Citations

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.

Survivors of human trafficking experience profound trauma with long-lasting psychological, physical, and social consequences that can complicate medical care, particularly in the context of serious illness. This case highlights the palliative care approach to a 38-year-old woman with metastatic cervical cancer and a history of trafficking-related trauma. The clinical team encountered nuanced challenges, including disrupted trust, limited social support, high symptom burden, and distress related to bodily autonomy. A trauma-informed, multidisciplinary team—comprised of palliative care, gynecological oncology, psychiatry, and social work—prioritized safety, choice, and trust-building to align care with the patient’s values and goals. Despite significant health inequities and psychosocial vulnerabilities, individualized care planning and intentional communication supported dignity, symptom control, and emotional safety during a prolonged hospitalization. This case illustrates the ethical and relational dimensions of caring for survivors of trafficking and underscores the importance of trauma-informed care principles, cultural humility, and interdisciplinary collaboration in palliative settings.

Invasive lobular breast carcinoma (ILC), the most common special histological subtype of breast cancer, is characterized by nearly universal expression of estrogen receptor alpha (ER) and unique sites of metastases, neither of which is fully recapitulated by genetically engineered mouse models. Using reporter-labeled ILC mouse xenografts, herein we used mammary fat pad, tail vein and intracardiac orthotopic growth to analyze spontaneous and experimental metastasis and gene expression. We observed ER-positive primary tumors with single-file histology and collagen deposition, and spontaneous metastasis from the mammary fat pad to bones, ovaries, and brain including the leptomeninges, thereby closely mirroring the growth and metastatic spread of human ILC. Brain metastases showed strong ER staining, confirmed by sequencing analyses which identified estrogen signaling as top activated pathway, and the lesions exhibited robust response to endocrine therapy. In summary, we report endocrine responsive mammary fat pad, tail vein and intracardiac xenografts that faithfully demonstrate unique ILC features and can serve as invaluable pre-clinical translational platforms for validating candidate ILC genetic drivers and testing novel therapeutics.