Surgical outcomes following neoadjuvant chemotherapy with and without immunotherapy in patients with triple-negative breast cancer.

PURPOSE: Adding pembrolizumab to neoadjuvant chemotherapy (NAC) for triple-negative breast cancer (TNBC) improves pathologic complete response (pCR) rates and event-free survival. The impact of adding immunotherapy to NAC on surgical outcomes is unknown. This study compares 90-day post-surgical complications (PSCs) and time to adjuvant treatment among patients undergoing NAC for TNBC with and without immunotherapy. METHODS: Patients treated with NAC alone or with immunotherapy (NAC-I) for stage I-III TNBC between 2018 and 2022 were retrospectively identified at a single academic institution. Kruskal-Wallis rank sum and Fisher's exact tests compared patient sociodemographic and clinical characteristics. Multivariable logistic regression determined odds ratios (OR) predicting PSCs. RESULTS: Of 54 patients, 29 received NAC alone and 25 received NAC-I. Compared to NAC patients, NAC-I patients had more advanced stage tumors (p = 0.038), and had slightly higher rates of mastectomy with reconstruction (p = 0.193). 72.0% of NAC-I patients experienced a pCR, compared with 44.8% of NAC patients (p = 0.193). There were 10 PSCs (34.5%) in NAC patients compared to 9 PSCs (36.0%) in NAC-I patients (p > 0.99). Regression analysis demonstrated no association of PSCs with NAC-I (OR 0.83, 95% CI 0.19-3.60). Time to adjuvant therapy was shorter for NAC-I patients (28 days vs 36 days, p = 0.013). CONCLUSIONS: Patients with TNBC receiving NAC-I have higher pCR rates and do not appear to have added 90-day PSCs or delays to adjuvant therapy despite trending toward more extensive surgical procedures compared to NAC alone. Larger studies are needed to further evaluate the surgical safety of immunotherapy.

Skin cancer diagnosis associated with asthma and hay fever: a nationwide cross-sectional study.

Asthma is a respiratory disorder caused by airway inflammation which may worsen after allergen exposure. Recent cohort studies demonstrate a positive association between skin cancer and asthma or hay fever (allergy to outdoor allergens such as pollen). Nationally-representative data for adults in the United States remains limited. We aimed to characterize skin cancer prevalence among individuals in the United States who have asthma or hay fever. To achieve this aim, we extracted nationwide cross-sectional data from 16,277 adult participants (total survey-weighted sample = 174,765,931) of the Third National Health and Nutrition Examination Survey from 1988 to 1994. This study uses survey-weighted regression to compare the nationwide prevalence of skin cancer among participants with or without a history of asthma or hay fever. Sensitivity analysis examined the influence of sex, 25-hydroxyvitamin D, chronic bronchitis or emphysema, geographical region, urban proximity, and oral glucocorticoid use. Of the included participants, the age-adjusted prevalence of skin cancer was 7.2%, similar to national estimates. Skin cancer prevalence was higher among participants who had asthma with hay fever (adjusted prevalence ratio, 1.79; 95% confidence interval, 1.16, 2.76), but not among participants with asthma only or hay fever only. Similarly, skin cancer prevalence was higher for those with asthma and positive pollen allergen skin prick testing (SPT), but not for those with hay fever and positive pollen SPT. No association was noted between skin cancer and wheezing triggered by pollen. Hay fever or immunoglobulin-E sensitization to pollen may increase skin cancer prevalence among individuals with a history of asthma.

Haplotype Analysis Reveals Pleiotropic Disease Associations in the HLA Region.

The human leukocyte antigen (HLA) region plays an important role in human health through involvement in immune cell recognition and maturation. While genetic variation in the HLA region is associated with many diseases, the pleiotropic patterns of these associations have not been systematically investigated. Here, we developed a haplotype approach to investigate disease associations phenome-wide for 412,181 Finnish individuals and 2,459 traits. Across the 1,035 diseases with a GWAS association, we found a 17-fold average per-SNP enrichment of hits in the HLA region. Altogether, we identified 7,649 HLA associations across 647 traits, including 1,750 associations uncovered by haplotype analysis. We find some haplotypes show trade-offs between diseases, while others consistently increase risk across traits, indicating a complex pleiotropic landscape involving a range of diseases. This study highlights the extensive impact of HLA variation on disease risk, and underscores the importance of classical and non-classical genes, as well as non-coding variation.

Exposure to Total Suspended Solids (TSS) Impacts Gill Structure and Function in Adult Zebrafish.

Total suspended solids (TSS) are a major contributor of anthropogenic impacts to aquatic systems. TSS exposure have been shown to affect the function of gills, but the mode of action is unclear. Zebrafish (Danio rerio) is emerging as an excellent model for mechanistic toxicology, and as there are no baseline studies on TSS effects in zebrafish gills, we tested the hypothesis that environmental concentrations of TSS damages gill structure and function in this species. Adult zebrafish were exposed to either 0, 10, 100, 500, 1000, or 2000 mg/L TSS for 4 days to assess the gill morphology. The minimal concentration that affected the gill structure was further tested for the distribution of key ion transporters, including Na+/K+- ATPase (NKA) and vacuolar-type H+-ATPase (VHA), using confocal microscopy. Our results reveal that TSS concentration as low as 100 mg/L alters the morphology of gills, including greater filament thickness, lamellae thickness, and epithelial lifting. This was also associated with a reduction in NKA immunoreactive (IR) cell count and intensity in the 100 mg/L TSS group, while there was neither a change in the VHA-IR cell count or expression nor the transcript abundance of atp6v1a and atp1a1a4 in the gills. Markers of stress response in these animals, including levels of cortisol, glucose, lactate, and glycogen were not altered after 4 days of TSS exposure. Overall, environmentally relevant concentrations of TSS can damage the gill structure and function in zebrafish and has the potential to enhance the toxicity of contaminants acting via the gills.

A Data-Driven Approach to Estimate Human Center of Mass State During Perturbed Locomotion Using Simulated Wearable Sensors.

Center of mass (COM) state, specifically in a local reference frame (i.e., relative to center of pressure), is an important variable for controlling and quantifying bipedal locomotion. However, this metric is not easily attainable in real time during human locomotion experiments. This information could be valuable when controlling wearable robotic exoskeletons, specifically for stability augmentation where knowledge of COM state could enable step placement planners similar to bipedal robots. Here, we explored the ability of simulated wearable sensor-driven models to rapidly estimate COM state during steady state and perturbed walking, spanning delayed estimates (i.e., estimating past state) to anticipated estimates (i.e., estimating future state). We used various simulated inertial measurement unit (IMU) sensor configurations typically found on lower limb exoskeletons and a temporal convolutional network (TCN) model throughout this analysis. We found comparable COM estimation capabilities across hip, knee, and ankle exoskeleton sensor configurations, where device type did not significantly influence error. We also found that anticipating COM state during perturbations induced a significant increase in error proportional to anticipation time. Delaying COM state estimates significantly increased accuracy for velocity estimates but not position estimates. All tested conditions resulted in models with R2 > 0.85, with a majority resulting in R2 > 0.95, emphasizing the viability of this approach. Broadly, this preliminary work using simulated IMUs supports the efficacy of wearable sensor-driven deep learning approaches to provide real-time COM state estimates for lower limb exoskeleton control or other wearable sensor-based applications, such as mobile data collection or use in real-time biofeedback.

Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders on a disease spectrum that are characterized by the cytoplasmic mislocalization and aberrant phase transitions of prion-like RNA-binding proteins (RBPs). The common accumulation of TAR DNA-binding protein-43 (TDP-43), fused in sarcoma (FUS), and other nuclear RBPs in detergent-insoluble aggregates in the cytoplasm of degenerating neurons in ALS/FTD is connected to nuclear pore dysfunction and other defects in the nucleocytoplasmic transport machinery. Recent advances suggest that beyond their canonical role in the nuclear import of protein cargoes, nuclear-import receptors (NIRs) can prevent and reverse aberrant phase transitions of TDP-43, FUS, and related prion-like RBPs and restore their nuclear localization and function. Here, we showcase the NIR family and how they recognize cargo, drive nuclear import, and chaperone prion-like RBPs linked to ALS/FTD. We also discuss the promise of enhancing NIR levels and developing potentiated NIR variants as therapeutic strategies for ALS/FTD and related neurodegenerative proteinopathies.

Perturbational phenotyping of human blood cells reveals genetically determined latent traits associated with subsets of common diseases.

Although genome-wide association studies (GWAS) have successfully linked genetic risk loci to various disorders, identifying underlying cellular biological mechanisms remains challenging due to the complex nature of common diseases. We established a framework using human peripheral blood cells, physical, chemical and pharmacological perturbations, and flow cytometry-based functional readouts to reveal latent cellular processes and performed GWAS based on these evoked traits in up to 2,600 individuals. We identified 119 genomic loci implicating 96 genes associated with these cellular responses and discovered associations between evoked blood phenotypes and subsets of common diseases. We found a population of pro-inflammatory anti-apoptotic neutrophils prevalent in individuals with specific subsets of cardiometabolic disease. Multigenic models based on this trait predicted the risk of developing chronic kidney disease in type 2 diabetes patients. By expanding the phenotypic space for human genetic studies, we could identify variants associated with large effect response differences, stratify patients and efficiently characterize the underlying biology.

Transcriptomics and chromatin accessibility in multiple African population samples.

Mapping the functional human genome and impact of genetic variants is often limited to European-descendent population samples. To aid in overcoming this limitation, we measured gene expression using RNA sequencing in lymphoblastoid cell lines (LCLs) from 599 individuals from six African populations to identify novel transcripts including those not represented in the hg38 reference genome. We used whole genomes from the 1000 Genomes Project and 164 Maasai individuals to identify 8,881 expression and 6,949 splicing quantitative trait loci (eQTLs/sQTLs), and 2,611 structural variants associated with gene expression (SV-eQTLs). We further profiled chromatin accessibility using ATAC-Seq in a subset of 100 representative individuals, to identity chromatin accessibility quantitative trait loci (caQTLs) and allele-specific chromatin accessibility, and provide predictions for the functional effect of 78.9 million variants on chromatin accessibility. Using this map of eQTLs and caQTLs we fine-mapped GWAS signals for a range of complex diseases. Combined, this work expands global functional genomic data to identify novel transcripts, functional elements and variants, understand population genetic history of molecular quantitative trait loci, and further resolve the genetic basis of multiple human traits and disease.

Glycoproteomic landscape and structural dynamics of TIM family immune checkpoints enabled by mucinase SmE.

Mucin-domain glycoproteins are densely O-glycosylated and play critical roles in a host of biological functions. In particular, the T cell immunoglobulin and mucin-domain containing family of proteins (TIM-1, -3, -4) decorate immune cells and act as key regulators in cellular immunity. However, their dense O-glycosylation remains enigmatic, primarily due to the challenges associated with studying mucin domains. Here, we demonstrate that the mucinase SmE has a unique ability to cleave at residues bearing very complex glycans. SmE enables improved mass spectrometric analysis of several mucins, including the entire TIM family. With this information in-hand, we perform molecular dynamics (MD) simulations of TIM-3 and -4 to understand how glycosylation affects structural features of these proteins. Finally, we use these models to investigate the functional relevance of glycosylation for TIM-3 function and ligand binding. Overall, we present a powerful workflow to better understand the detailed molecular structures and functions of the mucinome.

Across-Agency Partnerships and Within-Agency Capacities Facilitate Holistic, Tailored Approaches to Addressing Food Insecurity: A Qualitative Study.

BACKGROUND: Capacity-oriented approaches have the potential to reduce food insecurity (FI) and promote nutrition and health equity in low-resource settings. OBJECTIVE: The objective of this study was to identify multilevel capacities in San Diego County, CA that key informants from diverse food- and nutrition-related stakeholder agencies perceived to be helping to address FI. DESIGN: Trained qualitative interviewers conducted face-to-face, semi-structured interviews (30-60 minutes) with key informants. The Socioecological Model and a capacity-oriented approach informed interview guides. PARTICIPANTS/SETTING: Participants were key informants (n = 23) from diverse purposively sampled stakeholder agencies (n = 16) providing food or nutrition services and programs across San Diego County. Interviews were conducted between April 2019 and December 2021. ANALYSES PERFORMED: Interviews were audio-recorded, transcribed verbatim, and checked for accuracy. The research team conducted thematic content analysis to identify themes. RESULTS: Two interrelated themes, within-agency capacities and across-agency partnerships, collectively appeared to influence each individual agency's ability to provide tailored, holistic care to their clients and, thus, expand each agency's reach and impact to address the 4 domains of food security (ie, quantity, quality, psychological, and social). Multilevel (ie, individual, interpersonal, organizational, and macro) within-agency human, social, and cultural capital (eg, volunteers, staff-client relationships, and cultural competency) positively influenced the reach and impact of the individual agencies by enabling them to provide clients with personalized, holistic care. Alongside within-agency capacities, multilevel (ie, interpersonal, organizational, community, and macro levels) across-agency partnerships allowed individual agencies to address FI more effectively and holistically by connecting clients to other services (eg, housing and mental health) related to the circumstances of FI. CONCLUSIONS: In San Diego County, multilevel capacities in the form of within-agency capacities and across-agency partnerships collectively influenced the effectiveness of stakeholder agencies in addressing the 4 domains of FI among at-risk households. Future research should consider how to evaluate the impact of these existing capacities on FI.

Fermenting a place in history: The first outbreak of Escherichia coli O157 associated with kimchi in Canada.

A Canadian outbreak investigation was initiated in January 2022 after a cluster of cases of Shiga-toxin-producing Escherichia coli (STEC) O157 was identified through whole genome sequencing (WGS). Exposure information was collected through case interviews. Traceback investigations were conducted, and samples from case homes, retail, and the manufacturer were tested for STEC O157. Fourteen cases were identified in two provinces in Western Canada, with isolates related by 0-5 whole genome multi-locus sequence typing allele differences. Symptom onset dates ranged from 11 December 2021 to 7 January 2022. The median age of cases was 29.5 (range 0-61); 64% were female. No hospitalisations or deaths were reported. Of 11 cases with information available on fermented vegetable exposures, 91% (10/11) reported consuming Kimchi Brand A during their exposure period. The traceback investigation identified Manufacturer A in Western Canada as the producer. One open and one closed sample of Kimchi Brand A tested positive for STEC O157, with isolates considered genetically related by WGS to the outbreak strain. Napa cabbage within the kimchi product was hypothesised as the most likely source of contamination. This paper summarises the investigation into this STEC O157 outbreak associated with kimchi, the first reported outside of East Asia.

Circulating tumor DNA reveals mechanisms of lorlatinib resistance in patients with relapsed/refractory ALK-driven neuroblastoma.

Activating point mutations in Anaplastic Lymphoma Kinase (ALK) have positioned ALK as the only mutated oncogene tractable for targeted therapy in neuroblastoma. Cells with these mutations respond to lorlatinib in pre-clinical studies, providing the rationale for a first-in-child Phase 1 trial (NCT03107988) in patients with ALK-driven neuroblastoma. To track evolutionary dynamics and heterogeneity of tumors, and to detect early emergence of lorlatinib resistance, we collected serial circulating tumor DNA samples from patients enrolled on this trial. Here we report the discovery of off-target resistance mutations in 11 patients (27%), predominantly in the RAS-MAPK pathway. We also identify newly acquired secondary compound ALK mutations in 6 (15%) patients, all acquired at disease progression. Functional cellular and biochemical assays and computational studies elucidate lorlatinib resistance mechanisms. Our results establish the clinical utility of serial circulating tumor DNA sampling to track response and progression and to discover acquired resistance mechanisms that can be leveraged to develop therapeutic strategies to overcome lorlatinib resistance.

Impact of the COVID-19 Pandemic on the Reported Incidence of Select Bacterial Enteric Diseases in Canada, 2020.

The aim of this study was to describe the impact of the COVID-19 pandemic on reported cases and clusters of select enteric diseases in Canada, for the period of March 2020 to December 2020. Weekly counts of laboratory confirmed cases of Salmonella, Shigella, Shiga toxin-producing Escherichia coli (STEC), and Listeria monocytogenes were obtained from laboratory surveillance data. These data were supplemented with epidemiological information on the suspected source of illness, collected for cases identified within whole genome sequencing clusters. Incidence rate ratios were calculated for each pathogen. All data were compared with a prepandemic reference period. Decreases in the number of reported cases in 2020 compared with the previous 5-year period were noted for Salmonella, Shigella, Escherichia coli O157, and non-O157 STEC. Reported number of cases for L. monocytogenes in 2020 remained similar to those of the previous 5-year period. There was a considerable decline (59.9%) in the number of cases associated with international travel compared with a 10% decline in the number of domestic cases. Comparison of reported incidence rates of clustered versus sporadic cases for each pathogen showed little variation. This study represents the first formal assessment of the impact of COVID-19 on reported enteric diseases in Canada. Reported case counts across several pathogens saw notable declines in 2020 compared with prepandemic levels, with restrictions on international travel playing a key role. Additional research is needed to understand how limitations on social gatherings, lock downs, and other public health measures have impacted enteric diseases.

Factors of transurethral incision effectiveness for ureteroceles in pediatric patients: A 28-year, single-institution retrospective review.

BACKGROUND: As a congenital anomaly, ureteroceles occur in 1 in 4000 children, and are usually diagnosed prenatally. However, there remains a lack of definite consensus on the optimal management of congenital ureteroceles. OBJECTIVE: We evaluated factors associated with success of primary transurethral incision (TUI) in ureterocele pediatric patients. METHODS: Demographic and clinical information for 120 pediatric patients who were diagnosed with congenital ureterocele between 1993 and 2021 at our institution were obtained through retrospective chart review. Data were analyzed using Fisher's exact tests, t-tests, and logistic regression with a significance threshold of p < 0.05. The primary outcome of ureterocele management was TUI effectiveness, defined by no need for further surgical intervention. RESULTS: Of the 120 patients (39 boys, 81 girls) with ureteroceles, 75 patients (22 boys, 53 girls) met our inclusion criteria of undergoing initial TUI ureterocele. Initial TUI was effective in 51/75 patients (68.0%). We analyzed possible correlative factors for TUI efficacy. Simplex system was a significant predictor of primary TUI efficacy (85% effective in simplex systems, 62% in duplex systems). Prior urinary tract infection, prenatal diagnosis, and electrocautery technique were all associated with an increased risk of needing additional surgeries after primary TUI. DISCUSSION: The most significant predictors of effective primary TUI were simplex system and the absence of preoperative vesicoureteral reflux. Prenatal diagnosis, preoperative febrile urinary tract infection, higher preoperative hydronephrosis grade, and the use of electrocautery were all associated with decreased primary TUI efficacy. Study limitations include that it was a retrospective chart review, and cohort size was limited by incomplete urology follow-up and operative records. CONCLUSIONS: Initial TUI was an effective procedure for the majority of our pediatric ureterocele patients, a higher success rate compared to other cohorts. Patients with a simplex system were more likely to have an effective first TUI than patients with duplex systems, as were patients without preoperative reflux. Although not statistically significant, our data suggest prior UTI, prenatal diagnosis, higher preoperative hydronephrosis grade, and the use of electrocautery may be associated with having additional surgeries.

Linking whole-body angular momentum and step placement during perturbed human walking.

Human locomotion is remarkably robust to environmental disturbances. Previous studies have thoroughly investigated how perturbations influence body dynamics and what recovery strategies are used to regain balance. Fewer studies have attempted to establish formal links between balance and the recovery strategies that are executed to regain stability. We hypothesized that there would be a strong relationship between the magnitude of imbalance and recovery strategy during perturbed walking. To test this hypothesis, we applied transient ground surface translations that varied in magnitude, direction and onset time while 11 healthy participants walked on a treadmill. We measured stability using integrated whole-body angular momentum (iWBAM) and recovery strategy using step placement. We found the strongest relationships between iWBAM and step placement in the frontal plane for earlier perturbation onset times in the perturbed step (R2=0.52, 0.50) and later perturbation onset times in the recovery step (R2=0.18, 0.25), while correlations were very weak in the sagittal plane (all R2≤0.13). These findings suggest that iWBAM influences step placement, particularly in the frontal plane, and that this influence is sensitive to perturbation onset time. Lastly, this investigation is accompanied by an open-source dataset to facilitate research on balance and recovery strategies in response to multifactorial ground surface perturbations, including 96 perturbation conditions spanning all combinations of three magnitudes, eight directions and four gait cycle onset times.

Commodity discounting: Obstacles and solutions.

Addictive behaviors involve patterns of impulsive choices. Discount functions are a useful means of describing the behavioral contingencies involved in those impulsive choices. Although monetary discounting tasks have proven useful, most impulsive behaviors of interest involve nonmonetary consequences. OBJECTIVE: Developing effective commodity discounting tasks is critical for assessing how delay (and other variables) influences choice with respect to meaningful real-world commodities (e.g., high-calorie foods, alcohol, opioids, and other drugs). METHOD: Identifying the obstacles specific to nonmonetary commodity discounting and evaluating solutions to those obstacles. RESULTS: Those obstacles include (1) real versus hypothetical commodities, (2) framing, (3) commodity indivisibility, (4) diminishing marginal utility, and (5) variations in economic context. CONCLUSIONS: Solutions are presented and evaluated for each of these five obstacles, including the following: (1) assessing relevant experiences and explicitly stipulating transportation and storage issues, (2) systematic analyses across various wordings and holding wording constant across commodities, (3) using an adjusting delay procedure with only whole commodities, (4) assessing value for different commodity amounts (without delay) and adopting quantitative models of discounting that include marginal utility, and (5) controlling for motivating operations, accounting for individual histories, and using closed economies. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A systematic review of social determinants of health in pediatric organ transplant outcomes.

BACKGROUND: Equitable access to pediatric organ transplantation is critical, although risk factors negatively impacting pre- and post-transplant outcomes remain. No synthesis of the literature on SDoH within the pediatric organ transplant population has been conducted; thus, the current systematic review summarizes findings to date assessing SDoH in the evaluation, listing, and post-transplant periods. METHODS: Literature searches were conducted in Web of Science, Embase, PubMed, and Cumulative Index to Nursing and Allied Health Literature databases. RESULTS: Ninety-three studies were included based on pre-established criteria and were reviewed for main findings and study quality. Findings consistently demonstrated disparities in key transplant outcomes based on racial or ethnic identity, including timing and likelihood of transplant, and rates of rejection, graft failure, and mortality. Although less frequently assessed, variations in outcomes based on geography were also noted, while findings related to insurance or SES were inconsistent. CONCLUSION: This review underscores the persistence of SDoH and disparity in equitable transplant outcomes and discusses the importance of individual and systems-level change to reduce such disparities.

Nuclear import receptors are recruited by FG-nucleoporins to rescue hallmarks of TDP-43 proteinopathy.

BACKGROUND: Cytoplasmic mislocalization and aggregation of TAR DNA-binding protein-43 (TDP-43) is a hallmark of the amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) disease spectrum, causing both nuclear loss-of-function and cytoplasmic toxic gain-of-function phenotypes. While TDP-43 proteinopathy has been associated with defects in nucleocytoplasmic transport, this process is still poorly understood. Here we study the role of karyopherin-ß1 (KPNB1) and other nuclear import receptors in regulating TDP-43 pathology. METHODS: We used immunostaining, immunoprecipitation, biochemical and toxicity assays in cell lines, primary neuron and organotypic mouse brain slice cultures, to determine the impact of KPNB1 on the solubility, localization, and toxicity of pathological TDP-43 constructs. Postmortem patient brain and spinal cord tissue was stained to assess KPNB1 colocalization with TDP-43 inclusions. Turbidity assays were employed to study the dissolution and prevention of aggregation of recombinant TDP-43 fibrils in vitro. Fly models of TDP-43 proteinopathy were used to determine the effect of KPNB1 on their neurodegenerative phenotype in vivo. RESULTS: We discovered that several members of the nuclear import receptor protein family can reduce the formation of pathological TDP-43 aggregates. Using KPNB1 as a model, we found that its activity depends on the prion-like C-terminal region of TDP-43, which mediates the co-aggregation with phenylalanine and glycine-rich nucleoporins (FG-Nups) such as Nup62. KPNB1 is recruited into these co-aggregates where it acts as a molecular chaperone that reverses aberrant phase transition of Nup62 and TDP-43. These findings are supported by the discovery that Nup62 and KPNB1 are also sequestered into pathological TDP-43 aggregates in ALS/FTD postmortem CNS tissue, and by the identification of the fly ortholog of KPNB1 as a strong protective modifier in Drosophila models of TDP-43 proteinopathy. Our results show that KPNB1 can rescue all hallmarks of TDP-43 pathology, by restoring its solubility and nuclear localization, and reducing neurodegeneration in cellular and animal models of ALS/FTD. CONCLUSION: Our findings suggest a novel NLS-independent mechanism where, analogous to its canonical role in dissolving the diffusion barrier formed by FG-Nups in the nuclear pore, KPNB1 is recruited into TDP-43/FG-Nup co-aggregates present in TDP-43 proteinopathies and therapeutically reverses their deleterious phase transition and mislocalization, mitigating neurodegeneration.