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Four decades into the HIV pandemic, HIV-2 infection remains an underutilized comparative resource for HIV-1 cure research. HIV-2 is associated with lower plasma viral loads, slower CD4+ T-cell decline, and delayed disease progression in many individuals. Early studies attributed these features to intrinsic viral attenuation, pointing to differences in accessory protein function, transcriptional regulation, and reservoir size. However, accumulating molecular and epidemiological evidence challenges this interpretation. The transcriptional status of HIV-2 in vivo is not uniform across studies. Some studies report comparable viral RNA levels between HIV-1 and HIV-2 in CD4-matched individuals. In contrast, others find lower per-cell transcriptional output in HIV-2, suggesting that the degree of transcriptional restriction varies with cohort composition, disease stage, and measurement approach. Importantly, neither finding supports a model of uniform proviral silencing. This review examines the molecular biology, immune responses, and reservoir dynamics of HIV-2 infection, weighing evidence that both supports and challenges the view of HIV-2 as an attenuated comparator to HIV-1. The available data suggest that HIV-2 persistence involves regulated viral expression and ongoing, albeit attenuated, immune engagement, rather than transcriptional silence. However, the extent to which immune activation in HIV-2 is quantitatively or qualitatively distinct from that in HIV-1 remains incompletely resolved. HIV-2 does not provide a prescriptive cure blueprint, but it reveals a key biological constraint: ongoing viral transcription can coexist with prolonged immune containment. This finding argues against transcription-only approaches to HIV-1 remission and underscores the need for strategies that combine transcriptional modulation with sustained immune engagement.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive, rapid deterioration of motor neurons (MNs). Rare mutations in a handful of genes are sufficient to cause ALS; however, 90% of ALS cases are not linked to these genes and their underlying cause remains unknown. Abnormal subcellular distribution, structure or aggregation of the TDP-43 protein are nearly universal hallmarks of the disease, suggesting a shared molecular mechanism across both genetic and sporadic ALS (sALS). However, the heterogeneity of the ALS clinical syndrome suggests that the underlying mechanisms culminating in ALS and TDP-43 pathology may partly differ among individuals and may need to be understood to develop successful therapies that target subgroups of patients. Here, we harnessed the power of machine learning (ML) to begin to decode, in a systematic and unbiased fashion, the cellular signatures of ALS. We used high-content imaging of live, human iPSC-derived motor neurons (iMNs) from ALS patients or gene-edited and gene-corrected TDP-43 mutant lines to train shallow connected ML algorithms (SMLs) and deep convolutional neural networks (DNNs). Our models identified and distinguished mutant and control iMNs with moderately high accuracy. We then used explainability methods to uncover the discriminating cellular signals and found that the strongest ones mapped to the nuclear area, suggesting underlying alterations within the nucleus. We validated this finding by revealing that TDP-43 mutant iMNs display alterations in nucleocytoplasmic shuttling and cellular integrity. Further, a time-interaction ML model uncovered dynamic morphological transitions preceding degeneration, offering a window into early pathogenic events as well as neurodevelopmental changes. Extending our ML pipeline to iMNs with mutations in the ALS gene C9orf72 or derived from sALS revealed both overlapping and distinguishable signatures, suggesting shared yet distinct mechanistic pathways. Together, these findings establish ML-driven phenotypic profiling as a powerful approach to stratify people with ALS, help disentangle the molecular heterogeneity of ALS and produce a more holistic phenotypic definition in cell-based models, and ultimately find causes and treatments. This strategy offers a scalable and innovative paradigm for uncovering early disease mechanisms not only in ALS but potentially across a spectrum of neurodegenerative and sporadic disorders.

Metastasis remains the primary cause of cancer-related deaths and is characterized by complex reprogramming of systemic processes. Emerging evidence indicates that extraosseous tumors can rewire bone marrow physiology and disrupt hematopoiesis, thereby compromising effective systemic immune responses. However, how tumor-induced immune alterations in bone marrow contribute to skeletal metastasis remains poorly defined. Here, using immunocompetent mouse models of mammary tumor bone metastasis, we show that mammary cancer cells precondition the bone marrow niche prior to metastatic colonization, driving early remodeling of the microenvironment and depleting bone marrow lymphoid populations. Specifically, cancer cells induce a dramatic B cell reduction, the most abundant lymphoid subset in bone marrow, resulting from dysregulated cell cycle gene expression in pre-B cells, along with impaired B-cell proliferation and differentiation. These findings are further validated in breast cancer bone metastasis patients, who exhibit significant bone marrow B-cell loss alongside disrupted molecular and developmental programs. A causal role for B cells in restraining skeletal metastasis is supported by the finding that experimental B-cell depletion significantly increases both incidence and severity of bone metastasis. Mechanistically, we find that B-cell loss is driven by systemic elevation of G-CSF. Accordingly, pharmacological neutralization of G-CSF significantly reduces both B-cell depletion and bone metastasis susceptibility. Collectively, our data reveal that breast cancer cells can distantly hijack B-cell developmental trajectories, promoting skeletal metastasis. This work identifies B cells and G-CSF as potential therapeutic targets in bone metastasis and highlights the importance of targeting early bone marrow immune dysregulation to prevent or limit skeletal metastasis. Mammary tumor cells reshape the bone marrow niche inducing B cell lossBone marrow B cell development is impaired in mammary tumor metastasisExperimental depletion of B cells promotes bone metastasisG-CSF mediates B cell loss in mammary tumor metastasis.

MRE11 safeguards genome stability at stalled replication forks, where its activity must be tightly controlled to prevent nascent strand DNA degradation (NSD). However, the upstream signaling mechanisms that limit NSD remain poorly defined. Here, we identify Ser649 (S649) as a previously unrecognized phosphorylation site that limits MRE11 association with stalled forks. We show that S649 phosphorylation is robustly induced by replication stress or elevated cytosolic calcium levels, and is mediated by the calcium-responsive CaMKK2-AMPKα axis in concert with ATR, but independently of CHK1. Loss of S649 phosphorylation enhances MRE11 binding to DNA and increases its association with stalled forks, driving excessive NSD, elevated DNA damage, and increased sensitivity to PARP inhibition. We find that the ATM-mediated S676/S678 phosphorylation primes S649 phosphorylation, which in turn facilitates subsequent phosphorylation of SQ/TQ sites in MRE11. Moreover, we find that CaMKK2-AMPKα activation requires ATR but is independent of ATM. Collectively, our findings reveal a hierarchical signaling mechanism that couples calcium signaling with ATM/ATR pathways to prevent NSD at stalled forks and preserve genome integrity.

Transitional Kindergarten (TK) is a relatively new and under-researched model of early childhood education. Using data from Michigan TK, this study examines impacts for children (50% female, 78% White, 9% Black, 7% Hispanic) who enrolled at age 4 in 2014-2015 and 2018-2019 using a regression discontinuity design. Michigan TK improved kindergarten readiness (0.9 SD, N = 1,943) and third-grade math scores (0.2-0.3 SD, N = 15,680). It had no impact on ever being placed in special education from kindergarten through second grade, but it did cause earlier entry into special education in kindergarten (N = 15,704). Our findings add to the larger evidence base on early education programs and contribute substantially to the evidence base on TK specifically. Transitional Kindergarten (TK) is a relatively new and under-researched model of early childhood education. This study examines how enrolling in TK at age 4 affects children's early educational outcomes. We use statewide education data from Michigan public schools and focus on children who were 4 years old in the 2014–15 and 2018–19 school years. We find that TK enrollment boosted children's performance on kindergarten readiness assessments and, years later, on third-grade math exams. It had no impact on ever being placed in special education between kindergarten and second grade, though it did cause earlier entry into special education in kindergarten. These findings add to the larger evidence base on early education programs and contribute substantially to the evidence base on TK specifically.

How protein quality control is maintained during acute metabolic stress remains poorly understood. In budding yeast, abrupt glucose depletion rapidly lowers ATP levels and leads to the formation of chaperone-containing inclusions, suggesting that ATP-dependent degradation of misfolded proteins may be compromised when energy becomes limiting. Here we find that selective degradation of misfolded proteins remains active during acute glucose starvation despite reduced cellular ATP levels. Using model misfolded substrates in yeast Saccharomyces cerevisiae , we show that misfolded proteins continue to be efficiently degraded throughout both early and late phases of acute glucose depletion. This degradation requires the proteasome and depends on its functional 19S regulatory particle, indicating that ATP-dependent proteasomal activity persists during metabolic stress. We further find that nucleus-vacuole junctions (NVJs) promote efficient degradation during prolonged glucose starvation, revealing a role for organelle contact sites in supporting proteostasis under energy limitation. Together, these findings indicate that cells preserve proteasome-mediated proteostasis during acute glucose starvation, while NVJ membrane contact sites help sustain degradation capacity when metabolic resources are scarce.

Alternative polyadenylation is a mechanism by which cells tune gene expression, and dysregulation can lead to development of disease. PABPC1 has been implicated in poly(A) site selection, but its function in gene regulation remains contradictory and poorly defined. Here, we investigate its role in B cell development, where APA controls immunoglobulin secretion. To define this role, we mapped PABPC1-RNA interactions using CLAP-seq and perturbed PABPC1 expression using a degron based strategy. PABPC1 localizes to the 3'UTR in 70% of its gene targets and primarily binds to A-rich regions. Integration with transcriptomic data suggests PABPC1 downregulates 60% of its gene targets. While transcriptome-wide shifts in 3' UTR length were limited, PABPC1 binding was specifically enriched in genes exhibiting significant 3' UTR shortening. Using a foundational genomics model, we find the PAS-proximal region is the most predictive of gene expression within PABPC1 binding sites. Positional analysis revealed PABPC1 localizes closer to the PAS in genes downregulated following depletion. In immunoglobulin transcripts, PABPC1 binds to both secreted and membrane isoforms and is more enriched at the secretory PAS, and depletion modestly alters immunoglobulin expression. Together, our findings demonstrate PABPC1 primarily shortens and downregulates its targets in a context dependent manner.

Mutations in DOCK7 have been identified in individuals with epileptic encephalopathies. Given that epileptic encephalopathies are a set of disorders that result in seizure activity and associated cognitive and behavioral impairments, we investigated the role of Dock7 in seizure susceptibility and flurothyl kindling using the repeated flurothyl seizure model in mice. Male and female Dock7 +/+ and Dock7 △ex3-4/△ex3-4 mice were subjected to 8 daily flurothyl exposures (kindling, induction phase) followed by a 28-day incubation period and a subsequent flurothyl rechallenge (retest). No significant differences were observed in baseline myoclonic jerk or generalized seizure thresholds between genotypes or sexes. However, over the kindling period, male Dock7 △ex3-4/△ex3-4 mice exhibited slightly higher myoclonic jerk and generalized seizure thresholds compared to Dock7 +/+ males across trials. Female mice showed similar trends, but the differences were only significant for generalized seizure thresholds. Following the 28-day incubation period and flurothyl retest, male mice of both genotypes maintained their seizure thresholds upon retest. Dock7 +/+ female mice showed increased myoclonic jerk and generalized seizure thresholds during retest, while Dock7 △ex3-4/△ex3-4 females maintained their thresholds. A key finding was the emergence of more severe forebrain→brainstem seizures upon flurothyl retest in a significant percentage of mice across all groups. However, the proportion of mice developing these seizures did not differ significantly between genotypes. Although DOCK7 mutations have been linked to human epileptic encephalopathies and neurodevelopmental dysfunction, we find that Dock7 △ex3-4/△ex3-4 male and female mice do not show heightened excitability or seizure susceptibilities using the repeated flurothyl seizure model. Dock7 △ex3-4/△ex3-4 mice show slightly higher seizure thresholds during flurothyl kindling Dock7 △ex3-4/△ex3-4 mice do not exhibit heightened seizure susceptibility upon retest. Forebrain-brainstem seizures emerged upon retest regardless of Dock7 genotype.

Length variation in tandem repeats is a well-established driver of disease risk and is commonly assumed to arise from persistent genomic instability. Here, we characterize TRACT, a 30-bp variable number tandem repeat (VNTR) intronic to the calcium channel gene CACNA1C . TRACT exhibits extreme length variation (3-30+ kb) and has been previously linked to risk for bipolar disorder and schizophrenia. By examining multiple human cohorts, we find that TRACT alleles are strikingly bimodal in both length and sequence composition. Short alleles (TRACT S , ∼6 kb) and long alleles (TRACT L , ∼24 kb) are enriched for distinct 30-bp variants and are found on separate haplotypes that arose prior to the human migration out of Africa. Our data suggest that these ancient alleles expanded via perfect repeat tracts that were disrupted by accumulated mutations to result in relative length stability in extant humans, where there is no evidence for overt germline or somatic instability. Interestingly, neuropsychiatric disease risk is associated with specific 30-bp variants within TRACT S alleles, but not with overall TRACT length or with 30-bp variants enriched in TRACT L alleles. Instead, TRACT L alleles are associated with decreased gene expression in fibroblasts and testis. Together, these findings motivate joint examination of both sequence composition and length variation to fully understand the effects of VNTRs on evolution, trait variation, and disease risk.

Cells respond to acute environmental stress by rapidly reorganizing transcriptional machinery and genome architecture, yet how these processes are mechanistically integrated remain poorly understood. We find that Mediator Tail subunits function in a hierarchical fashion to coordinate transcription factor condensate assembly, three-dimensional genome organization and transcriptional output during the heat shock response (HSR) in Saccharomyces cerevisiae . We identify the Mediator Tail triad-Med2, Med3, and Med15-as exceptionally enriched in intrinsically disordered regions and possessing strong intrinsic liquid-liquid phase separation potential, in contrast to the more structured Tail subunits Med5 and Med16. Live-cell imaging reveals that this IDR-rich triad is critically required for thermal stress-induced Heat Shock Factor 1 (Hsf1) condensate formation, HSR gene coalescence and robust transcriptional induction. Mechanistically, Med15 executes these functions through its activator-binding domains, with the IDR-rich ABD2 playing a dominant role in stabilizing Hsf1, Mediator, and RNA polymerase II (Pol II) occupancy at HSR loci, while the C-terminal IDRs of Med2 and Med3 provide critical interaction platforms that couple condensate formation to genome organization. Strikingly, Med16 defines a parallel regulatory axis: although dispensable for Hsf1 condensate nucleation, Med16 is required for Mediator and Pol II condensate formation and for HSR gene coalescence, revealing that transcription factor clustering and productive transcriptional condensates are mechanistically separable. Finally, Med5 plays a minor yet detectable role in HSR transcription and gene coalescence. Together, our findings establish a modular and hierarchical organization of the Mediator Tail that integrates phase separation, transcriptional condensate composition, and 3D genome architecture to drive rapid stress-induced gene activation.

While occupational therapists (OTs) promote quality of life through meaningful occupation, little attention has been paid to the role that leisure plays in palliative care. This review aims to explore the perceptions of service users and OTs regarding engagement in leisure activities at the end-of-life. 1. Determine the value of leisure activities for older adults living with cancer on the palliative pathway, 2. To identify interventions to promote occupational engagement. A qualitative systematic review was conducted in accordance with the PRISMA Statement. The electronic databases namely ASSIA, AMED, CINAHL, Medline, PsycArticles, and PubMed were searched. Qualitative studies meeting the eligibility criteria were included. Two reviewers independently screened the identified articles. The findings were qualitatively synthesised using thematic analysis. We included seven articles with 405 participants. This review demonstrated that leisure could help people in palliative care maintain a sense of identity and normalcy. Leisure also increased happiness and provided relief from pain. Occupational therapy interventions targeting leisure allowed people to maintain a consistent level of engagement. Further empirical research is required to explore palliative patients' perspectives on leisure and to develop specific occupational therapy interventions that enable OTs to facilitate leisure engagement for people in palliative care. Why we conducted this review: • There is little focus on engaging people in leisure when they experience palliative care and there is a big emphasis on managing symptoms of cancer. • More and more people need palliative care due to the increasing ageing population who live longer with debilitating chronic illness. What did We do: • We systematically identified relevant articles and reviewed the literature from the past 14 years to understand the perspectives of older adults receiving palliative care on participating in leisure. What did we find out: • Older adults living with cancer value leisure activities because leisure gives them a greater sense of control over their lives, helps them to maintain a sense of normalcy, provides relief from pain, and increases feelings of happiness. • Occupational therapists have the skills to enable people to participate in leisure by changing the way an activity is done or changing the environment.

Defects in RNA metabolism are a defining feature of neurodevelopmental disease, yet the contribution of RNA decay pathways to human brain development remains poorly understood. Notably, mutations in genes encoding ubiquitously expressed RNA surveillance machinery often cause highly tissue-selective disease, underscoring a central paradox in human biology. The RNA exosome is a conserved ribonuclease complex long considered a housekeeping machine for RNA turnover, yet recessive mutations in genes encoding structural subunits of the complex disproportionately cause neurological disease, suggesting an instructive role in nervous system development. Here, we show that the RNA exosome regulates the temporal progression of gene expression programs during human cerebellar differentiation. Using CRISPR-engineered human cerebellar organoids modeling EXOSC3 variants, we find that RNA exosome dysfunction does not broadly alter transcript abundance, but instead disrupts transitions between developmental states. Mutant organoids exhibit persistence of early transcriptional programs, impaired maturation of Purkinje and rhombic lip-derived lineages, and altered cellular composition. These defects are accompanied by disorganized laminar architecture and reduced coordination of neuronal activity, despite preserved intrinsic excitability. More broadly, our findings suggest that defects in RNA decay represent a general mechanism underlying neurodevelopmental disease. Together, this work establishes RNA surveillance as a key determinant of developmental timing, neural identity, and disease.

Myelination requires precise integration of physical cues by oligodendrocyte lineage cells (OLCs), but the molecular sensors that detect these cues remain incompletely understood. Here, we demonstrate that oligodendrocyte progenitor cells (OPCs) are sensitive to sub-micron changes in membrane displacement. Based on channel properties, RNA expression, and protein abundance, we find that the mechanosensitive ion channel PIEZO1 contributes to OPC mechanosensitivity. In vivo , zebrafish with oligodendrocyte (OL)-specific disruption of piezo1 have fewer sheaths per OL. Zebrafish with OL-specific piezo2 disruption also have fewer sheaths as well as decreased total myelin capacity over time. OL-specific disruption of both piezo1 and piezo2 caused more severe phenotypes, with reduced OPC volume, and in myelinating OLs, reduced sheath number, sheath length, and total myelin output. Furthermore, piezo1 / piezo2 disruption leads to sporadic sheath formation outside the normal developmental window. Our findings indicate that OLs use Piezo channels in vivo to influence sheath formation, expansion, and retractions.

The transcription factor p63 is critical for epithelial development and implicated in tumorigenesis. However, our understanding of the role of p63 in development and disease has been complicated by its diverse isoforms. As a member of the p53 family member of genes, TP63 encodes for numerous isoforms, including the N-terminal variants TAp63 and ΔNp63, which are generated through alternative promoter usage. TAp63 and ΔNp63 share various structural domains, including the DNA-binding domain, and primarily differ in their N-terminus which consists of intrinsically disordered regions (IDRs). The isoforms are known to have different functions, including tumor suppression in the case of TAp63 and pro-tumor formation for ΔNp63, but how the N-terminus contributes to isoform-specific gene regulatory effects has yet to be elucidated. Using both genomic and TurboID proximity-labeling proteomic approaches, we show that the N-terminus mediates differential interactions with cofactors that have direct effects on isoform function, specifically the regulation of apoptosis. We find that the N-terminus of TAp63 interacts with more transcriptional machinery, leading to stronger transcriptional activity by TAp63 than ΔNp63. However, ΔNp63 maintains interactions with coactivators, suggesting it can retain some transactivation capabilities. Strikingly, the N-terminus of TAp63 displays enriched interactions with chromatin modifiers, including the histone acetyltransferase KAT2A, that result in TAp63-specific binding at inaccessible sites. We find that an IDR-mediated interaction with KAT2A is involved in regulation of apoptosis by TAp63. Collectively, our results suggest a model in which TAp63 and ΔNp63 broadly share genomic occupancy, but differential interactions with cofactors contribute to isoform-specific regulation by TAp63 and ΔNp63.

Radiation-induced ureteral stricture (RIUS) is a rare but refractory late complication of pelvic radiotherapy, driven by severe fibrosis and microvascular injury that undermines the effectiveness of conventional interventions such as balloon dilation, ureteral stenting, and reconstructive surgery. This review summarizes the pathophysiological basis of treatment resistance in RIUS and critically appraises current management strategies. Beyond its clinical relevance, RIUS is discussed as a paradigmatic model of advanced fibrotic ureteral disease, offering broader insights into the limitations of purely mechanical approaches. We further examine emerging biologically oriented strategies, including mesenchymal stem cell-derived extracellular vesicle-based regenerative therapies, next-generation ureteral stents incorporating advanced biomaterials, and drug-eluting stent platforms for localized antifibrotic and antimicrobial delivery. Although largely investigational, these approaches collectively signal a conceptual shift from palliative drainage toward biologically informed, restorative management of RIUS and related refractory ureteral strictures. New ways to treat radiation-induced ureteral stricture 1. Why was this study done? Radiation therapy for cancers in the pelvis can sometimes cause a blockage in the ureter (the tube that carries urine from the kidney to the bladder). This condition, called radiation-induced ureteral stricture (RIUS), is rare but very difficult to treat. Standard treatments, such as balloon dilation, stents, or surgery, often do not work well because the radiation damage continues to cause scarring and poor blood supply. 2. What did the researchers do? This review looked at why current treatments fail and explored new ideas that scientists are testing in the laboratory and in early studies. 3. What did the researchers find? Three main areas of innovation were identified: Using tiny particles from stem cells (called extracellular vesicles) to reduce scarring and help healing. Developing new types of stents made from advanced materials, including metals or biodegradable plastics. Designing drug-coated stents that can release medicines directly into the ureter to fight scarring or infection. 4. What do the findings mean? These new approaches are still at the experimental stage, but they represent a shift in thinking—from simply relieving symptoms to trying to repair the ureter and restore its function.

Death literacy - the knowledge, skills, and capacity to navigate end-of-life care, advance care planning, dying, and death care - is shaped by cultural, religious, and linguistic factors. The Death Literacy Index (DLI) captures practical, experiential, factual, and community domains. Currently, there is limited evidence about death literacy levels among culturally and linguistically diverse communities in multicultural settings, and little is known about how translated versions of the DLI perform psychometrically in these groups or how culturally tailored, community-delivered interventions can strengthen death literacy. (1) To evaluate the impact of culturally adapted, community-designed and delivered interventions on DLI subscale and total scores among Filipino, German, Italian, and Vietnamese communities in South Australia; and (2) to examine the preliminary psychometric properties (factor structure and reliability) of translated DLI instruments in these populations. Pre-post intervention study. Community leaders in each group co-designed and delivered a community-specific intervention over 3-5 months using culturally familiar channels (workshops, radio/podcasts, social media, and printed/online resources). Thus, four parallel but distinct interventions were implemented, one in each cultural/language community. The DLI was professionally translated (German, Italian, Tagalog, Vietnamese) with community review. Surveys were administered in preferred languages at baseline (T1) and ~6 weeks post-intervention (T2). Psychometrics (T1, n = 242): confirmatory factor analysis (CFA) and reliability. Impact (matched pairs, n = 100): Wilcoxon signed-rank tests. Psychometrics (T1, n = 228): Subscale CFAs supported the translated DLI across groups, while the total-scale fit was poor - reinforcing a multidimensional construct; internal consistency was good-excellent overall, with weaker reliability for Talking Support subscale (Vietnamese) and some variability in Experiential Knowledge. Intervention impact (matched pairs, n = 100): Filipino participants showed significant increases in median scores across all four DLI subscales and the total DLI score (medium-large effects); Vietnamese participants showed significant decreases in Practical Knowledge and total DLI scores, with little change on other subscales; German and Italian groups demonstrated small, mostly non-significant increases on selected DLI subscales (particularly Factual and Community Knowledge), with minimal change in total DLI scores. Across groups, DLI subscales capturing knowledge of resources and supports generally improved. Culturally tailored, community-delivered interventions can strengthen death literacy, but effects vary by cultural/linguistic context. DLI subscales function adequately across groups, whereas total-scale fit is poor. Future work should refine translations (e.g. DLI-R), address weaker domains, and adapt content and delivery to community preferences to enhance cultural responsiveness and equity in end-of-life literacy. The study demonstrates how death literacy can operate as a culturally responsive, community-level public health indicator and provides evidence to guide adaptation of both the DLI and community programs to advance equity in end-of-life literacy and care. Community-led death literacy in multicultural settings: Testing initiatives and validating the DLI People often find it hard to talk about death, dying, and end-of-life care. ‘Death literacy’ is the practical knowledge and confidence we need to plan, make choices, and support each other at the end of life. This study looked at how to build death literacy in multicultural communities and whether a short questionnaire (the Death Literacy Index) works well in different languages. We worked with community leaders from Filipino, German, Italian, and Vietnamese groups in South Australia. Together, we designed and delivered activities over several months-such as workshops, radio and podcast segments, social media posts, and printed resources-using preferred community channels and languages. Community members completed a survey in their chosen language before the activities and again about six weeks after. What did we find? Filipino participants showed clear improvements across all parts of death literacy. German and Italian groups had smaller, mixed improvements. Vietnamese participants did not improve overall and, in some areas, scores went down-highlighting that different communities may need different kinds of support or materials. Across groups, people generally felt more aware of resources and support available. We also checked how well the survey worked in translation. Most parts of the survey performed well across languages, but the total score did not fit as a single measure, and one section was less reliable in Vietnamese. This suggests death literacy is made up of several related skills rather than one simple trait, and that some survey wording needs refining for certain languages. Why does this matter? Culturally tailored, community-led approaches can strengthen end-of-life knowledge, but one size does not fit all. Services should partner with communities to design activities that suit their language, culture, and preferences. Future work will refine the survey (e.g., using the revised DLI-R) and adapt programs to better support every community.

In the treatment of high grade serous ovarian cancer (HGSC), patients initially diagnosed with unresectable tumors are first treated with neoadjuvant chemotherapy (NACT) to reduce tumor burden prior to surgery. Analysis of matched pre- and post-NACT samples from the same patients enables the investigation of chemotherapy impacts and the biomarkers of progression. Although the tumor immune microenvironment (TIME) has increasingly been recognized as critical in shaping the development and progression of HGSC, we lack a comprehensive understanding of how chemotherapy remodels the TIME. Previous studies have found evidence for a general inflammatory response post-NACT, despite inconsistencies regarding which differentially expressed genes and pathways are implicated. We combine matched NanoString gene expression data from multiple sources to create a large dataset of matched pre- and post- NACT samples (N=83, with 29 novel to this study) and investigate reproducibility. Further, we use machine learning methods to investigate whether patient progression-free survival (PFS) can be predicted from the observed impact of chemotherapy on the TIME as represented by the comprehensive set of NanoString features. We find overall low predictability of PFS from all NanoString features, suggesting that previous results may have been limited by small sample size effects and that larger datasets are needed to identify more generalizable and translatable findings. We identify a set of differential expression features that are the most important for predicting patient outcomes that can be validated in future computational and biological studies. A subset of patients with high grade serous ovarian cancer are treated with chemotherapy before surgery to reduce tumor burden. We investigate a large dataset of samples taken before and after chemotherapy. These matched samples enable an investigation of how the environment around tumors, for example immune cell infiltration, reacts to chemotherapy, providing insights into biomarkers for treatment response and treatments that could complement chemotherapy. This larger dataset only partially replicates results from previous studies, while also providing new insights. Machine learning models designed to predict the time to patient recurrence from available biomarkers indicate that they are not strongly predictive of patient outcomes, in contrast to past studies. These results suggest that larger datasets are needed. We identify a set of genes that change with chemotherapy and are indicative of and potentially useful for predicting time to disease recurrence and can be further investigated.

Germline pathogenic variants in BRCA1 and BRCA2 confer disproportionately elevated cancer risks in breast and ovarian tissues, yet the basis for this tissue specificity remains incompletely understood. Here, we integrate bulk-tumor aneuploidy analysis across 340,824 cancer cases from three independent cohorts (TCGA, ICGC PCAWG, and FoundationCore) with single-cell whole-genome sequencing from two independent studies to investigate whether tissue-specific patterns of chromosomal deletion contribute to this phenomenon. We find that breast and ovarian cancers are consistently enriched for deletions of chromosome arms 17q and 13q-harboring the BRCA1 and BRCA2 genes, respectively-relative to other solid tumor types, and that mutational timing analysis independently places these deletions among the earliest somatic events in these cancers. Phylogenetic reconstruction of single-cell data reveals that in pre-malignant breast tissue from germline BRCA1/2 carriers, chr17q and chr13q deletions appear as localized subclonal events within small clades against a largely diploid background. In established malignancies, these same deletions are found within dominant clonal lineages accompanied by widespread genomic instability-consistent with clonal sweeps originating from early deletion events. These findings suggest that breast and ovarian cellular environments confer a selective advantage for chr17q and chr13q deletions, providing a mechanism that may contribute to the tissue-specific cancer risk observed in gBRCA1/2 carriers.

Certain regulatory DNA regions remain accessible even under conditions of widespread chromatin compaction. These regions are often marked by specific protein factors and histone modifications that help maintain their accessibility. Here, we examine the genomic landscape of acetyl-methyllysine (Kacme), a recently discovered histone post-translational modification. Across multiple systems, Kacme is highly enriched at sites of accessible chromatin, including active promoters, enhancers, silencers, and CTCF-binding sites. We find that Kacme is selectively retained at loci that resist condensation during mitosis, marks XIST and escapee regions on the inactive X chromosome in female cells and demarcates the boundaries of broad heterochromatin domains. Kacme-marked insulator elements block heterochromatin spreading and protect adjacent genes from transcriptional repression, even when H3K27me3 levels are pharmacologically elevated through KDM6A/6B inhibition. Taken together, our findings establish the chromatin features associated with Kacme and support a model in which Kacme helps safeguard chromatin accessibility at loci that resist compaction.