Citations

Introduction As the age of the world’s population continues to increase it is important to investigate behaviors, such as alcohol consumption, that may negatively impact the health of the older population. Materials In the present study, aged, young adult and adolescent female and male C57BL/6J mice underwent a measure of acute alcohol withdrawal via a handling induced convulsion study followed by a drinking in the dark procedure to measure alcohol self-administration. Results We report that aged animals enter acute alcohol withdrawal later than younger animals as measured by later onset of handling induced convulsions. The later onset is likely due to reduced alcohol metabolism. Furthermore, aged animals consumed significantly less alcohol in the drinking in the dark paradigm but had similar blood alcohol concentrations compared to younger animals. Discussion The current work demonstrates for the first time differential alcohol self-administration and acute alcohol withdrawal in aged animals compared to younger animals.

Abstract Objective This report describes the first use of the Affera Sphere-9 dual-energy catheter for slow pathway modification in atrioventricular nodal re-entrant tachycardia (AVNRT) during atrial fibrillation (AF) ablation in a patient with a dual-chamber pacemaker, illustrating a streamlined single-catheter approach. Case presentation A 74-year-old man with prior cryoablation for AF, mitral valve repair, and a recently implanted dual-chamber pacemaker was referred for repeat AF ablation due to symptomatic, recurrent AF (30% burden). Left atrial mapping with the Sphere-9 catheter revealed reconnection at the right superior pulmonary vein, right carina, and across prior roof and floor lines. Using pulsed field (4-s lesions, 8 mm spacing) and supplemental radiofrequency (RF) energy, the left atrial posterior wall was re-isolated. Cavo-tricuspid isthmus ablation was performed with RF and pulsed field applications, achieving bidirectional block. During subsequent testing, typical AVNRT was induced. To maximize efficiency, slow pathway modification was performed with the same Sphere-9 catheter, using shortened RF applications (3 s), a lower target temperature (60°C), and an 80% current limit, at an inferior-posterior site 1.3–2.5 cm from the His signal. Junctional acceleration was observed without atrioventricular block, indicating successful slow pathway modification. The procedure was completed without fluoroscopy or complications, and follow-up device interrogation showed no recurrence of AF or AVNRT. Conclusion This case demonstrates the feasibility and acute safety of using a single dual-energy lattice-tip catheter for combined AF and AVNRT ablation, potentially reducing procedure time, catheter exchanges, and cost; larger studies are needed to assess long-term outcomes.

Abstract The maintenance of cooperative behaviors within microbial populations remains an evolutionary puzzle, particularly in spatially structured environments like those found in chronic infection. In Pseudomonas aeruginosa , quorum sensing (QS) directs the production of costly public goods that are vulnerable to exploitation by non-producing cheaters. However, the biophysical mechanisms that stabilize this cooperation in complex environments remain poorly understood. Here, we elucidate how the biophysical properties of the bacterial cell surface govern the micron-scale architecture of bacterial aggregates to promote or constrain the stability of cooperation. Using a polymer-structured growth environment, we demonstrate that cell surface hydrophobicity acts as a primary determinant of spatial organization, where hydrophilic wild-type cells assemble into “stacked” aggregates, whereas hydrophobic O-specific antigen-deficient cells form dense “clumps”. In mixed populations, distinct surface properties exhibit phase-separation-like immiscibility, segregating the cells at the micron scale. We show that this segregation directly suppresses cheater fitness by physically sequestering cooperative clusters. Specifically, hydrophobic QS-deficient cells were effectively excluded by hydrophilic QS cooperators, limiting their access to public goods. Furthermore, invasion experiments revealed that hydrophilic cells are inherently fitter, capable of unidirectionally invading populations with a hydrophobic cell surface and independent of social dynamics. Conversely, the need to gain access to nutrient resources can fine-tune these barriers, enabling hydrophilic QS-deficient cells to cluster proximally to hydrophobic cooperators. These findings establish that bacterial cell surface traits impact strongly on microbial social interactions and offer new insights into the maintenance and loss of cooperative traits in chronic infections such as those found in chronic lung infections. Significance Statement Cooperative behaviors are essential for the survival of pathogenic bacteria like Pseudomonas aeruginosa , yet they are continually threatened by “cheater” cells that exploit shared public good resources. We demonstrate that the physical properties of the cell surface, specifically hydrophobicity, act as a key architect of microbial social structure. In polymer-rich environments, differences in surface hydrophobicity drive a distinct “oil-and-water” segregation between cell populations. This micron-scale phase separation physically sequesters cooperative cells, insulating them from exploitation by cheaters. Consequently, spatial structure serves as a biophysical stabilizer of cooperation, limiting the metabolic advantages typically held by cheaters. Our findings demonstrate that microbial social evolution is governed not only by genetic strategies, but by fundamental biophysical constraints that dictate the spatial limits of exploitation.

» Thorough patient presurgical counseling should emphasize individual patient goals, which may include improving ambulation, reducing reliance on orthoses, alleviating pain, or facilitating caregiver support. » Careful physical examination is essential to differentiate whether the primary cause of dysfunction is weakness, spasticity, or both. » Diagnostic adjuncts including botulinum toxin, short-acting blocks, instrumented gait analysis, and dynamic electromyography provide valuable insight and guide operative decisions. » Surgical treatment must be individualized, with nerve-based procedures indicated for pure spasticity and tendon lengthening, tenotomy, or joint procedures being required to treat soft tissue and joint contractures.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal cancer with a 5-year survival rate of 13%. Despite recent molecular stratification of tumors into distinct classical and basal-like cell states, most tumors are heterogeneous and contain both subtypes. Therefore, therapeutic approaches targeting only one subtype are unlikely to be effective as standalone PDAC treatments. Here, we integrated chromatin accessibility [assay for transposase-accessible chromatin with sequencing (ATAC-seq)], genome-wide occupancy [chromatin immunoprecipitation sequencing (ChIP-seq)] for epigenetic status (H3K27ac), and H3K4me3-anchored chromatin topology (HiChIP) to uncover subtype-independent highly interactive enhancers that interact with essential genes in PDAC. Motif analysis revealed that these common enhancers were bound by KLF5 with subsequent depletion leading to decreased cell viability via induction of apoptosis. To elucidate the transcriptional and epigenetic mechanisms by which KLF5 functions in PDAC, we used rapid depletion of KLF5 with dTAG technology and profiled the effects on the open and active chromatin landscape and transcription with nascent RNA and messenger RNA sequencing over time. Enhancer inactivation via KRAB domain Zim3-dCas9 fusion protein confirmed KLF5-bound enhancers regulate target genes, including the anti-apoptotic gene BCL2L1 . Multiplex immunofluorescence confirmed costaining of KLF5 and Bcl-xL in patient samples and overexpression of Bcl-xL rescued the induction of apoptosis after KLF5 depletion. Together, this study provides insights into common mechanisms to target highly heterogeneous PDAC tumors.

Establishes a robust long-term human adipocyte organoid culture system maintained for over 90 days. Recapitulates key features of OSA-related intermittent hypoxia in human adipocytes in vitro. Demonstrates IH-induced adipocyte aging, including ultrastructural damage and epigenetic reprogramming. Identifies impaired adipogenesis and insulin signaling under intermittent hypoxia. Provides a physiologically relevant platform for mechanistic studies and drug screening.

Abstract Purpose Although the Woven EndoBridge (WEB) device is increasingly used for the treatment of wide-neck intracranial aneurysms, including in the acute rupture setting, comparative evidence assessing the impact of rupture status remains limited. This study compared angiographic, safety, and clinical outcomes between ruptured and unruptured intracranial aneurysms treated with WEB. Methods We conducted a retrospective analysis of prospectively collected data from the multicenter cohort registry WorldWideWEB, including consecutive adult patients with intracranial aneurysms treated with the WEB. Patients were stratified into groups of ruptured and unruptured aneurysms. Propensity score matching was used to balance baseline characteristics between both groups. Retreatment rate was the primary outcome. Secondary outcomes included mRS, safety events (thromboembolic complications) and angiographic outcomes (periprocedurally and last follow-up). Results Among 1,220 patients, 342 (28.0%) presented with ruptured aneurysms. There was no significant difference in the rate of thromboembolic complications between groups (11.8% vs 5.9%, p = 0.056). At follow-up, adequate occlusion was lower (82.2% vs 93.3%, p < 0.002) and functional outcomes were worse (mRS ≥2 in 34.1% vs 21.9%, p = 0.012) among patients with ruptured aneurysms. Periprocedural adequate occlusion (53.3% vs 53.8%, p>0.9) and retreatment rates (11.8% vs 7.1%, p = 0.14) did not differ between groups after matching. Conclusion Ruptured aneurysms demonstrated expected inferior follow-up functional and angiographic outcomes when compared with unruptured aneurysms, but no difference in retreatment rate and procedural safety. These findings support WEB as a safe and effective treatment option for appropriately selected ruptured intracranial aneurysms in routine clinical practice.