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Objective Genetic risk factors for unruptured intracranial aneurysms (UIA) and aneurysmal subarachnoid hemorrhage (aSAH) are poorly understood. We aimed to verify recently reported risk genes and to identify novel sequence variants involved in the etiology of UIA/aSAH. Methods We performed exome sequencing (ES) in 35 unrelated individuals and 3 family members, each with a history of UIA and/or aSAH. We searched for sequence variants with minor allele frequency (MAF) ≤ 5% in the reported risk genes ADAMTS15 , ANGPTL6 , ARHGEF17 , LOXL2 , PCNT , RNF213 , THSD1 and TMEM132B . To identify novel putative risk genes we looked for unknown (MAF = 0) variants shared by the three relatives. Results We identified 20 variants with MAF ≤ 5% in 18 individuals: 9 variants in PCNT (9 patients), 4 in RNF213 (3 patients), 3 in THSD1 (6 patients), 2 in ANGPTL6 (3 patients), 1 in ADAMTS15 (1 patient) and 1 in TMEM132B (1 patient). In the affected family, prioritization of shared sequence variants yielded five novel putative risk genes. Based on predicted pathogenicity of identified variants, population genetics data and a high functional relevance for vascular biology, EDIL3 was selected as top candidate and screened in additional 37 individuals with UIA and/or aSAH: a further very rare EDIL3 sequence variant in two unrelated sporadic patients was identified. Conclusions Our data support a role of sequence variants in PCNT , RNF213 and THSD1 as susceptibility factors for cerebrovascular disease. The documented function in vascular wall integrity, the crucial localization of affected amino acids and gene/variant association tests suggest EDIL3 as a further valid candidate disease gene for UIA/aSAH.

Purpose Heritable factors play an important etiologic role in connective tissue disorders (CTD) with vascular involvement, and a genetic diagnosis is getting increasingly important for gene-tailored, personalized patient management. Methods We analyzed 32 disease-associated genes by using targeted next-generation sequencing and exome sequencing in a clinically relevant cohort of 199 individuals. We classified and refined sequence variants according to their likelihood for pathogenicity. Results We identified 1 pathogenic variant (PV; in FBN1 or SMAD3 ) in 15 patients (7.5%) and ≥1 likely pathogenic variant (LPV; in COL3A1 , FBN1 , FBN2 , LOX , MYH11 , SMAD3 , TGFBR1 , or TGFBR2 ) in 19 individuals (9.6%), together resulting in 17.1% diagnostic yield. Thirteen PV/LPV were novel. Of PV/LPV-negative patients 47 (23.6%) showed ≥1 variant of uncertain significance (VUS). Twenty-five patients had concomitant variants. In-depth evaluation of reported/calculated variant classes resulted in reclassification of 19.8% of variants. Conclusion Variant classification and refinement are essential for shaping mutational spectra of disease genes, thereby improving clinical sensitivity. Obligate stringent multigene analysis is a powerful tool for identifying genetic causes of clinically related CTDs. Nonetheless, the relatively high rate of PV/LPV/VUS-negative patients underscores the existence of yet unknown disease loci and/or oligogenic/polygenic inheritance.

Genetic factors are fundamental in the etiology of thoracic aortic aneurysm and dissection (TAAD), but the genetic cause is detected in only about 30% of cases. To define unreported TAAD-associated sequence variants, exome and gene panel sequencing was performed in 323 patients. We identified heterozygous CDKL1 variants [c.427T>C p.(Cys143Arg), c.617C>T p.(Ser206Leu), and c.404C>T p.(Thr135Met)] in 6 patients from 3 families with TAAD spectrum disorders. CDKL1 encodes a protein kinase involved in ciliary biology. Amino acid substitutions were predicted to affect CDKL1 catalytic activity or protein binding properties. CDKL1 was expressed in vascular smooth muscle cells in normal and diseased human aortic wall tissue. Cdkl1 knockdown and transient knockout in zebrafish resulted in intersomitic vessel (ISV) malformations and aortic dilation. Coinjection of human CDKL17\"'1+· RNA, but not CDKL 1054349 and CDKL7··2051·1 RNA, rescued ISV malformations. All variants affected CDKL1 kinase function and profiling data, and altered protein-protein binding properties, particularly with ciliary transport molecules. Expression of CDKL1 variants in heterologous cells interfered with cilia formation and length, CDKL1 localization, and p38 MAPK and Vegf signaling. Our data suggest a role of CDKL1 variants in the pathogenesis of TAAD spectrum disorders. The association between primary cilia dysregulation and TAAD expands our knowledge of the underlying molecular pathophysiology.

Genetic factors are fundamental in the etiology of thoracic aortic aneurysm and dissection (TAAD), but the genetic cause is detected in only about 30% of cases. To define unreported TAAD-associated sequence variants, exome and gene panel sequencing was performed in 323 patients. We identified heterozygous CDKL1 variants [c.427T>C p.(Cys143Arg), c.617C>T p.(Ser206Leu), and c.404C>T p.(Thr135Met)] in 6 patients from 3 families with TAAD spectrum disorders. CDKL1 encodes a protein kinase involved in ciliary biology. Amino acid substitutions were predicted to affect CDKL1 catalytic activity or protein binding properties. CDKL1 was expressed in vascular smooth muscle cells in normal and diseased human aortic wall tissue. Cdkl1 knockdown and transient knockout in zebrafish resulted in intersomitic vessel (ISV) malformations and aortic dilation. Coinjection of human CDKL1wild-type RNA, but not CDKL1Cys143Arg and CDKL1Ser206Leu RNA, rescued ISV malformations. All variants affected CDKL1 kinase function and profiling data, and altered protein-protein binding properties, particularly with ciliary transport molecules. Expression of CDKL1 variants in heterologous cells interfered with cilia formation and length, CDKL1 localization, and p38 MAPK and Vegf signaling. Our data suggest a role of CDKL1 variants in the pathogenesis of TAAD spectrum disorders. The association between primary cilia dysregulation and TAAD expands our knowledge of the underlying molecular pathophysiology.

Cigarette butts (CBs) are known as one of the most prevalent forms of environmental waste, needing global attention to mitigate their detrimental health and ecological impacts. Owing to their filter composition, discarded CBs can persistently release microfibers (MFs) into the environment. In this research, the levels, characteristics, and ecological risks associated with MFs released from cigarette filters (CFs) into water (distilled and seawater) were investigated under various environmental conditions (laboratory and outdoor environments). The assessment focused on short-term exposure durations of 1, 2, 7, 15, 30, and 60 days, forming the initial phase of this research. The mean level of released MFs ranged from 5.78 to 92.43 items/g CFs. The results highlighted that more MFs were released from CFs into the seawater and outdoor environment at a contact time of 60 days. The predominant size and color of the released MFs were 20–50 μm and white/transparent, respectively. The main detected polymer composition of MFs was cellulose acetate. The computed pollution load index (PLI) values were > 30, indicating severe pollution. Additionally, the risk quotient (RQ) values were greater than 1, indicating a potential threat to the water environment. Based on mean levels of released MFs through CFs during contact times of 1 to 60 days and the amount of discarded CFs yearly on a global scale, CFs may release 14 × 10 12 to 51 × 10 12 MFs into the aquatic environments. The results of present research allow scientific society to better comprehend the CFs’ role in transporting MFs in the aquatic systems as well as their potential environmental risks.

Termination of RNA polymerase II (Pol II) transcription is an important step in the transcription cycle, which involves the dislodgement of polymerase from DNA, leading to release of a functional transcript. Recent studies have identified the key players required for this process and showed that a common feature of these proteins is a conserved domain that interacts with the phosphorylated C-terminus of Pol II (CTD-interacting domain, CID). However, the mechanism by which transcription termination is achieved is not understood. Using genome-wide methods, here we show that the fission yeast CID-protein Seb1 is essential for termination of protein-coding and non-coding genes through interaction with S2-phosphorylated Pol II and nascent RNA. Furthermore, we present the crystal structures of the Seb1 CTD- and RNA-binding modules. Unexpectedly, the latter reveals an intertwined two-domain arrangement of a canonical RRM and second domain. These results provide important insights into the mechanism underlying eukaryotic transcription termination. Termination of RNA polymerase II is a critical step in transcription. Here, the authors provide evidence that the fission yeast CID-RRM protein Seb1 is required for termination of coding and non-coding genes through interaction with both the polymerase and the nascent RNA.

The contamination of yogurt and buttermilk (doogh), two widely consumed dairy products, with microplastics (MPs) and phthalic acid esters (PAEs), and subsequently the health effects caused by the contamination of these products on humans, is a potential concern. In this study, the abundance and characteristics of MPs as well as the PAEs concentration in different types of yogurts and buttermilk available in the Iranian market were investigated. The average abundance of MPs in different types of yogurts and buttermilk was between 0.63 and 0.76 and 0.52–0.7 items/mL, respectively. Most detected MPs in yogurt and buttermilk samples were in the size range of 1000–5000 μm with the predominant color and shape of transparent and fiber, respectively. Polyethylene terephthalate (PET) and polyamide (PA) were the dominant polymers in yogurt and buttermilk samples, respectively. The average concentrations of PAEs in different types of yogurt and buttermilk samples were between 5.79 and 11.36 and 1.46–6.93 µg/L, respectively. The findings showed that Di(2-ethylhexyl) phthalate (DEHP) levels in yogurt and buttermilk samples may have a carcinogenic risk for adults and adolescents. According to the results of this study, the intake of MPs and PAEs through high consumption of yogurt and buttermilk should be recognized as a significant source of MPs in the human body.

Despite recent advances in cryo-electron microscopy and artificial intelligence-based model predictions, a significant fraction of structure determinations by macromolecular crystallography still requires experimental phasing, usually by means of single-wavelength anomalous diffraction (SAD) techniques. Most synchrotron beamlines provide highly brilliant beams of X-rays of between 0.7 and 2 Å wavelength. Use of longer wavelengths to access the absorption edges of biologically important lighter atoms such as calcium, potassium, chlorine, sulfur and phosphorus for native-SAD phasing is attractive but technically highly challenging. The long-wavelength beamline I23 at Diamond Light Source overcomes these limitations and extends the accessible wavelength range to λ  = 5.9 Å. Here we report 22 macromolecular structures solved in this extended wavelength range, using anomalous scattering from a range of elements which demonstrate the routine feasibility of lighter atom phasing. We suggest that, in light of its advantages, long-wavelength crystallography is a compelling option for experimental phasing. Structural biology has undergone a revolution thanks to cryo-EM and artificial intelligence-based model predictions; nonetheless, experimental phasing continues to be essential. Here, the authors utilize the long-wavelength I23 beamline at Diamond Light Source to solve macromolecular structures using single-wavelength anomalous diffraction techniques, showcasing their proficiency in phasing with lighter atoms.