation, migration assays and in murine orthotopic xenograft experiments. In premalignant lesions, apelin was expressed in epithelial lesions whereas APJ was found in isolated cells tightly attached to premalignant lesions. However, in the invasive stage, apelin and APJ were co-expressed by tumor cells. In human tumor cells, apelin induced a long-lasting activation of PI3K/Akt, upregulated β-catenin and the oncogenes c-myc and cyclin D1 and promoted proliferation, migration and glucose uptake. Apelin receptor blockades reduced cancer cell proliferation along with a reduction in pancreatic tumor burden. These findings identify the apelin signaling pathway as a new actor for PDAC development and a novel therapeutic target for this incurable disease.
The field of environmental DNA (eDNA) has rapidly advanced in recent years, providing a non‐invasive and time‐saving method for assessing biodiversity. The First International Environmental DNA ...(eDNA) Workshop in Hong Kong was held from 16 to 27 October 2023 and provided early career professionals with hands‐on training and collaboration opportunities in eDNA research. With support from The Croucher Foundation Limited (Hong Kong), the workshop covered all stages of an eDNA‐based research project, including study design, field sampling, eDNA extraction, library preparation, bioinformatics, statistical data analysis, and ethics in scientific research. Participants gained insights into the principles and practical applications of eDNA technology, emphasizing the importance of careful experimental design and data interpretation. The workshop also highlighted the need for standardized protocols, comprehensive and local DNA reference databases, and careful selection of primer sets to overcome current issues and limitations. Workshop participants expressed enthusiasm for the potential of eDNA metabarcoding as a valuable tool for ecological monitoring, biodiversity assessment, and conservation decision‐making. The future of eDNA research looks promising overall, with continued advancements in technology, collaboration among researchers, and the integration of eDNA into large‐scale ecological monitoring. Future iterations of the Hong Kong International eDNA workshop will continue to provide hands‐on training and collaboration opportunities for early career professionals interested in eDNA research, focusing on addressing current limitations and challenges in the field.
The First International Environmental DNA (eDNA) Workshop in Hong Kong offered early career professionals hands‐on training and collaboration opportunities in eDNA research. The workshop covered all aspects of the eDNA workflow, emphasizing the importance of careful experimental design and data interpretation. Participants expressed enthusiasm for the potential of eDNA metabarcoding as a valuable tool for ecological monitoring and conservation decision‐making.
Despite decades of effort in understanding pancreatic ductal adenocarcinoma (PDAC), there is still a lack of innovative targeted therapies for this devastating disease. Herein, we report the ...expression of apelin and its receptor, APJ, in human pancreatic adenocarcinoma and its protumoral function. Apelin and APJ protein expression in tumor tissues from patients with PDAC and their spatiotemporal pattern of expression in engineered mouse models of PDAC were investigated by immunohistochemistry. Apelin signaling function in tumor cells was characterized in pancreatic tumor cell lines by Western blot as well as proliferation, migration assays and in murine orthotopic xenograft experiments. In premalignant lesions, apelin was expressed in epithelial lesions whereas APJ was found in isolated cells tightly attached to premalignant lesions. However, in the invasive stage, apelin and APJ were co-expressed by tumor cells. In human tumor cells, apelin induced a long-lasting activation of PI3K/Akt, upregulated β-catenin and the oncogenes c-myc and cyclin D1 and promoted proliferation, migration and glucose uptake. Apelin receptor blockades reduced cancer cell proliferation along with a reduction in pancreatic tumor burden. These findings identify the apelin signaling pathway as a new actor for PDAC development and a novel therapeutic target for this incurable disease.
Svårläkta bensår är ett tillstånd som drabbar många personer i Sverige och i världen. De flesta personer är mellan 75 och 80 år gamla. Att leva med svårläkta bensår kan vara ansträngande på grund av ...symtom såsom smärta, lukt och sårsekretion. Patientens hälsa och livskvalitet påverkas individuellt och i olika grad. Konsekvenserna i patientens dagliga liv verkar mest vara av fysisk karaktär och orsakad av smärta. Men hälsotillståndet kan också påverka patientens mentala hälsa och sociala liv med till exempel känslor av skam och social isolering. Patientens symtom behandlas i första hand både omvårdnadsmässigt och farmakologiskt för att minska lidandet. Men främst av allt behöver patienten stöd från sjukvården och särskilt från sin sjuksköterska. Att sjuksköterskan och patienten samarbetar under goda förutsättningar är av vikt för att nå sårläkning. Andelen patienter med svårläkta bensår beräknas öka i framtiden till följd av ökad mängd som blir äldre. Denna litteraturöversikts syfte var att belysa vuxna patienters upplevelse av det dagliga livet i samband med svårläkta bensår samt betydelsen av vårdgivarens roll med hjälp av elva kvalitativa och kvantitativa vetenskapliga artiklar. Studien avser att skapa en översikt över befintlig kunskap och forskning inom detta område. Resultatet presenteras i fyra huvudkategorier och nio underkategorier. Studiens resultat visar att vuxna patienter som lever med svårläkta bensår drabbas av symtom, inskränkt fysisk aktivitet, social begränsning och tillståndet leder många gånger till långvarig kontakt med vården. I diskussionsdelen diskuteras vikten av fysisk aktivitet för att uppleva hälsa men också människans behov av sammanhang och betydelsen av ett gott vårdbemötande för att öka livskvaliteten.
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