The rockefeller university

The autosomal recessive form of hyperimmunoglobulin E syndrome (AR-HIES), caused by mutations in the DOCK8 (Dedicator of Cytokinesis 8) gene, presents a wide range of clinical manifestations and phenotypically overlaps with several types of combined immunodeficiency disorders characterized by elevated serum IgE levels. Due to the high rates of morbidity and mortality, as well as the potential curability through hematopoietic stem cell transplantation (HSCT), early and accurate differential diagnosis of this syndrome is crucial for optimal management and improved prognosis. Flow cytometry tests can be beneficial for early diagnosis of many inborn errors of immunity (IEIs), including this syndrome. This study, conducted for the first time on Iranian patients, investigated the expression of the DOCK8 protein. DOCK8 expression was assessed by flow cytometry in 14 patients (6 males and 8 females) with a clinical diagnosis of DOCK8 deficiency. The diagnosis was ultimately confirmed through genetic testing. The results showed that DOCK8 expression in patients was significantly lower compared to the healthy control group.Flow cytometric evaluation of DOCK8 protein expression offers a rapid and efficient diagnostic method with a sensitive detection range suitable for many cases. This approach can facilitate the diagnosis of DOCK8 deficiency, thereby enabling timely and effective disease management.

Nuclear pore complexes (NPCs) mediate selective exchange of macromolecules between the nucleus and cytoplasm, but the organization of their transport barrier has been a matter of debate. Here we used high-speed atomic force microscopy, complemented with orthogonal in vitro and in vivo approaches, to probe the dynamic behaviour of the NPC central channel at millisecond resolution. We found that nuclear transport factors dynamically remodel intrinsically disordered phenylalanine-glycine (FG) domains tethered within the NPC channel, partitioning the barrier into two zones: a rapidly fluctuating annular region and a highly mobile central plug. Increased FG-repeat density in mutant NPCs dampened barrier dynamics and impaired transport. Notably, NPC-like behaviour was recapitulated in DNA origami nanopores bearing transport factors and correctly tethered FG domains but not in in vitro FG hydrogels. Thus, the rotationally symmetric architecture of NPCs supports a nanoscopic barrier organization that contrasts with many of the bulk properties of in vitro FG-domain assemblies.

JGP study (De Giorgis et al. https://doi.org/10.1084/jgp.202413739) reveals that the auxiliary Ca-v beta(3) subunit regulates the cardiac calcium channel Ca(v)1.2 by modulating the two-step activation of VSD II.

Vocal learning, the ability to imitate sounds, is a complex convergent trait crucial for spoken language and observed in a few independent lineages of mammals and birds. While convergences in gene expression have been found in vocal learning brain regions, amino acid convergences remain unclear. Here, we investigated whether avian vocal learning clades have amino acid convergences linked to their specialized trait. We developed a tool, Convergent Variant Finder, and applied it to an alignment of 48 species representing nearly all bird orders to identify convergent single amino acid variants among vocal learners and over 8,000 other polyphyletic species combinations. We discovered that the number of convergent variants was associated with the product of branch lengths of the most recent common ancestors of each species combination. The number of convergent variants in vocal learning clades did not exceed that of control species combinations. However, a subset of genes with vocal learner-specific convergent amino acid variants was enriched in the "learning" process, under positive selection, and significantly overlapped with gene sets for FOXP2 targets, singing-induced regulation in vocal learning nuclei, and differentially expressed in vocal learning nuclei. Moreover, we confirmed that the majority of convergent patterns in vocal learners were in the genomes of 363 species densely sampled across the avian tree. We propose that amino acid and nucleotide convergence accumulates at a steady state, with the rate proportional to divergence time. Selection associated with convergent traits, such as vocal learning, then likely acts on a subset of these changes.

The life-threatening coronavirus disease 2019 (COVID-19) affects about 1 in 1,000 healthy people under 50 without underlying conditions. Among patients with critical COVID-19 pneumonia, rare germline variants at genes controlling type I IFN immunity have been reported in up to 5% of patients. Causal etiologies in 80-85% of cases are still unknown. We analyzed two families with hypoxemic COVID-19 pneumonia for known single-gene inborn errors of immunity. In Family 1, two siblings with critical COVID-19 were homozygous for a DOCK2 variant, c.3624+5G>A. DOCK2 deficiency is a known T-cell disorder underlying severe viral diseases. The variant resulted in skipping exon 35, which was predicted to produce a frameshift truncated protein (p.L1157Ifs*12). The proband showed markedly decreased blood CD4 T-helper cell counts, impaired T lymphocyte transformation test, and increased serum IgG, IgA, and IgE levels, as documented in other DOCK2-deficient patients. In Family 2, the proband had lethal COVID-19 and HPV-2-associated multiple recalcitrant warts. She was heterozygous for a deletion in GATA2:c.1075_1102del28, p.W360Sfs*18. GATA2 haploinsufficiency is a known cause of severe viral diseases due to a lack of plasmacytoid dendritic cell (pDC) development. The proband had monocytopenia and a lack of circulating pDCs, as reported in other patients with GATA2 haploinsufficiency. Overall, both DOCK2 deficiency and GATA2 haploinsufficiency are associated with critical and often fatal COVID-19 pneumonia.

T cell exhaustion is a major barrier to effective cancer immunotherapy. Although immune checkpoint blockade can reinvigorate exhausted T cells, not all patients achieve long-term responses, partly due to the refractory nature of terminally exhausted T cells. Beyond persistent antigen stimulation, the environmental drivers of exhaustion remain to be thoroughly characterized. Here we identify CD47 upregulation in tumor-infiltrating exhausted CD8+ T cells in both human and murine tumors. We reveal a novel role for the extracellular matrix protein thrombospondin-1 (TSP-1) in engaging CD47 on T cells to promote exhaustion. This interaction activates calcineurin-NFAT signaling, inducing upregulation of TOX and expression of inhibitory receptors, and impairing effector function during tumor progression. Importantly, disrupting the TSP-1-CD47 axis prevents T cell exhaustion and enhances tumor control. Our findings identify a novel pathway promoting T cell dysfunction and suggest that targeting the TSP-1-CD47 axis is a promising strategy to enhance T cell immunity and immunotherapy efficacy.

Fulminant viral hepatitis (FVH) is a devastating condition caused by hepatotropic viruses such as hepatitis A virus (HAV), hepatitis B virus (HBV), and HSV-1/2. We studied 149 FVH patients (73 males and 76 females, aged 1-76) for blood autoantibodies (auto-Abs) neutralizing type I interferons (IFNs; IFN-alpha 2, -beta, -omega). Six of 16 (37.5%) HSV-triggered FVH patients carried such auto-Abs on admission, including three with a previously known autoimmune disease. These patients contrasted with 133 HAV- (n = 46) or HBV-triggered (n = 87) patients, none of whom had such detectable auto-Abs. Odds ratios for HSV-triggered FVH in individuals with auto-Abs ranged from 35.3 (95% CI: 13.0-96.2; P < 10-7) for those neutralizing only 100 pg/ml IFN-alpha/omega to 1,895 (CI: 448.5-8,002; P < 10-12) for those neutralizing both IFN-alpha and IFN-omega at 10 ng/ml. Over one third of HSV-triggered FVH cases in this international cohort were due to preexisting auto-Abs. This finding highlights auto-Abs against type I IFNs as a major determinant of HSV-FVH and paves the way for targeted preventive or therapeutic interventions.

Optogenetics has transformed basic research on neural circuitry, led to diverse experimental insights into human brain function and dysfunction, and opened pathways for clinical translation based on new understanding of how specific cell types contribute to cognition and behavior. Many of these translational pathways do not rely on the direct application of optogenetics in humans, but rather develop and advance other treatment modalities by leveraging causal knowledge derived from optogenetic circuit neuroscience. However, a recent proof-of-principle study-showing that optogenetics applied directly to the human central nervous system can treat blindness-underscores not only the curative potential but also the need for careful ethical consideration in the extension of direct optogenetic intervention to other disorders. Here, we review relevant considerations-including the selection of clinical indications, identification of molecular and optical strategies for specificity, and navigation of safety and regulatory issues-that together inform the development of optogenetic translation targeting cells and circuits that have been causally implicated through optogenetic discoveries.

Ants primarily communicate via pheromones, and other modes of communication have remained understudied. A new paper shows that fire ant workers employ substrate-borne vibrations to induce the killing and cannibalism of young queens when the colony is starved, showing that ant communication can be multifaceted.