Effect of stroke etiology on treatment-related outcomes in young adults with large vessel occlusion: Results from a retrospective cohort study.

INTRODUCTION: Large vessel occlusion-acute ischemic stroke (LVO-AIS) is infrequent in young adults and exhibits distinct stroke mechanisms compared to older adults. This study sought to evaluate the impact of varying stroke etiologies on treatment-related outcomes in young adults with LVO-AIS, an aspect that remains unclear. METHODS: This retrospective cohort study included patients aged 18-50 presenting with AIS from January 2017 to December 2021 within our multi-center stroke network. Patients with LVO on CTA/MRA at presentation were included. We assessed demographics, stroke etiology (TOAST classification), and treatment-related outcomes. Based on intervention received, patients were divided into 5 groups [IV-thrombolysis (IVT) only, Mechanical Thrombectomy (MT) only, IVT+MT, no treatment, unsuccessful MT]. RESULTS: Among 1210 AIS patients, 220 with LVO were included. The median age was 42 (36, 46). 75 (34.1 %) patients underwent successful MT (46.7 % received IVT+MT). 26 (11.8 %) received IVT only, 110 (50 %) received neither intervention, and 9 (4.1 %) underwent unsuccessful MT. Per TOAST, 17.4 % had large artery atherosclerosis (LAA), 19.2 % cardio-embolism, 28.6 % stroke of other etiology, and 34.7 % had undetermined etiology. Favorable thrombectomy outcomes (TICI 2b/2c/3) were observed in 87.2 %. Discharge NIH Stroke Scale (NIHSS) scores improved for patients with IVT+MT in all TOAST categories except LAA. CONCLUSIONS: Young adults with LVO-AIS had good outcomes irrespective of stroke etiology, except LAA, which was associated with a higher discharge NIHSS. Moreover, 50 % of young adults in our study received no intervention, a quarter of those owing to delayed presentation. Further studies are needed to identify barriers in seeking acute treatment in young adults with LVO-AIS.

Drosophila Condensin II subunit Chromosome-associated protein D3 regulates cell fate determination through non-cell-autonomous signaling.

The pattern of the Drosophila melanogaster adult wing is heavily influenced by the expression of proteins that dictate cell fate decisions between intervein and vein during development. dSRF (Blistered) expression in specific regions of the larval wing disc promotes intervein cell fate, whereas EGFR activity promotes vein cell fate. Here, we report that the chromatin-organizing protein CAP-D3 acts to dampen dSRF levels at the anterior/posterior boundary in the larval wing disc, promoting differentiation of cells into the anterior crossvein. CAP-D3 represses KNOT expression in cells immediately adjacent to the anterior/posterior boundary, thus blocking KNOT-mediated repression of EGFR activity and preventing cell death. Maintenance of EGFR activity in these cells depresses dSRF levels in the neighboring anterior crossvein progenitor cells, allowing them to differentiate into vein cells. These findings uncover a novel transcriptional regulatory network influencing Drosophila wing vein development, and are the first to identify a Condensin II subunit as an important regulator of EGFR activity and cell fate determination in vivo.

Chromosome-associated protein D3 promotes bacterial clearance in human intestinal epithelial cells by repressing expression of amino acid transporters.

BACKGROUND & AIMS: Defects in colonic epithelial barrier defenses are associated with ulcerative colitis (UC). The proteins that regulate bacterial clearance in the colonic epithelium have not been completely identified. The Drosophila chromosome-associated protein D3 (dCAP-D3) regulates responses to bacterial infection. We examined whether CAP-D3 promotes bacterial clearance in human colonic epithelium. METHODS: Clearance of Salmonella or adherent-invasive Escherichia coli LF82 was assessed by gentamycin protection assays in HT-29 and Caco-2 cells expressing small hairpin RNAs against CAP-D3. We used immunoblot assays to measure levels of CAP-D3 in colonic epithelial cells from patients with UC and healthy individuals (controls). RNA sequencing identified genes activated by CAP-D3. We analyzed the roles of CAP-D3 target genes in bacterial clearance using gentamycin protection and immunofluorescence assays and studies with pharmacologic inhibitors. RESULTS: CAP-D3 expression was reduced in colonic epithelial cells from patients with active UC. Reduced CAP-D3 expression decreased autophagy and impaired intracellular bacterial clearance by HT-29 and Caco-2 colonic epithelial cells. Lower levels of CAP-D3 increased transcription of genes encoding SLC7A5 and SLC3A2, the products of which heterodimerize to form an amino acid transporter in HT-29 cells after bacterial infection; levels of SLC7A5-SLC3A2 were increased in tissues from patients with UC compared with controls. Reduced CAP-D3 in HT-29 cells resulted in earlier recruitment of SLC7A5 to Salmonella-containing vacuoles, increased activity of mTORC1, and increased survival of bacteria. Inhibition of SLC7A5-SLC3A2 or mTORC1 activity rescued the bacterial clearance defects of CAP-D3-deficient cells. CONCLUSIONS: CAP-D3 down-regulates transcription of genes that encode amino acid transporters (SLC7A5 and SLC3A2) to promote bacterial autophagy by colon epithelial cells. Levels of CAP-D3 protein are reduced in patients with active UC; strategies to increase its levels might restore mucosal homeostasis to patients with active UC.

Condensin II subunit dCAP-D3 restricts retrotransposon mobilization in Drosophila somatic cells.

Retrotransposon sequences are positioned throughout the genome of almost every eukaryote that has been sequenced. As mobilization of these elements can have detrimental effects on the transcriptional regulation and stability of an organism's genome, most organisms have evolved mechanisms to repress their movement. Here, we identify a novel role for the Drosophila melanogaster Condensin II subunit, dCAP-D3 in preventing the mobilization of retrotransposons located in somatic cell euchromatin. dCAP-D3 regulates transcription of euchromatic gene clusters which contain or are proximal to retrotransposon sequence. ChIP experiments demonstrate that dCAP-D3 binds to these loci and is important for maintaining a repressed chromatin structure within the boundaries of the retrotransposon and for repressing retrotransposon transcription. We show that dCAP-D3 prevents accumulation of double stranded DNA breaks within retrotransposon sequence, and decreased dCAP-D3 levels leads to a precise loss of retrotransposon sequence at some dCAP-D3 regulated gene clusters and a gain of sequence elsewhere in the genome. Homologous chromosomes exhibit high levels of pairing in Drosophila somatic cells, and our FISH analyses demonstrate that retrotransposon-containing euchromatic loci are regions which are actually less paired than euchromatic regions devoid of retrotransposon sequences. Decreased dCAP-D3 expression increases pairing of homologous retrotransposon-containing loci in tissue culture cells. We propose that the combined effects of dCAP-D3 deficiency on double strand break levels, chromatin structure, transcription and pairing at retrotransposon-containing loci may lead to 1) higher levels of homologous recombination between repeats flanking retrotransposons in dCAP-D3 deficient cells and 2) increased retrotransposition. These findings identify a novel role for the anti-pairing activities of dCAP-D3/Condensin II and uncover a new way in which dCAP-D3/Condensin II influences local chromatin structure to help maintain genome stability.

Psychological correlates of patients with postural orthostatic tachycardia syndrome (POTS).

Psychological symptoms are frequently reported in patients with Postural Orthostatic Tachycardia Syndrome (POTS); however, the nature of these symptoms is not well understood. The current study described baseline psychological symptoms in patients with POTS, and examined associations between psychological and self-report autonomic symptoms. Participants reported mild anxiety symptoms, moderate depressive symptoms, severe somatization, and elevated anxiety sensitivity. Depressive symptoms and pain catastrophizing were significantly associated with autonomic symptoms. The current study adds to the literature by documenting elevated levels of anxiety sensitivity, and relationships between psychological and autonomic symptoms.