Citations

The LMNA gene encodes lamin A and lamin C, which play important roles in nuclear organization. Pathogenic variants in LMNA cause laminopathies, a group of disorders with diverse phenotypes. There are two main groups of disease-causing variants: missense variants affecting dimerization and intermolecular interactions, and heterozygous substitutions activating cryptic splice sites. These variants lead to different disorders, such as dilated cardiomyopathy and Hutchinson–Gilford progeria (HGP). Among these, the phenotypic terms for LMNA-associated cardiocutaneous progeria syndrome (LCPS), which does not alter lamin A processing and has an older age of onset, have been described. Here, we present the workup of an LMNA variant of uncertain significance, NM_170707.2 c. 4G>A, p.(Glu2Lys), in a 36-year-old female with severe calcific aortic stenosis, a calcified mitral valve, premature aging, and a family history of similar symptoms. Due to the uncertainty of in silico predictions for this variant, an assessment of nuclear morphology was performed using the immunocytochemistry of stable cell lines to indicate whether the p.(Glu2Lys) had a similar pathogenic mechanism as a previously described pathogenic variant associated with LCPS, p.Asp300Gly. Indirect immunofluorescence analysis of nuclei from stable cell lines showed abnormal morphology, including lobulation and occasional ringed nuclei. Relative to the controls, p.Glu2Lys and p.Asp300Gly nuclei had significantly (p < 0.001) smaller average nuclear areas than controls (mean = 0.10 units, SD = 0.06 for p.Glu2Lys; and mean = 0.09 units, SD = 0.05 for p.Asp300Gly versus mean = 0.12, SD = 0.05 for WT). After functional studies and segregation studies, this variant was upgraded to likely pathogenic. In summary, our findings suggest that p.Glu2Lys impacts nuclear morphology in a manner comparable to what was observed in p.Asp300Gly cells, indicating that the variant is the likely cause of the LCPS segregating within this family.

Background The Woven Endo-Bridge (WEB) device revolutionized the treatment of wide-necked bifurcation aneurysms by intrasaccular flow diversion. The latest advancement is the WEB-17 system, offering greater flexibility with fewer wires, enabling treatment of smaller distal aneurysms using smaller microcatheters than the WEB-21 system. Methods We conducted a systematic review following preferred reporting items for systematic reviews and meta-analyses guidelines, analyzing data from seven retrospective cohort studies involving 483 aneurysms treated with the WEB-17 device. Statistical analysis computed pooled prevalence rates and 95% confidence intervals using appropriate models for each outcome and R software version 4.3.1 (R Foundation for Statistical Computing, Vienna, Austria). Results Technical success was achieved in 475 out of 483 aneurysms treated with the WEB-17 device, with a success rate of 98.34% (95% confidence interval (CI) = 96.72–99.17). Among the successful cases, 4.97% (95% CI = 1.60–14.39) required adjunctive devices. Adequate occlusion, defined as complete occlusion or neck remnants, was observed in 94.41% (95% CI = 88.17–97.46) of cases. Periprocedural complications were infrequent, with thromboembolic complications occurring in 4.93% (95% CI = 3.29–7.30) of cases, hemorrhagic complications in 1.28% (95% CI = 0.58–2.83), and postprocedural neurologic complications in 0.99% (95% CI = 0.31–3.14). Procedure-related morbidity was observed in 1.71% (95% CI = 0.86–3.39) of cases, and there was one procedure-related mortality reported at 0.21% (95% CI = .03–1.50). Mortality unrelated to the procedure occurred in 1% (95% CI = 0.23–4.15). Conclusion Our findings suggest that the WEB-17 device is associated with a high rate of technical success, favorable angiographic outcomes, and a low rate of periprocedural complications. Further research, including prospective trials, is needed to confirm these findings and establish its safety and efficacy definitively.

Key Points Drosophila can be a model for Dent Disease type 1. Drosophila Clc-C mutations function similar to human CLC-5 Dent 1 mutations. Background Drosophila serve as exceptional alternative models for in vivo and ex vivo research and may provide an avenue for in-depth investigation for human ClC-5 and Dent disease type 1 (DD1). The Drosophila ClC-c (CG5284) has sequence homology with human ClC-5 and is hypothesized to encompass similar functional and phenotypical roles with ClC-5 and variants that cause DD1. Methods Ion transport function and activity of Drosophila ClC-c and homologous DD1 variants were assessed by voltage clamp electrophysiology. Membrane localization was demonstrated in Drosophila expressing a GFP-labeled construct of ClC-c. Genetic expression of an RNAi against ClC-c mRNA was used to generate a knockdown fly that serves as a DD1 disease model. Tubule secretion of cations and protein were assessed, as well as the crystal formation in the Malpighian tubules. Results Voltage clamp experiments demonstrate that ClC-c is voltage-gated with Cl − -dependent and pH-sensitive currents. Inclusion of homologous DD1 mutations pathogenic variants (S393L, R494W, and Q777X) impairs ClC-c ion transport activity. In vivo expression of ClC-c-eGFP in Malpighian tubules reveals that the membrane transporter localizes to the apical membrane and nearby cytosolic regions. RNAi knockdown of ClC-c (48% decreased mRNA expression) causes increased secretion of both urinary protein and Ca 2+ and increased occurrence of spontaneous tubule crystals. Conclusions Drosophila ClC-c shows orthologous function and localization to human ClC-5. Thus, Drosophila and ClC-c regulation may be useful for future investigations of Cl − transport, Ca 2+ homeostasis, and urinary protein loss in DD1.

Abstract Motivation Emerging omics technologies have introduced a two-way grouping structure in multiple testing, as seen in single-cell omics data, where the features can be grouped by either genes or cell types. Traditional multiple testing methods have limited ability to exploit such two-way grouping structure, leading to potential power loss. Results We propose a new 2D Group Benjamini–Hochberg (2dGBH) procedure to harness the two-way grouping structure in omics data, extending the traditional one-way adaptive GBH procedure. Using both simulated and real datasets, we show that 2dGBH effectively controls the false discovery rate across biologically relevant settings, and it is more powerful than the BH or q-value procedure and more robust than the one-way adaptive GBH procedure. Availability and implementation 2dGBH is available as an R package at: https://github.com/chloelulu/tdGBH. The analysis code and data are available at: https://github.com/chloelulu/tdGBH-paper.

Genetic variation at the transmembrane protein 106B gene ( TMEM106B) has been linked to risk of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) through an unknown mechanism. We found that presence of the TMEM106B rs3173615 protective genotype was associated with longer survival after symptom onset in a postmortem FTLD-TDP cohort, suggesting a slower disease course. The seminal discovery that filaments derived from TMEM106B is a common feature in aging and, across a range of neurodegenerative disorders, suggests that genetic variants in TMEM106B could modulate disease risk and progression through modulating TMEM106B aggregation. To explore this possibility and assess the pathological relevance of TMEM106B accumulation, we generated a new antibody targeting the TMEM106B filament core sequence. Analysis of postmortem samples revealed that the TMEM106B rs3173615 risk allele was associated with higher TMEM106B core accumulation in patients with FTLD-TDP. In contrast, minimal TMEM106B core deposition was detected in carriers of the protective allele. Although the abundance of monomeric full-length TMEM106B was unchanged, carriers of the protective genotype exhibited an increase in dimeric full-length TMEM106B. Increased TMEM106B core deposition was also associated with enhanced TDP-43 dysfunction, and interactome data suggested a role for TMEM106B core filaments in impaired RNA transport, local translation, and endolysosomal function in FTLD-TDP. Overall, these findings suggest that prevention of TMEM106B core accumulation is central to the mechanism by which the TMEM106B protective haplotype reduces disease risk and slows progression.

Abstract Background Rapid cycling (RC) at least 4 recurrent episodes per year in bipolar disorder (BD) has been recognized since the 1970s. We now comment on our recent review of the topic and extensive RC analysis in a large clinical cohort, emphasizing therapeutics research. Comments Prevalence of RC-BD averages 36% for any year versus 22% in the preceding year. Rapid cycling is not a consistent feature over many years, although average long-term, annual recurrence rates are greater in RC-BD patients. Risk of RC may be somewhat greater among women and with older ages. It is also associated with cyclothymic temperament, prominent depression, and mood-switching with antidepressant treatment and is associated with increased suicidal risk. Treatment of individual episodes in RC-BD and effective long-term prevention remain inadequately studied, although antidepressant treatment can worsen RC. Some research supports treatment with aripiprazole, lamotrigine, and lithium, and interest in second-generation antipsychotics is emerging. All such options are used in various inadequately evaluated combinations. Conclusions Rapid cycling is prevalent among BD patients but seems to vary in risk over time without evidence of progressive worsening. Treatment of acute episodes in RC-BD patients and effective long-term preventive management require much more intensive investigation.