Heterozygous variant as a novel genetic cause of telomere biology disorders.

Premature telomere shortening or telomere instability is associated with a group of rare and heterogeneous diseases collectively known as telomere biology disorders (TBDs). Here we identified two unrelated individuals with clinical manifestations of TBDs and short telomeres associated with the identical monoallelic variant c.767A>G; Y256C in Although the replication protein A2 (RPA2) mutant did not affect ssDNA binding and G-quadruplex-unfolding properties of RPA, the mutation reduced the affinity of RPA2 with the ubiquitin ligase RFWD3 and reduced RPA ubiquitination.

Age-based stereotype threat in the workplace: A daily diary study of antecedents and mechanisms.

Both older and younger employees are stereotyped at work, making them susceptible to age-based stereotype threat or the concern about being negatively stereotyped based on their age. To date, there is limited understanding of the workplace events that spark age-based stereotype threat and the mechanisms through which they do so. The current daily diary study aimed to assess the frequency with which older and younger employees experience various events that have been identified as potential antecedents of age-based stereotype threat (e.

Condensin positioning at telomeres by shelterin proteins drives sister-telomere disjunction in anaphase.

The localization of condensin along chromosomes is crucial for their accurate segregation in anaphase. Condensin is enriched at telomeres but how and for what purpose had remained elusive. Here, we show that fission yeast condensin accumulates at telomere repeats through the balancing acts of Taz1, a core component of the shelterin complex that ensures telomeric functions, and Mit1, a nucleosome remodeler associated with shelterin.

Pot1 promotes telomere DNA replication via the Stn1-Ten1 complex in fission yeast.

Telomeres are nucleoprotein complexes that protect the chromosome-ends from eliciting DNA repair while ensuring their complete duplication. Pot1 is a subunit of telomere capping complex that binds to the G-rich overhang and inhibits the activation of DNA damage checkpoints. In this study, we explore new functions of fission yeast Pot1 by using a pot1-1 temperature sensitive mutant.

Stn1-Ten1 and Taz1 independently promote replication of subtelomeric fragile sequences in fission yeast.

Efficient replication of terminal DNA is crucial to maintain telomere stability. In fission yeast, Taz1 and the Stn1-Ten1 (ST) complex play prominent roles in DNA-ends replication. However, their function remains elusive.

Interactions across the ages: How concerns about warmth and competence impact age-based stereotype threat in the workplace.

Although the disengagement consequences of age-based stereotype threat in the workplace are well-documented, it is less clear what causes employees to experience age-based stereotype threat. Based on socioemotional selectivity theory, the present study examines whether and why daily cross-age interactions in the workplace lead to stereotype threat. Using a diary study design over 2 weeks, 192 employees (86 employees aged 30 and younger; 106 employees aged 50 and older), completed 3570 reports on daily interactions with coworkers.

Choroidal Effusions after Glaucoma Drainage Implant Surgery: Risk Factors and Surgical Management.

Objective: To report the incidence of patients who developed choroidal effusions after glaucoma drainage implant (GDI) surgery and determine risk factors for and outcomes of surgical intervention.

Design: Retrospective case series.

Subjects: Medical records of 605 patients who underwent GDI surgery from January 1, 2017 to June 7, 2021 at New York University Langone Health and New York Eye and Ear Infirmary of Mount Sinai were reviewed.

Outcomes of Glaucoma Reoperations in the Primary Tube Versus Trabeculectomy Study.

Purpose: To describe the incidence and outcomes of reoperations for glaucoma in the Primary Tube Versus Trabeculectomy (PTVT) Study.

Design: Cohort study of patients in a multicenter randomized clinical trial.

Participants: The PTVT Study enrolled 242 patients with medically uncontrolled glaucoma and no previous incisional ocular surgery.

A proto-telomere is elongated by telomerase in a shelterin-dependent manner in quiescent fission yeast cells.

Telomere elongation is coupled with genome replication, raising the question of the repair of short telomeres in post-mitotic cells. We investigated the fate of a telomere-repeat capped end that mimics a single short telomere in quiescent fission yeast cells. We show that telomerase is able to elongate this single short telomere during quiescence despite the binding of Ku to the proto-telomere.

Health literacy and ophthalmology: A scoping review.

As of 2020, it is estimated that 43.3 million people are blind, and an additional 553 million have mild to severe vision impairment. At least 1 billion worldwide have a vision impairment that could have been prevented or has yet to be addressed.

Regulation of Mus81-Eme1 structure-specific endonuclease by Eme1 SUMO-binding and Rad3ATR kinase is essential in the absence of Rqh1BLM helicase.

The Mus81-Eme1 structure-specific endonuclease is crucial for the processing of DNA recombination and late replication intermediates. In fission yeast, stimulation of Mus81-Eme1 in response to DNA damage at the G2/M transition relies on Cdc2CDK1 and DNA damage checkpoint-dependent phosphorylation of Eme1 and is critical for chromosome stability in absence of the Rqh1BLM helicase. Here we identify Rad3ATR checkpoint kinase consensus phosphorylation sites and two SUMO interacting motifs (SIM) within a short N-terminal domain of Eme1 that is required for cell survival in absence of Rqh1BLM.

A novel glaucoma approach: Stem cell regeneration of the trabecular meshwork.

Glaucoma is the leading cause of global irreversible blindness, necessitating research for new, more efficacious treatment options than currently exist. Trabecular meshwork (TM) cells play an important role in the maintenance and function of the aqueous outflow pathway, and studies have found that there is decreased cellularity of the TM in glaucoma. Regeneration of the TM with stem cells has been proposed as a novel therapeutic option by several reports over the last few decades.

Erythrocytosis associated with IgA nephropathy.

Background: Erythrocytosis is a hematological disorder usually related to hematopoietic stem cell somatic mutations. However, unexplained erythrocytosis remains frequent. In this study, we evaluated the involvement of IgA1, a regulator of erythropoiesis also implicated in IgA nephropathy (IgAN) pathophysiology, in unexplained polycythemia/erythrocytosis (PE) of IgAN patients.

Gain-of-function mutations in RPA1 cause a syndrome with short telomeres and somatic genetic rescue.

Human telomere biology disorders (TBD)/short telomere syndromes (STS) are heterogeneous disorders caused by inherited loss-of-function mutations in telomere-associated genes. Here, we identify 3 germline heterozygous missense variants in the RPA1 gene in 4 unrelated probands presenting with short telomeres and varying clinical features of TBD/STS, including bone marrow failure, myelodysplastic syndrome, T- and B-cell lymphopenia, pulmonary fibrosis, or skin manifestations. All variants cluster to DNA-binding domain A of RPA1 protein.

Comorbidities and concomitant medications in patients with chronic hepatitis C virus infection receiving second-generation direct-acting antiviral regimens in Belgium: an observational study.

Objective: To describe comorbidities and concomitant medications in patients initiating treatment for hepatitis C virus (HCV) infection with direct-acting antiviral (DAA) regimens in Belgium.

Methods: This was a noninterventional, observational, multicenter study of data from patient charts. Adult patients with HCV infection receiving second-generation DAA therapy were included.

Myositis of an Extraocular Muscle, a Possible Drug Reaction: Histopathologic and Immunopathologic Analysis.

A 58-year-old man presented with left-sided orbital inflammation, including chemosis and a lateral rectus abduction defect. Initially presumed to represent cellulitis, the condition responded poorly to oral and intravenous antibiotics. CT showed the epicenter of an infiltrate to involve the lateral rectus.

PARACENTRAL ACUTE MIDDLE MACULOPATHY ASSOCIATED WITH HYPERCOAGULABILITY IN PREGNANCY.

Purpose: To report a case of paracentral acute middle maculopathy in an otherwise healthy young, multiparous woman in her second trimester of pregnancy.

Methods: A case report.

Results: A 38-year-old woman in her twentieth week of pregnancy presented with a four-day history of an acute paracentral scotoma in her left eye.

Lessons Learned in Implementing VA Video Connect for Evidence-Based Psychotherapies for Anxiety and Depression in the Veterans Healthcare Administration.

A top priority for the Veteran's Healthcare Administration is improving access to high-quality mental healthcare. Mobile and telemental healthcare are a vital component of increasing access for veterans. The Veteran's Healthcare Administration is making efforts to further broaden how veterans receive their care through VA Video Connect, which allows veterans to connect with their provider from their residence or workplace.

RPA and Pif1 cooperate to remove G-rich structures at both leading and lagging strand.

In , the absence of Pif1 helicase induces the instability of G4-containing CEB1 minisatellite during leading strand but not lagging strand replication. We report that RPA and Pif1 cooperate to maintain CEB1 stability when the G4 forming strand is either on the leading or lagging strand templates. At the leading strand, RPA acts in the same pathway as Pif1 to maintain CEB1 stability.

Telomerase Repairs Collapsed Replication Forks at Telomeres.

Telomeres are difficult-to-replicate sites whereby replication itself may threaten telomere integrity. We investigate, in fission yeast, telomere replication dynamics in telomerase-negative cells to unmask problems associated with telomere replication. Two-dimensional gel analysis reveals that replication of telomeres is severely impaired and correlates with an accumulation of replication intermediates that arises from stalled and collapsed forks.

Aurora B and condensin are dispensable for chromosome arm and telomere separation during meiosis II.

In mitosis, while the importance of kinetochore (KT)-microtubule (MT) attachment has been known for many years, increasing evidence suggests that telomere dysfunctions also perturb chromosome segregation by contributing to the formation of chromatin bridges at anaphase. Recent evidence suggests that Aurora B kinase ensures proper chromosome segregation during mitosis not only by controlling KT-MT attachment but also by regulating telomere and chromosome arm separation. However, whether and how Aurora B governs telomere separation during meiosis has remained unknown.

Telomeric Transcription and Telomere Rearrangements in Quiescent Cells.

Despite the condensed nature of terminal sequences, the telomeres are transcribed into a group of noncoding RNAs, including the TElomeric Repeat-containing RNA (TERRA). Since the discovery of TERRA, its evolutionary conserved function has been confirmed, and its involvement in telomere length regulation, heterochromatin establishment, and telomere recombination has been demonstrated. We previously reported that TERRA is upregulated in quiescent fission yeast cells, although the global transcription is highly reduced.

Nuclear envelope attachment of telomeres limits TERRA and telomeric rearrangements in quiescent fission yeast cells.

Telomere anchoring to nuclear envelope (NE) is a key feature of nuclear genome architecture. Peripheral localization of telomeres is important for chromatin silencing, telomere replication and for the control of inappropriate recombination. Here, we report that fission yeast quiescent cells harbor predominantly a single telomeric cluster anchored to the NE.