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Objective: To assess whether gut microbiota composition is associated with patient characteristics and may have predictive value on the response to TNF inhibitor (TNFi) treatment in axial spondyloarthritis (AxSpA)., Methods: The study involved 61 patients fulfilling the Assessment of SpondyloArthritis International Society classification criteria for AxSpA. All patients had active disease despite non-steroidal anti-inflammatory drugs intake and were eligible for treatment with a TNFi. At baseline, the mean Ankylosing Spondylitis Disease Activity Score was 2.9±1 and mean C reactive protein (CRP) level 9.7±11.4 mg/L. Bacterial 16S ribosomal RNA gene sequencing was performed on stool samples collected at baseline (month 0 (M0)) and 3 months after TNFi initiation (month 3 (M3)). Alpha and beta diversity metrics were calculated on the relative abundance of core operational taxonomic units (OTUs)., Results: The HLA-B27 status affected at least in part the global composition of faecal microbiota at M0 as well as the abundance/prevalence of several anaerobic bacteria in the families Oscillospiraceae , Lachnospiraceae and Bifidobacteriaceae . In contrast, smoking affected the global composition of faecal microbiota at both M0 and M3. The prevalence/abundance of seven bacterial OTUs at M0 was associated with response to TNFi treatment. One of the candidates, present only in non-responders, is the genus Sutterella , and the other six candidates are in the class Clostridia ., Conclusions: Several SpA patients' characteristics modulate the composition of gut microbiota as did TNFi treatment. Moreover, the abundance/prevalence of seven OTUs at baseline may be used as a novel non-invasive index that predicts the response to TNFi with greater accuracy than HLA-B27 status, CRP level and measures of disease activity., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The triggering and development of Rheumatoid Arthritis (RA) is conditioned by environmental and genetic factors. Despite the identification of more than one hundred genetic variants associated with the disease, not all the cases can be explained. Here, we performed Whole Exome Sequencing in 9 multiplex families (N = 30) to identify rare variants susceptible to play a role in the disease pathogenesis. We pre-selected 77 genes which carried rare variants with a complete segregation with RA in the studied families. Follow-up linkage and association analyses with pVAAST highlighted significant RA association of 43 genes (p-value < 0.05 after 106 permutations) and pinpointed their most likely causal variant. We re-sequenced the 10 most significant likely causal variants (p-value ≤ 3.78*10-3 after 106 permutations) in the extended pedigrees and 9 additional multiplex families (N = 110). Only one SNV in SUPT20H: c.73A>T (p.Lys25*), presented a complete segregation with RA in an extended pedigree with early-onset cases. In summary, we identified in this study a new variant associated with RA in SUPT20H gene. This gene belongs to several biological pathways like macro-autophagy and monocyte/macrophage differentiation, which contribute to RA pathogenesis. In addition, these results showed that analyzing rare variants using a family-based approach is a strategy that allows to identify RA risk loci, even with a small dataset., Competing Interests: The authors have declared that no competing interests exist.

Background: A Tat Oyi vaccine preparation was administered with informed consent to 48 long-term HIV-1 infected volunteers whose viral loads had been suppressed by antiretroviral therapy (cART). These volunteers were randomized in double-blind method into four groups (n = 12) that were injected intradermally with 0, 11, 33, or 99 µg of synthetic Tat Oyi proteins in buffer without adjuvant at times designated by month 0 (M0), M1 and M2, respectively. The volunteers then underwent a structured treatment interruption between M5 and M7., Results: The primary outcomes of this phase I/IIa clinical trial were the safety and lowering the extent of HIV RNA rebound after cART interruption. Only one undesirable event possibly due to vaccination was observed. The 33 µg dose was most effective at lowering the extent of HIV RNA and DNA rebound (Mann and Whitney test, p = 0.07 and p = 0.001). Immune responses against Tat were increased at M5 and this correlated with a low HIV RNA rebound at M6 (p = 0.01)., Conclusion: This study suggests in vivo that extracellular Tat activates and protects HIV infected cells. The Tat Oyi vaccine in association with cART may provide an efficient means of controlling the HIV-infected cell reservoir.

Objective: To identify the genetic defects present in 3 families with muscular dystrophy, contractures, and calpain 3 deficiency., Methods: We performed targeted exome sequencing on one patient presenting a deficiency in calpain 3 on Western blot but for which mutations in the gene had been excluded. The identification of a homozygous truncating mutation in the M-line part of titin prompted us to sequence this region in 2 additional patients presenting similar clinical and biochemical characteristics., Results: The 3 patients shared similar features: coexistence of limb-girdle weakness and early-onset diffuse joint contractures without cardiomyopathy. The biopsies showed rimmed vacuoles, a dystrophic pattern, and secondary reduction in calpain 3. We identified a novel homozygous mutation in the exon Mex3 of the TTN gene in the first patient. At protein level, this mutation introduces a stop codon at the level of Mex3. Interestingly, we identified truncating mutations in both alleles in the same region of the TTN gene in patients from 2 additional families. Molecular protein analyses confirm loss of the C-ter part of titin., Conclusions: Our study broadens the phenotype of titinopathies with the report of a new clinical entity with prominent contractures and no cardiac abnormality and where the recessive mutations lead to truncation of the M-line titin and secondary calpain 3 deficiency., (© 2015 American Academy of Neurology.)

The human ERBB2 proto-oncogene is widely considered a key gene involved in human breast cancer onset and progression. Among spontaneous tumors, mammary tumors are the most frequent cause of cancer death in cats and second most frequent in humans. In fact, naturally occurring tumors in domestic animals, more particularly cat mammary tumors, have been proposed as a good model for human breast cancer, but critical genetic and molecular information is still scarce. The aims of this study include the analysis of the cat ERBB2 gene partial sequences (between exon 17 and 20) in order to characterize a normal and a mammary lesion heterogeneous populations. Cat genomic DNA was extracted from normal frozen samples (n = 16) and from frozen and formalin-fixed paraffin-embedded mammary lesion samples (n = 41). We amplified and sequenced two cat ERBB2 DNA fragments comprising exons 17 to 20. It was possible to identify five sequence variants and six haplotypes in the total population. Two sequence variants and two haplotypes show to be specific for cat mammary tumor samples. Bioinformatics analysis predicts that four of the sequence variants can produce alternative transcripts or activate cryptic splicing sites. Also, a possible association was identified between clinicopathological traits and the variant haplotypes. As far as we know, this is the first attempt to examine ERBB2 genetic variations in cat mammary genome and its possible association with the onset and progression of cat mammary tumors. The demonstration of a possible association between primary tumor size (one of the two most important prognostic factors) and the number of masses with the cat ERBB2 variant haplotypes reveal the importance of the analysis of this gene in veterinary medicine.

Background: Congenital heart disease (CHD) is the most common congenital anomaly. Up to 33% have an identifiable genetic etiology. Improved medical and surgical management of CHD has translated into longer life expectancy and a rapidly growing population of adults living with CHD. The adult CHD (ACHD) population did not have access during childhood to the genetic technologies available today and therefore have not had a robust genetic evaluation that is currently recommended for infants with CHD. Given this potential benefit; the aims of this study were to determine how ACHD cardiologists offer genetics services to patients and identify the indications that influence decision-making for genetics care. Methods: We performed a descriptive cross-sectional study of ACHD cardiologists. A study-developed questionnaire was distributed via emailed REDCap link. The recruitment email was sent to 104 potential respondents. The survey was open from 06/2022 to 01/2023. Results: Thirty-five cardiologists participated in the study (response rate of 34%). Most cardiologists identified as white (77%) and male (66%). Cardiologists were more likely to refer patients to genetics (91%) than to order testing themselves (57%). Of the testing ordered, chromosomal testing (55%) was ordered more than gene sequencing (14%). Most cardiologists would refer a patient with a conotruncal lesion (interrupted aortic arch) over other indications for a genetics evaluation. There were more reported barriers to ordering genetic testing (66%) compared to referring to genetics for a genetics evaluation (23%). Cardiologists were more confident recognizing features suggestive of a genetic syndrome than ordering the correct test (p = 0.001). Regarding associations between clinical factors and current practices, more years in practice trended towards less referrals and testing. Evaluating a greater number of patients (p = 0.11) and greater confidence recognizing syndromic features (p = 0.12) and ordering the correct test (p = 0.09) were all associated with ordering more testing. Conclusion: Testing for microdeletion syndromes is being offered and completed in the ACHD population, however testing for single-gene disorders associated with CHD is being under-utilized. Developing guidelines for genetic testing in adults with CHD could increase access to genetic services, impact medical management, reduce uncertainty regarding prognosis, and inform recurrence risk estimates. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease caused by a combination of genetic and environmental factors. Rare variants with low predicted effects in genes participating in the same biological function might be involved in developing complex diseases such as RA. From whole-exome sequencing (WES) data, we identified genes containing rare non-neutral variants with complete penetrance and no phenocopy in at least one of nine French multiplex families. Further enrichment analysis highlighted focal adhesion as the most significant pathway. We then tested if interactions between the genes participating in this function would increase or decrease the risk of developing RA disease. The model-based multifactor dimensionality reduction (MB-MDR) approach was used to detect epistasis in a discovery sample (19 RA cases and 11 healthy individuals from 9 families and 98 unrelated CEU controls from the International Genome Sample Resource). We identified 9 significant interactions involving 11 genes (MYLK, FLNB, DOCK1, LAMA2, RELN, PIP5K1C, TNC, PRKCA, VEGFB, ITGB5, and FLT1). One interaction (MYLK*FLNB) increasing RA risk and one interaction decreasing RA risk (DOCK1*LAMA2) were confirmed in a replication sample (200 unrelated RA cases and 91 GBR unrelated controls). Functional and genomic data in RA samples or relevant cell types argue the key role of these genes in RA. [ABSTRACT FROM AUTHOR]

Objective: Inflammation has been associated with an increased risk for cancer development, while innate immune system activation could counteract the risk for malignancies. Familial Mediterranean fever (FMF) is a severe systemic inflammatory condition and also represents the archetype of innate immunity deregulation. Therefore, the aim of this study is to investigate the risk for cancer development in FMF. Methods: The risk ratio (RR) for malignancies was separately compared between FMF patients and fibromyalgia subjects, Still's disease patients and Behçet's disease patients. Clinical variables associated with cancer development in FMF patients were searched through binary logistic regression. Results: 580 FMF patients and 102 fibromyalgia subjects, 1012 Behçet's disease patients and 497 Still's disease patients were enrolled. The RR for the occurrence of malignant neoplasms was 0.26 (95% Confidence Interval [CI.] 0.10-0.73, p=0.006) in patients with FMF compared to fibromyalgia subjects; the RR for the occurrence of malignant cancer was 0.51 (95% CI. 0.23-1.16, p=0.10) in FMF compared to Still's disease and 0.60 (95% CI. 0.29-1.28, p=0.18) in FMF compared to Behçet's disease. At logistic regression, the risk of occurrence of malignant neoplasms in FMF patients was associated with the age at disease onset (β1 = 0.039, 95% CI. 0.001-0.071, p=0.02), the age at the diagnosis (β1 = 0.048, 95% CI. 0.039-0.085, p=0.006), the age at the enrolment (β1 = 0.05, 95% CI. 0.007-0.068, p=0.01), the number of attacks per year (β1 = 0.011, 95% CI. 0.001-0.019, p=0.008), the use of biotechnological agents (β1 = 1.77, 95% CI. 0.43-3.19, p=0.009), the use of anti-IL-1 agents (β1 = 2.089, 95% CI. 0.7-3.5, p=0.002). Conclusions: The risk for cancer is reduced in Caucasic FMF patients; however, when malignant neoplasms occur, this is more frequent in FMF cases suffering from a severe disease phenotype and presenting a colchicine-resistant disease. [ABSTRACT FROM AUTHOR]

The rolandic and sylvian fissures divide the human cerebral hemispheres and the adjacent areas participate in speech processing. The relationship of rolandic (sylvian) seizure disorders with speech and cognitive impairments is well known, albeit poorly understood. We have identified the Xq22 gene SRPX2 as being responsible for rolandic seizures (RSs) associated with oral and speech dyspraxia and mental retardation (MR). SRPX2 is a secreted sushi-repeat containing protein expressed in neurons of the human adult brain, including the rolandic area. The disease-causing mutation (N327S) resulted in gain-of-glycosylation of the secreted mutant protein. A second mutation (Y72S) was identified within the first sushi domain of SRPX2 in a male with RSs and bilateral perisylvian polymicrogyria and his female relatives with mild MR or unaffected carrier status. In cultured cells, both mutations were associated with altered patterns of intracellular processing, suggesting protein misfolding. In the murine brain, Srpx2 protein expression appeared in neurons at birth. The involvement of SRPX2 in these disorders suggests an important role for SRPX2 in the perisylvian region critical for language and cognitive development.

The successful exploitation of natural genetic diversity requires a basic knowledge of the extent of the variation present in a species. To study natural variation in Arabidopsis thaliana, we defined nested core collections maximizing the diversity present among a worldwide set of 265 accessions. The core collections were generated based on DNA sequence data from a limited number of fragments evenly distributed in the genome and were shown to successfully capture the molecular diversity in other loci as well as the morphological diversity. The core collections are available to the scientific community and thus provide an important resource for the study of genetic variation and its functional consequences in Arabidopsis. Moreover, this strategy can be used in other species to provide a rational framework for undertaking diversity surveys, including single nucleotide polymorphism (SNP) discovery and phenotyping, allowing the utilization of genetic variation for the study of complex traits.

Reconstruction of haplotypes, or the allelic phase, of single nucleotide polymorphisms (SNPs) is a key component of studies aimed at the identification and dissection of genetic factors involved in complex genetic traits. In humans, this often involves investigation of SNPs in case/control or other cohorts in which the haplotypes can only be partially inferred from genotypes by statistical approaches with resulting loss of power. Moreover, alternative statistical methodologies can lead to different evaluations of the most probable haplotypes present, and different haplotype frequency estimates when data are ambiguous. Given the cost and complexity of SNP studies, a robust and easy-to-use molecular technique that allows haplotypes to be determined directly from individual DNA samples would have wide applicability. Here, we present a reliable, automated and high-throughput method for molecular haplotyping in 2 kb, and potentially longer, sequence segments that is based on the physical determination of the phase of SNP alleles on either of the individual paternal haploids. We demonstrate that molecular haplotyping with this technique is not more complicated than SNP genotyping when implemented by matrix-assisted laser desorption/ionisation mass spectrometry, and we also show that the method can be applied using other DNA variation detection platforms. Molecular haplotyping is illustrated on the well-described beta(2)-adrenergic receptor gene.

As the largest set of sequence variants, single-nucleotide polymorphisms (SNPs) constitute powerful assets for mapping genes and mutations related to common diseases and for pharmacogenetic studies. A major goal in human genetics is to establish a high-density map of the genome containing several hundred thousand SNPs. Here we assayed 3.7 Mb (154,397 bp in 24 alleles) of chromosome 14 expressed sequence tags (ESTs) and sequence-tagged sites, for sequence variation in DNA samples from 12 African individuals. We identified and mapped 480 biallelic markers (459 SNPs and 21 small insertions and deletions), equally distributed between EST and non-EST classes. Extensive research in public databases also yielded 604 chromosome 14 SNPs (dbSNPs), 520 of which could be mapped and 19 of which are common between CNG (i.e., identified at the Centre National de Génotypage) and dbSNP polymorphisms. We present a dense map of SNP variation of human chromosome 14 based on 981 nonredundant biallelic markers present among 1345 radiation hybrid mapped sequence objects. Next, bioinformatic tools allowed 945 significant sequence alignments to chromosome 14 contigs, giving the precise chromosome sequence position for 70% of the mapped sequences and SNPs. In addition, these tools also permitted the identification and mapping of 273 SNPs in 159 known genes. The availability of this SNP map will permit a wide range of genetic studies on a complete chromosome. The recognition of 45 genes with multiple SNPs, by allowing the construction of haplotypes, should facilitate pharmacogenetic studies in the corresponding regions.

Background: A large family with autosomal dominant nocturnal frontal lobe epilepsy from the south of Spain was studied. The clinical appearance of the disease in this family, which included 28 members, of whom 11 were affected and 2 were obligate carriers, was identical to that previously described in an Australian family and a Norwegian family, in which mutations in exon 5 of the CHRNA4 gene were found., Methods: Following DNA extraction, the family was genotyped with 4 fluorescent markers flanking the locus to the CHRNA4 gene on chromosome 20q13.3, and lod score computations were performed. The exon 5 of the CHRNA4 gene was amplified between nucleotides 535 and 825 and polymerase chain reaction products were purified and sequenced directly., Results: The same missense mutation as that found in the Australian family, C-->T, which causes the replacement of a serine with phenylalanine in amino acid 252 in exon 5, was detected. This mutation segregated with the disorder in all 11 affected members, in the 2 obligate carriers, and in 1 asymptomatic sibling, and was not found in 1 spouse and 1 daughter. Neither of the 2 polymorphisms found in a series of families with epilepsy were found in our sample [corrected]., Conclusions: These data confirm the clinical homogeneity in the phenotypic expression of autosomal dominant nocturnal frontal lobe epilepsy caused by mutation in the CHRNA4 gene, and the pathogenic role of the Ser252Phe mutation in this disorder.

Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by recurring attacks of fever and serositis. It affects primarily North African Jews, Armenians, Turks and Arabs, in which a founder effect has been demonstrated. The marenostrin-pyrin-encoding gene has been proposed as a candidate gene for the disease ( MEFV ), on the basis of the identification of putative mutations clustered in exon 10 (M680V, M694I, M694V and V726A), each segregating with one ancestral haplotype. In a search for additional MEFV mutations in 120 apparently non-founder FMF chromosomes, we observed eight novel mutations in exon 2 (E148Q, E167D and T267I), exon 5 (F479L) and exon 10 (I692del K695R, A744S and R761H). Except for E148Q and K695R, all mutations were found in a single chromosome. Mutation E148Q was found in all ethnic groups studied and in association with a novel ancestral haplotype in non-Ashkenazi Jews (S2). Altogether, these new findings definitively establish the marenostrin/pyrin-encoding gene as the MEFV locus.

Familial Mediterranean fever (FMF) is a recessively inherited disorder characterized by attacks of fever and serositis, which affects primarily non-Ashkenazi Jews, Armenians, Turks, and Arabs. We present here a transcriptional map covering the FMF locus that we constructed in the course of the positional cloning of the gene responsible for this disease. This map was established from a contig constructed with YAC, BAC, and cosmid clones and covers about 500 kb of 16p13.3. It contains nine transcriptional units corresponding to known genes or to genes belonging to known gene families, 23 gene fragments characterized by partial sequences, and an endogenous retrovirus sequence. It thus considerably increases the number of genes in this interval and improves our knowledge concerning some of the genes or gene families present in this region. Data accumulated in this region were also used in a comparative study of different methods of exon detection.

The association between Inflammatory Bowel Disease (IBD) and Spondyloarthritis (SpA) has been known for years, as has the concept that IBD is associated with an altered intestinal bacterial composition, a condition known as "dysbiosis". Recently, a state of intestinal dysbiosis has also been found in SpA. Dysbiosis in the field of IBD has been well characterized so far, as well as in SpA. The aim of this review is to summarize what is known to date and to emphasize the similarities between the microbiota conditions in these two diseases: particularly, an altered distribution in the gut of Enterobacteriaceae, Streptococcus, Haemophilus, Clostridium, Akkermansia, Ruminococcus, Faecalibacterium Prausnitzii, Bacteroides Vulgatus, Dialister Invisus, and Bifidubacterium Adolescentis is common to both IBD and SpA. At the same time, little is known about intestinal dysbiosis in IBD-related SpA. Only a single recent study has found an increase in Escherichia and Shigella abundances and a decrease in Firmicutes, Ruminococcaceae, and Faecalibacterium abundances in an IBD-related SpA group. Based on what has been discovered so far about the altered distribution of bacteria that unite both pathologies, it is appropriate to carry out further studies aiming to improve the understanding of IBD-related SpA for the purpose of developing new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Each time the virus starts a new round of expression/replication, even under effective antiretroviral therapy (ART), the transactivator of viral transcription Tat is one of the first HIV-1 protein to be produced, as it is strictly required for HIV replication and spreading. At this stage, most of the Tat protein exits infected cells, accumulates in the extracellular matrix and exerts profound effects on both the virus and neighbor cells, mostly of the innate and adaptive immune systems. Through these effects, extracellular Tat contributes to the acquisition of infection, spreading and progression to AIDS in untreated patients, or to non-AIDS co-morbidities in ART-treated individuals, who experience inflammation and immune activation despite virus suppression. Here, we review the role of extracellular Tat in both the virus life cycle and on cells of the innate and adaptive immune system, and we provide epidemiological and experimental evidence of the importance of targeting Tat to block residual HIV expression and replication. Finally, we briefly review vaccine studies showing that a therapeutic Tat vaccine intensifies ART, while its inclusion in a preventative vaccine may blunt escape from neutralizing antibodies and block early events in HIV acquisition. [ABSTRACT FROM AUTHOR]

To explore the developmental processes of epileptogenesis/ictogenesis, this study determined age-dependent functional abnormalities associated with purinergic transmission in a genetic rat model (S286L-TG) of autosomal-dominant sleep-related hypermotor epilepsy (ADSHE). The age-dependent fluctuations in the release of ATP and L-glutamate in the orbitofrontal cortex (OFC) were determined using microdialysis and ultra-high-performance liquid chromatography with mass spectrometry (UHPLC-MS). ATP release from cultured astrocytes was also determined using UHPLC-MS. The expressions of P2X7 receptor (P2X7R), connexin 43, phosphorylated-Akt and phosphorylated-Erk were determined using capillary immunoblotting. No functional abnormalities associated with purinergic transmission could be detected in the OFC of 4-week-old S286L-TG and cultured S286L-TG astrocytes. However, P2X7R expression, as well as basal and P2X7R agonist-induced ATP releases, was enhanced in S286L-TG OFC in the critical ADSHE seizure onset period (7-week-old). Long-term exposure to a modest level of P2X7R agonist, which could not increase astroglial ATP release, for 14 d increased the expressions of P2X7R and connexin 43 and the signaling of Akt and Erk in astrocytes, and it enhanced the sensitivity of P2X7R to its agonists. Akt but not Erk increased P2X7R expression, whereas both Akt and Erk increased connexin 43 expression. Functional abnormalities, enhanced ATP release and P2X7R expression were already seen before the onset of ADSHE seizure in S286L-TG. Additionally, long-term exposure to the P2X7R agonist mimicked the functional abnormalities associated with purinergic transmission in astrocytes, similar to those in S286L-TG OFC. Therefore, these results suggest that long-term modestly enhanced purinergic transmission and/or activated P2X7R are, at least partially, involved in the development of the epileptogenesis of ADSHE, rather than that of ictogenesis. [ABSTRACT FROM AUTHOR]

Background: Developmental and epileptic encephalopathy 9 (DEE9) is characterized by early infantile seizures and mild‐to‐severe neuropsychiatric symptoms. Despite being an X‐linked dominant disorder, DEE9 mainly affects heterozygous females or mosaic males, while hemizygous males are less affected. PCDH19 gene has been documented as the causative gene. Methods: Karyotyping analysis and copy number variation sequencing (CNV‐seq) were performed on a pregnant woman with epilepsy, together with her husband, son, and fetus. Results: A disease‐causing microdeletion, seq[GRCh37] del(X)(q21.31q22.1) (90310001–100360000), was identified in the pregnant woman and her female fetus. The microdeletion includes the entire PCDH19 gene and is classified as "pathogenic" according to the American College of Medical Genetics and Genomics guidelines. Conclusion: In this case study, we have not only identified the epilepsy type of the woman as DEE9 but have also made an unfavorable prognosis for her fetus. Our findings from this prenatal case provide valuable clinical resources for prenatal diagnosis and genetic counseling, while also implying the potential of CNV‐seq as a viable method for uncovering PCDH19‐related epilepsy. [ABSTRACT FROM AUTHOR]

Axial spondyloarthritis (axSpA) is a chronic inflammatory disease of the spine and sacroiliac joints. This review discusses recent advances across multiple scientific fields that promise to transform axSpA management. Traditionally, axSpA was considered an immune-mediated disease driven by human leukocyte antigen B27 (HLA-B27), interleukin (IL)-23/IL-17 signaling, biomechanics, and dysbiosis. Diagnosis relies on clinical features, laboratory tests, and imaging, particularly magnetic resonance imaging (MRI) nowadays. Management includes exercise, lifestyle changes, non-steroidal anti-inflammatory drugs and if this is not sufficient to achieve disease control also biological and targeted-synthetic disease modifying anti-rheumatic drugs. Beyond long-recognized genetic risks like HLA-B27, high-throughput sequencing has revealed intricate gene-environment interactions influencing dysbiosis, immune dysfunction, and aberrant bone remodeling. Elucidating these mechanisms promises screening approaches to enable early intervention. Advanced imaging is revolutionizing the assessment of axSpA's hallmark: sacroiliac bone-marrow edema indicating inflammation. Novel magnetic resonance imaging (MRI) techniques sensitively quantify disease activity, while machine learning automates complex analysis to improve diagnostic accuracy and monitoring. Hybrid imaging like synthetic MRI/computed tomography (CT) visualizes structural damage with new clarity. Meanwhile, microbiome analysis has uncovered gut ecosystem alterations that may initiate joint inflammation through HLA-B27 misfolding or immune subversion. Correcting dysbiosis represents an enticing treatment target. Moving forward, emerging techniques must augment patient care. Incorporating patient perspectives will be key to ensure innovations like genetics, microbiome, and imaging biomarkers translate into improved mobility, reduced pain, and increased quality of life. By integrating cutting-edge, multidisciplinary science with patients' lived experience, researchers can unlock the full potential of new technologies to deliver transformative outcomes. The future is bright for precision diagnosis, tightly controlled treatment, and even prevention of axSpA. [ABSTRACT FROM AUTHOR]

Introduction/objectives: Familial Mediterranean Fever (FMF) is a genetic disorder of the innate immunity characterized by chronic inflammatory state. The diagnosis is mainly based on clinical criteria and supported by genotyping, especially in atypical phenotypes. The primary objective was to depict the Familial Mediterranean Fever (FMF) genotype of Greek patients and investigate the contribution of Next Generation Sequencing (NGS) beyond the contemporary techniques [(Polymerase Chain Reaction (PCR)/hybridization and Non-Isotopic RNase Cleavage Assay (NIRCA). The secondary objective was to unravel any associations between the mutated genes with the disease course and response to treatment., Methods: In this single center, retrospective study 31 patients with clinical diagnosis with FMF, but non-conclusive genetic analysis with PCR/hybridization and NIRCA, underwent NGS genotyping., Results: PCR/NIRCA detected ≥ 1 mutation in 25/31 patients, most frequently M694V (29%), while NGS in 26/31 (83.9%), most frequently R202Q (61.3%). NGS genetically confirmed the clinical diagnosis (heterozygosity to compound or complex genotype) in 19 (61.3%) patients of our cohort. R202Q was significantly more prevalent by NGS than by contemporary techniques (61.3 vs 12.9%, p = 0.0002) and was associated with FMF. Rare mutations were detected by NGS in 19.2% patients., Conclusion: NGS clarifies the genetic profile of patients with atypical phenotypes and supports therapeutic management decisions. NGS unveiled the frequent involvement of R202Q in the pathogenesis of our FMF patients., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Simple Summary: Oncology is a rapidly advancing field in small-animal medicine, underscoring the importance of innovative therapeutic approaches. Tyrosine kinase inhibitors (TKIs) are drugs that block various important cellular functions and play an important role in treating cancer in people and dogs. However, their role in feline oncology is less established. This comprehensive review surveys the existing literature on tyrosine kinases (TKs) and the use of TKIs in cats, aiming to identify knowledge gaps, speculate on potential indications and lay the groundwork for future investigations. Diverse feline tissues have been examined for various TK expressions. However, although limited evidence exists on the use of TKIs in specific feline tumors, it trails behind progress in human and canine oncology. We believe additional research could identify new uses for these drugs and improve therapeutic options for cats with cancer in the future. Tyrosine kinase inhibitors (TKIs) have become invaluable in the treatment of human and canine malignancies, but their role in feline oncology is less defined. While toceranib phosphate and masitinib mesylate are licensed for use in dogs, no TKI is yet approved for cats. This review systematically maps the research conducted on the expression of tyrosine kinases in neoplastic and non-neoplastic domestic feline tissues, as well as the in vitro/in vivo use of TKIs in domestic cats. We identify and discuss knowledge gaps and speculate on the further research and potential indications for TKI use in cats. A comprehensive search of three electronic databases and relevant paper reference lists identified 139 studies meeting the inclusion criteria. The most commonly identified tumors were mast cell tumors (MCTs), mammary and squamous cell carcinomas and injection-site sarcomas. Based on the current literature, toceranib phosphate appears to be the most efficacious TKI in cats, especially against MCTs. Exploring the clinical use of TKIs in mammary carcinomas holds promise. Despite the progress, currently, the evidence falls short, underscoring the need for further research to discover new indications in feline oncology and to bridge the knowledge gaps between human and feline medicine. [ABSTRACT FROM AUTHOR]

Purpose: This exploratory study aimed to characterize motor speech impairments in a small sample of children with epilepsy, both with and without a known seizure etiology. A secondary aim was to evaluate the validity of the Profile for Childhood Apraxia of speech and Dysarthria (ProCAD), a newly developed tool for differential diagnosis of childhood apraxia of speech and dysarthria. Method: Thirteen children with seizure disorders completed a comprehensive speech and language assessment. Three expert speech-language pathologists rated the presence of auditory-perceptual features of motor speech impairment using the ProCAD. Motor speech features, diagnoses, and standardized test scores were compared between children with a known seizure etiology and children with idiopathic epilepsy. Results: Nine of the 13 children exhibited motor speech impairment; dysarthria was the most common diagnosis. Most children (11/13) exhibited language impairment. Group comparisons showed that children with a known seizure etiology had more atypical motor speech features and lower language scores than children with idiopathic seizures. Conclusion: These preliminary findings suggest a high rate of motor speech impairment among children with epilepsy. [ABSTRACT FROM AUTHOR]

Background: Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disease primarily affecting individuals of Turkish, Armenian, Arab, and non-Ashkenazi Jewish descent, caused by mutations in the MEFV gene. The aim of this study was to review the common genotype distributions of MEFV variants and mutations in the Turkish population and evaluate rare mutations., Methods and Results: The study included 2984 patients who applied to Ankara University Ibni Sina Hospital Immunology Laboratory with clinical suspicion of FMF between 2004 and 2014. The data of patients from different regions of the country who were followed up in the immunology-rheumatology clinic with clinical suspicion and presumptive diagnosis of FMF were evaluated retrospectively. Patients were tested for all mutations in Exon 2 and Exon 10, including M694V, M680I, M694I, V726A, E148Q and R202Q. There were 2504 patients with FMF variant. According to genotyping, R202Q (n = 1567, 39.2%) was the most common mutation. The most common co-variant was the R202Q/M694V genotype (n = 507, 16.98%). Allele frequencies for MEFV mutations were as follows: R202Q (n = 1567, 39.2%), M694V (n = 1004, 25.1%), E148Q (n = 463, 11.5%), M680I (n = 354, 8.8%), V726A (n = 319, 7.9%), A744S (n = 51, 1.2%), R761H (N = 41, 1.0%), P706P (N = 25, 0.6%), E167D (N = 23, 0.5%), M694I (N = 23, 0.5%), and K695R (N = 20, 0.5%)., Conclusion: This research revealed the prevalence of both common and rare MEFV gene mutations in Turkish FMF patients in various age groups. R202Q was the most prevalent mutation., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Periodic fever syndromes include autoinflammatory disorders (AID) that involve innate immunity. These disorders are characterized by recurrent fevers and aberrant multi-organ inflammation, without any involvement of T or B cells or the presence of autoantibodies. A complex genetic architecture has been recognized for many AID. However, this complexity has only been partially uncovered for familial Mediterranean fever and other conditions that have a classical monogenic origin and Mendelian transmission. Several gene panels are currently available for molecular diagnosis in patients suspected of having AID. However, even when an extensive number of genes (up to 50–100) are tested in a cohort of clinically selected patients, the diagnostic yield of AID ranges between 15% and 25%, depending on the clinical criteria used for patient selection. In the remaining 75–85% of cases, it is conceivable that the causative gene or genes responsible for a specific condition are still elusive. In these cases, the disease could be explained by variants, either recessive or dominant, that have a major effect on unknown genes, or by the cumulative impact of different variants in more than one gene, each with minor additive effects. In this study, we focused our attention on five familial cases of AID presenting with classical autosomal dominant transmission. To identify the probable monogenic cause, we performed exome sequencing. Through prioritization, filtering, and segregation analysis, we identified a few variants for each family. Subsequent bioinformatics evaluation and pathway analysis helped to narrow down the best candidate genes for each family to FCRL6, PKN1, STAB1, PTDGR, and VCAM1. Future studies on larger cohorts of familial cases will help confirm the pathogenic role of these genes in the pathogenesis of these complex disorders. [ABSTRACT FROM AUTHOR]

Background: Investigating genomic regions associated with morphometric traits in camels is valuable, because it allows a better understanding of adaptive and productive features to implement a sustainable management and a customised breeding program for dromedaries. Objectives: With a genome‐wide association study (GWAS) including 96 Iranian dromedaries phenotyped for 12 morphometric traits and genotyped‐by‐sequencing (GBS) with 14,522 SNPs, we aimed at identifying associated candidate genes. Methods: The association between SNPs and morphometric traits was investigated using a linear mixed model with principal component analysis (PCA) and kinship matrix. Results: With this approach, we detected 59 SNPs located in 37 candidate genes potentially associated to morphometric traits in dromedaries. The top associated SNPs were related to pin width, whither to pin length, height at whither, muzzle girth, and tail length. Interestingly, the results highlight the association between whither height, muzzle circumference, tail length, whither to pin length. The identified candidate genes were associated with growth, body size, and immune system in other species. Conclusions: We identified three key hub genes in the gene network analysis including ACTB, SOCS1 and ARFGEF1. In the central position of gene network, ACTB was detected as the most important gene related to muscle function. With this initial GWAS using GBS on dromedary camels for morphometric traits, we show that this SNP panel can be effective for genetic evaluation of growth in dromedaries. However, we suggest a higher‐density SNP array may greatly improve the reliability of the results. [ABSTRACT FROM AUTHOR]

(1) Background: Familial Mediterranean Fever (FMF) is the prototypal autoinflammatory disease, characterized by recurrent bursts of neutrophilic inflammation. (2) Methods: In this study we look at the most recent literature on this condition and integrate it with novel information on treatment resistance and compliance. (3) Results: The canonical clinical presentation of FMF is in children with self-limited episodes of fever and polyserositis, associated with severe long-term complications, such as renal amyloidosis. It has been described anecdotally since ancient times, however only recently it has been characterized more accurately. We propose an updated overview on the main aspects of pathophysiology, genetics, diagnosis and treatment of this intriguing disease. (4) Conclusions: Overall, this review presents the all the main aspects, including real life outcome of the latest recommendation on treatment resistance of FMF, a disease, that not only helped understanding the pathophysiology of the auto inflammatory process but also the functioning of the innate immune system itself. [ABSTRACT FROM AUTHOR]

Objective: To utilize whole exome or genome sequencing and the scientific literature for identifying candidate genes for cyclic vomiting syndrome (CVS), an idiopathic migraine variant with paroxysmal nausea and vomiting. Methods: A retrospective chart review of 80 unrelated participants, ascertained by a quaternary care CVS specialist, was conducted. Genes associated with paroxysmal symptoms were identified querying the literature for genes associated with dominant cases of intermittent vomiting or both discomfort and disability; among which the raw genetic sequence was reviewed. "Qualifying" variants were defined as coding, rare, and conserved. Additionally, "Key Qualifying" variants were Pathogenic/Likely Pathogenic, or "Clinical" based upon the presence of a corresponding diagnosis. Candidate association to CVS was based on a point system. Results: Thirty-five paroxysmal genes were identified per the literature review. Among these, 12 genes were scored as "Highly likely" (SCN4A, CACNA1A, CACNA1S, RYR2, TRAP1, MEFV) or "Likely" (SCN9A, TNFRSF1A, POLG, SCN10A, POGZ, TRPA1) CVS related. Nine additional genes (OTC, ATP1A3, ATP1A2, GFAP, SLC2A1, TUBB3, PPM1D, CHAMP1, HMBS) had sufficient evidence in the literature but not from our study participants. Candidate status for mitochondrial DNA was confirmed by the literature and our study data. Among the above-listed 22 CVS candidate genes, a Key Qualifying variant was identified in 31/80 (34%), and any Qualifying variant was present in 61/80 (76%) of participants. These findings were highly statistically significant (p < 0.0001, p = 0.004, respectively) compared to an alternative hypothesis/control group regarding brain neurotransmitter receptor genes. Additional, postanalyses, less-intensive review of all genes (exome) outside our paroxysmal genes identified 13 additional genes as "Possibly" CVS related. Conclusion: All 22 CVS candidate genes are associated with either cation transport or energy metabolism (14 directly, 8 indirectly). Our findings suggest a cellular model in which aberrant ion gradients lead to mitochondrial dysfunction, or vice versa, in a pathogenic vicious cycle of cellular hyperexcitability. Among the nonparoxysmal genes identified, 5 are known causes of peripheral neuropathy. Our model is consistent with multiple current hypotheses of CVS. [ABSTRACT FROM AUTHOR]

The autoinflammatory disease familial Mediterranean fever (FMF), characterized by recurrent attacks of sterile fever, serosal, and/or synovial inflammation, is caused by variants in the Mediterranean fever gene, MEFV, coding for the pyrin inflammasome sensor. The diagnosis of FMF is mainly based on clinical symptoms and confirmed by detection of disease-associated MEFV variants. However, the diagnosis is challenging among patients carrying variants of uncertain clinical significance (VUS). In this study, we aimed to identify potential FMF discriminatory diagnostic markers in a cohort of clinically characterized FMF patients. We established a cohort of clinically and MEFV genotype-characterized FMF patients by enrolling patients from major Danish hospitals (n = 91). The secretory profile of pyrin inflammasome-activated monocytes from healthy donors (HDs) and MEFV-characterized FMF patients (n = 28) was assessed by analysing cell supernatants for a custom-designed panel of 23 cytokines, chemokines, and soluble tumour necrosis factor receptors associated with monocyte and macrophage function. MEFV genotypes in Danish FMF patients were associated with age at symptom onset (p < 0.05), FMF among relatives (p < 0.01), proportion of patients in colchicine treatment (p < 0.01), and treatment response (p < 0.05). Secretion of chemokines CCL1 and CXCL1 from pyrin-activated FMF monocytes was significantly decreased compared to HDs (p < 0.05), and could discriminate FMF patients with 'non-confirmatory' MEFV genotypes from HDs with 80.0% and 70.0% sensitivity for CCL1 and CXCL1, respectively (p < 0.05). Our data suggest that a functional diagnostic assay based on CCL1 or CXCL1 levels in pyrin-activated patient monocytes may contribute to FMF diagnosis in patients with VUS. [ABSTRACT FROM AUTHOR]

Simple Summary: Feline mammary carcinomas are highly prevalent tumors, with aggressive behavior and scarce therapeutic options. Thus, there is a high need for novel biomarkers and therapeutic targets. In human medicine, immune checkpoint inhibitors targeting TIM-3 are emerging as promising treatment strategies; however, the clinical relevance of immune checkpoints in feline cancers is sparse. To unravel the clinical importance of TIM-3 in feline mammary carcinoma, we analyzed the intratumor expression and serum levels of the TIM-3 receptor in tumor-bearing cats. The results obtained show that TIM-3 is highly expressed in both immune and cancer cells, and the localization of TIM-3 expression can predict clinical outcomes in feline mammary carcinoma. TIM-3 levels in serum were reduced in diseased compared to healthy animals. These findings shed light on the biological role of TIM-3 in feline mammary carcinoma and support clinical testing of novel therapies targeting TIM-3. Recent findings in human breast cancer (HBC) indicate that T-cell immunoglobulin and mucin-domain-containing molecule-3 (TIM-3)-targeted therapies may effectively activate anticancer immune responses. Although feline mammary carcinoma (FMC) is a valuable cancer model, no studies on TIM-3 have been developed in this species. Thus, we evaluated the expression of TIM-3 by immunohistochemistry in total (t), stromal (s), and intra-tumoral (i) tumor-infiltrating lymphocytes (TILs) and in cancer cells, of 48 cats with mammary carcinoma. In parallel, serum TIM-3 levels were quantified using ELISA and the presence of somatic mutations in the TIM-3 gene was evaluated in 19 tumor samples. sTILs-TIM3+ were more frequent than iTILs-TIM-3+, with the TIM-3 ex-pression in sTILs and cancer cells being associated with more aggressive clinicopathological features. In contrast, the TIM-3 expression in iTILs and tTILs was associated with a more benign clinical course. Moreover, the serum TIM-3 levels were lower in animals with FMC when compared to healthy animals (p < 0.001). Only one somatic mutation was found in the TIM-3 gene, at intron 2, in one tumor sample. Altogether, our results suggest that the expression of TIM-3 among TILs subpopulations and cancer cells may influence the clinical outcome of cats with FMC, in line with the previous reports in HBC. [ABSTRACT FROM AUTHOR]

While precision medicine is still a challenge in rheumatic disease, in recent years many advances have been made regarding pathogenesis, the treatment of inflammatory arthropathies, and their interaction. New insight into the role of inflammasome and synovial tissue macrophage subsets as predictors of drug response give hope for future tailored therapeutic strategies and a personalized medicine approach in inflammatory arthropathies. Here, we discuss the main pathogenetic mechanisms and therapeutic approaches towards precision medicine in rheumatoid arthritis from the 2022 International GISEA/OEG Symposium. [ABSTRACT FROM AUTHOR]

Castanopsis hystrix is a valuable native, broad-leaved, and fast-growing tree in South China. In this study, 15 phenotypic traits and 32 simple sequence repeat (SSR) markers were used to assess the genetic diversity and population structure of a natural population of C. hystrix and to construct a core germplasm collection by a set of 232 accessions. The results showed that the original population of C. hystrix had relatively high genetic diversity, with the number of alleles (Na), effective number of alleles (Ne), observed heterozygosity (Ho), expected heterozygosity (He), Shannon's information index (I), and polymorphism information content (PIC) averaging at 26.188, 11.565, 0.863, 0.897, 2.660, and 0.889, respectively. Three sub-populations were identified based on a STRUCTURE analysis, indicating a strong genetic structure. The results from the phylogenetic and population structures showed a high level of agreement, with 232 germplasms being classified into three main groups. The analysis of molecular variance (AMOVA) test indicated that 96% of the total variance was derived from within populations, which revealed a low differentiation among populations. A core collection composed of 157 germplasms was firstly constructed thereafter, of which the diversity parameters non-significantly differed from the original population. These results revealed the genetic diversity and population structure of C. hystrix germplasms, which have implications for germplasm management and genome-wide association studies on C. hystrix, as well as for core collection establishment applications in other wood-producing hardwood species. [ABSTRACT FROM AUTHOR]

Optimizing root system architecture is a strategy for coping with soil fertility, such as low nitrogen input. An ample number of Arabidopsis thaliana natural accessions have set the foundation for studies on mechanisms that regulate root morphology. This report compares the Columbia-0 (Col-0) reference and Pyla-1 (Pyl-1) from a coastal zone in France, known for having the tallest sand dune in Europe. Seedlings were grown on vertical agar plates with different nitrate concentrations. The lateral root outgrowth of Col-0 was stimulated under mild depletion and repressed under nitrate enrichment. The Pyl-1 produced a long primary root and any or very few visible lateral roots across the nitrate supplies. This could reflect an adaptation to sandy soil conditions, where the primary root grows downwards to the lower strata to take up water and mobile soil resources without elongating the lateral roots. Microscopic observations revealed similar densities of lateral root primordia in both accessions. The Pyl-1 maintained the ability to initiate lateral root primordia. However, the post-initiation events seemed to be critical in modulating the lateral-root-less phenotype. In Pyl-1, the emergence of primordia through the primary root tissues was slowed, and newly formed lateral roots stayed stunted. In brief, Pyl-1 is a fascinating genotype for studying the nutritional influences on lateral root development. [ABSTRACT FROM AUTHOR]

Cortical development depends on neuronal migration of both excitatory and inhibitory interneurons. Neuronal migration disorders (NMDs) are conditions characterised by anatomical cortical defects leading to varying degrees of neurocognitive impairment, developmental delay and seizures. Refractory epilepsy affects 15 million people worldwide, and it is thought that cortical developmental disorders are responsible for 25% of childhood cases. However, little is known about the epidemiology of these disorders, nor are their aetiologies fully understood, though many are associated with sporadic genetic mutations. In this review, we aim to highlight X-linked NMDs including lissencephaly, periventricular nodular heterotopia and polymicrogyria because of their mostly familial inheritance pattern. We focus on the most prominent genes responsible: including DCX, ARX, FLNA, FMR1, L1CAM, SRPX2, DDX3X, NSHDL, CUL4B and OFD1, outlining what is known about their prevalence among NMDs, and the underlying pathophysiology. X-linked disorders are important to recognise clinically, as females often have milder phenotypes. Consequently, there is a greater chance they survive to reproductive age and risk passing the mutations down. Effective genetic screening is important to prevent and treat these conditions, and for this, we need to know gene mutations and have a clear understanding of the function of the genes involved. This review summarises the knowledge base and provides clear direction for future work by both scientists and clinicians alike., (© 2023 The Authors. International Journal of Developmental Neuroscience published by John Wiley & Sons Ltd on behalf of International Society for Developmental Neuroscience.)

The brain and spinal cord constitute the central nervous system (CNS), which when injured, can be exceedingly devastating. The mechanistic roles of proteoglycans (PGs) and their glycosaminoglycan (GAG) side chains in such injuries have been extensively studied. CNS injury immediately alters endothelial and extracellular matrix (ECM) PGs and GAGs. Subsequently, these alterations contribute to acute injury, postinjury fibrosis, and postinjury repair. These effects are central to the pathophysiology of CNS injury. This review focuses on the importance of PGs and GAGs in multiple forms of injury including traumatic brain injury, spinal cord injury, and stroke. We highlight the causes and consequences of degradation of the PG and GAG-enriched endothelial glycocalyx in early injury and discuss the pleiotropic roles of PGs in neuroinflammation. We subsequently evaluate the dualistic effects of PGs on recovery: both PG/GAG-mediated inhibition and facilitation of repair. We then report promising therapeutic strategies that may prove effective for repair of CNS injury including PG receptor inhibition, delivery of endogenous, pro-repair PGs and GAGs, and direct degradation of pathological GAGs. Finally, we discuss the importance of two PG- and GAG-containing ECM structures (synapses and perineuronal nets) in CNS injury and recovery. [ABSTRACT FROM AUTHOR]

Autoimmune diseases and autoinflammatory diseases are two types of the immune system disorders. Pyroptosis, a highly inflammatory cell death, plays an important role in diseases of immune system. The gasdermins belong to a pore-forming protein gene family which are mainly expressed in immune cells, gastrointestinal tract, and skin. Gasdermins are regarded as an executor of pyroptosis and have been shown to possess various cellular functions and pathological effects such as pro-inflammatory, immune activation, mediation of tumor, etc. Except for infectious diseases, the vital role of gasdermins in autoimmune diseases, autoinflammatory diseases, and immune-related neoplastic diseases has been proved recently. Therefore, gasdermins have been served as a potential therapeutic target for immune disordered diseases. The review summarizes the basic molecular structure and biological function of gasdermins, mainly discusses their role in autoimmune and autoinflammatory diseases, and highlights the recent research on gasdermin family inhibitors so as to provide potential therapeutic prospects. [ABSTRACT FROM AUTHOR]

About thirty years ago, a new form of pro-inflammatory lytic cell death was observed and termed pyroptosis. Only in 2015, gasdermins were defined as molecules that create pores at the plasma membrane and drive pyroptosis. Today, we know that gasdermin-mediated death is an important antimicrobial defence mechanism in bacteria, yeast and mammals as it destroys the intracellular niche for pathogen replication. However, excessive and uncontrolled cell death also contributes to immunopathology in several chronic inflammatory diseases, including arthritis. In this review, we discuss recent findings where pyroptosis contributes to tissue damage and inflammation with a main focus on injury-induced and autoimmune arthritis. We also review novel functions and regulatory mechanisms of the pyroptotic executors gasdermins. Finally, we discuss possible models of how pyroptosis may contribute to the cross-talk between fibroblast and macrophages, and also how this cross-talk may regulate inflammation by modulating inflammasome activation and pyroptosis induction. [ABSTRACT FROM AUTHOR]

Autosomal dominant sleep-related hypermotor epilepsy (ADSHE; previously autosomal dominant nocturnal frontal lobe epilepsy, ADNFLE), originally reported in 1994, was the first distinct genetic epilepsy shown to be caused by CHNRA4 mutation. In the past two decades, we have identified several functional abnormalities of mutant ion channels and their associated transmissions using several experiments involving single-cell and genetic animal (rodent) models. Currently, epileptologists understand that functional abnormalities underlying epileptogenesis/ictogenesis in humans and rodents are more complicated than previously believed and that the function of mutant molecules alone cannot contribute to the development of epileptogenesis/ictogenesis but play important roles in the development of epileptogenesis/ictogenesis through formation of abnormalities in various other transmission systems before epilepsy onset. Based on our recent findings using genetic rat ADSHE models, harbouring Chrna4 mutant, corresponding to human S284L-mutant CRHNA4, this review proposes a hypothesis associated with tripartite synaptic transmission in ADSHE pathomechanisms induced by mutant ACh receptors. LINKED ARTICLES: This article is part of a themed issue on Building Bridges in Neuropharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.8/issuetoc. [ABSTRACT FROM AUTHOR]

Plant stress responses can extend into the following generations, a phenomenon called transgenerational effects. Heat stress, in particular, is known to affect plant offspring, but we do not know to what extent these effects depend on the temporal patterns of the stress, and whether transgenerational responses are adaptive and genetically variable within species. To address these questions, we carried out a two-generation experiment with nine Arabidopsis thaliana genotypes. We subjected the plants to heat stress regimes that varied in timing and frequency, but not in mean temperature, and we then grew the offspring of these plants under controlled conditions as well as under renewed heat stress. The stress treatments significantly carried over to the offspring generation, with timing having stronger effects on plant phenotypes than stress frequency. However, there was no evidence that transgenerational effects were adaptive. The magnitudes of transgenerational effects differed substantially among genotypes, and for some traits the strength of plant responses was significantly associated with the climatic variability at the sites of origin. In summary, timing of heat stress not only directly affects plants, but it can also cause transgenerational effects on offspring phenotypes. Genetic variation in transgenerational effects, as well as correlations between transgenerational effects and climatic variability, indicates that transgenerational effects can evolve, and have probably already done so in the past. [ABSTRACT FROM AUTHOR]

Despite over 30 years of enormous effort and progress in the field, no preventative and/or therapeutic vaccines against human immunodeficiency virus (HIV) are available. Here, we briefly summarize the vaccine strategies and vaccine candidates that in recent years advanced to efficacy trials with mostly unsatisfactory results. Next, we discuss a novel and somewhat contrarian approach based on biological and epidemiological evidence, which led us to choose the HIV protein Tat for the development of preventive and therapeutic HIV vaccines. Toward this goal, we review here the role of Tat in the virus life cycle as well as experimental and epidemiological evidence supporting its key role in the natural history of HIV infection and comorbidities. We then discuss the preclinical and clinical development of a Tat therapeutic vaccine, which, by improving the functionality and homeostasis of the immune system and by reducing the viral reservoir in virologically suppressed vaccinees, helps to establish key determinants for intensification of combination antiretroviral therapy (cART) and a functional cure. Future developments and potential applications of the Tat therapeutic vaccine are also discussed, as well as the rationale for its use in preventative strategies. We hope this contribution will lead to a reconsideration of the current paradigms for the development of HIV/AIDS vaccines, with a focus on targeting of viral proteins with key roles in HIV pathogenesis. [ABSTRACT FROM AUTHOR]

Familial Mediterranean fever (FMF) is the most prevalent autoinflammatory disease. Typical findings are recurrent fever attacks with serositis, skin rash, and synovitis. FMF is caused by mutations in the MEFV gene, encoding pyrin protein. Pyrin functions in innate immunity and triggers inflammation via inflammatory mediators' production and acts as the primary regulatory component of the inflammasome. On the other hand, various miRNAs play crucial roles in the pathogenesis of different types of cancers and immune-related and neurodegenerative diseases. However, their association with FMF is still unclear. Therefore, in this study, we assessed the roles of selected thirteen miRNAs associated with immune functions. We recruited genetically diagnosed 28 FMF patients and 28 healthy individuals. The expression profiling of the miRNAs was determined by qRT-PCR and normalized to SNORD61. Our analysis revealed that miR-34a-5p, miR-142-3p, miR-216a-5p, miR-340-5p, miR-429, and miR-582-5p were upregulated, whereas miR-107, miR-569, and miR-1304-5p were downregulated in the FMF patients. Among them, miR-107 was found to be the most remarkable in M694V homozygous mutants compared to other homozygous mutants. During clinical follow-up of the patients with M694V mutation, which is closely related to amyloidosis, evaluation of mir-107 expression might be crucial and suggestive. Our results showed that miRNAs might serve a function in the pathogenesis of FMF. Further studies may provide novel and effective diagnostic and therapeutic agents that target examined miRNAs. Targeting miRNAs in FMF seems to be promising and may yield a new generation of rational therapeutics and diagnostic or monitoring tools enabling FMF treatment. [ABSTRACT FROM AUTHOR]

Feline mammary carcinoma (FMC) is a common aggressive malignancy with a low survival rate that lacks viable therapeutic options beyond mastectomy. Recently, increasing efforts have been made to understand the molecular mechanisms underlying FMC development, using the knowledge gained from studies on human breast cancer to discover new diagnostic and prognostic biomarkers, thus reinforcing the utility of the cat as a cancer model. In this article, we review the current knowledge on FMC pathogenesis, biomarkers, and prognosis factors and offer new insights into novel therapeutic options for HER2-positive and triple-negative FMC subtypes. [ABSTRACT FROM AUTHOR]