Epidemiology of Irritable Bowel Syndrome in a Large Academic Safety-Net Hospital.

(1) Background: Irritable bowel syndrome (IBS) is a highly prevalent disorder of gut-brain interaction (DGBI) that is known to reduce the quality of life and raise healthcare costs. The aim of this study was to describe the epidemiology of IBS in a large multiracial academic safety-net hospital. (2) Methods: An electronic query was performed using ICD-9 codes to identify 740 IBS outpatients seen at the Boston Medical Center (BMC) between 1 January 2005 and 30 September 2007. Demographic data were collected from electronic medical records. Bivariate analyses using chi-square tests and ANOVA were used to calculate the significance of categorical and continuous dependent variables, respectively. (3) Results: Compared with the general BMC outpatient population, the IBS cohort consisted of significantly higher proportions of White and Asian patients and lower proportions of Black and Hispanic patients (p < 0.0001). White and Asian patients predominantly had private insurance, while Black and Hispanic patients mostly had government/state-funded or no insurance (p < 0.0001). The IBS subgroup frequencies were similar across racial groups; however, Hispanic patients had IBS with constipation (32%, p < 0.02) more often compared to non-Hispanic patients. (4) Conclusions: Significant differences were found across the racial groups studied in this large outpatient IBS cohort. These findings are likely attributed to racial and socioeconomic disparities in healthcare access and utilization.

Co-Morbidities of Irritable Bowel Syndrome in a Racially and Ethnically Diverse Population.

Introduction: Irritable bowel syndrome (IBS) is a disorder of gut-brain interaction (DGBI), and associated co-morbidities worsen quality of life. Research concerning IBS co-morbidities in different racial/ethnic groups is very sparse. This study aimed to determine the prevalence rates of co-morbidities and possible differences in a multiracial/ethnic IBS cohort. Methods: Based on ICD-9-coded IBS diagnosis, 740 outpatients (≥18 years) were included in this retrospective study at Boston Medical Center. Demographics and ICD-9-coded co-morbidities were extracted from electronic records. Descriptive statistics and multiple logistic regression were used for data analyses. Results: The most prevalent co-morbidities in this IBS cohort included gastroesophageal reflux disorder (GERD) (30%), depression (27%), anxiety (23%), (chronic obstructive pulmonary disease) COPD/asthma (16%), and obesity (10%). GERD was more prevalent in Hispanics and Blacks (p = 0.0005), and non-ulcer dyspepsia (NUD) was more prevalent in Blacks and Asians (p = 0.003). Higher rates of diabetes mellitus type 2 (DMT2) (p = 0.0003) and depression (p = 0.03), but not anxiety (p = 0.9), were present in Blacks and Hispanics. GERD was significantly associated with Hispanics (p = 0.003), dependent on age, overweight, and obesity. NUD was significantly associated with Blacks (p = 0.01) and Asians (p = 0.006), independent of sex, age, and BMI. Cancer of the thyroid, ovaries, and testis occurred at a five-fold higher rate than expected. Conclusions: Significant racial/ethnic differences exist for IBS co-morbidities in this study cohort, including depression, DMT2, GERD, and NUD. Certain cancers were found to be more frequent in this IBS sample as compared with the general population.

Bilateral adrenal hemorrhage and severe anemia in a neonate.

Summary: Neonatal adrenal hemorrhage (NAH) occurs in up to 3% of infants and is the most common adrenal mass in newborns. The most common presentation of NAH is an asymptomatic palpable flank mass which resolves over time without intervention. In rare cases, NAH can present as hemorrhage, shock, or adrenal insufficiency. This case describes a preterm infant born with severe anemia in the setting of bilateral adrenal hemorrhages with resulting adrenal insufficiency. The infant was successfully treated with blood transfusions and steroids. This is a unique presentation of NAH as it was bilateral, presented with severe anemia, and resulted in prolonged adrenal insufficiency. Learning points: Consider adrenal hemorrhage for cases of severe anemia at birth. Adrenal insufficiency is a rare complication of adrenal hemorrhage. Adrenal recovery can take months, if not years.

Development and validation of the coffee task: a novel functional assessment for prosthetic grip selection.

BACKGROUND: Lack of standardized assessments that explicitly quantify performance during prosthetic grip selection poses difficulty determining whether efforts to improve the design of multi-grip hands and their control approaches are successful. In this study, we developed and validated a novel assessment of multi-grip prosthetic performance: The Coffee Task. METHODS: Individuals without limb loss completed the Box and Block Test and two versions of the Coffee Task - Continuous and Segmented - with a myoelectric prosthetic emulator. On different days, participants selected prosthetic grips using pattern recognition and trigger control. Outcomes of the Continuous and Segmented Coffee Task were completion time and number of errors, respectively. Two independent raters assessed outcomes of the Coffee Task using video recordings to determine inter-rater reliability. Known-group validity was assessed by comparing outcomes with the emulator to those with an intact limb. Convergent validity was assessed through the correlation of the Coffee Task outcomes and those of the Box and Blocks Test. Responsiveness to changes with practice and control approach were assessed using the standardized response mean (SRM). RESULTS: Inter-rater reliability was high for both versions of the Coffee Task (Intra-class coefficient > 0.981). Coffee Task outcomes were moderately correlated with the Box and Blocks outcomes (|r| ≥ 0.412, p ≤ 0.007). Participants completed the Coffee Task faster with their intact limb than with the emulator (p < 0.001). Both versions of the Coffee Task were responsive to changes with training (SRM ≥ 0.81) but not control approach (SRM ≤ 0.12). CONCLUSIONS: The Coffee Task is reliable, has good known-group and convergent validity, and is responsive to changes due to practice. Future work should assess whether the Coffee Task is feasible and reliable for people with upper limb loss who use multi-grip prostheses.

Efficacy and safety of oral anticoagulants according to kidney function among patients with atrial fibrillation.

BACKGROUND AND AIMS: Patients with severely reduced kidney function have been excluded from randomized controlled trials and data on safety and efficacy of direct oral anticoagulants (DOACs) according to kidney function remain sparse. The aim was to evaluate safety and efficacy of the DOACs across subgroups of kidney function. METHODS: Using multiple Danish nationwide registers and laboratory databases, we included patients initiated on oral anticoagulants (OACs) with atrial fibrillation and available creatinine level and followed patients for 2 years to evaluate occurrence of stroke/thromboembolism (TE) and major bleeding. RESULTS: Among 26,686 included patients, 3667 (13.7%) had an estimated glomerular filtration rate (eGFR) of 30-49 mL/min/1.73m2 and 596 (2.2%) had an eGFR below 30 mL/min/1.73m2. We found no evidence of differences regarding the risk of stroke/TE between the OACs (p-value interaction>0.05 for all). Apixaban was associated with a lower 2-year risk of major bleeding compared to VKA (risk ratio 0.79, 95% confidence interval (CI) 0.67-0.93), and the risk difference was significantly larger among patients with reduced kidney function (p-value interaction 0.018). Rivaroxaban was associated with higher risk of bleeding compared to apixaban (risk ratio 1.78, 95%CI 1.32-2.39) among patients with eGFR 30-49 mL/min/1.73m2. CONCLUSIONS: Overall, we found no differences regarding the risk of stroke/TE, but apixaban was associated with a 21% lower relative risk of major bleeding compared to VKA. This risk reduction was even greater when comparing apixaban and rivaroxaban among patients with eGFR 15-30 mL/min/1.73m2, and when comparing apixaban to dabigatran and rivaroxaban among patients with eGFR 30-49 mL/min/1.73m2.

Identification of small molecule inhibitors of G3BP-driven stress granule formation.

Stress granule formation is triggered by the release of mRNAs from polysomes and is promoted by the action of the RNA-binding proteins G3BP1/2. Stress granules have been implicated in several disease states, including cancer and neurodegeneration. Consequently, compounds that limit stress granule formation or promote their dissolution have potential as both experimental tools and novel therapeutics. Herein, we describe two small molecules, G3BP inhibitor a and b (G3Ia and G3Ib), designed to bind to a specific pocket in G3BP1/2 that is targeted by viral inhibitors of G3BP1/2 function. In addition to disrupting the co-condensation of RNA, G3BP1, and caprin 1 in vitro, these compounds inhibit stress granule formation in cells treated prior to or concurrent with stress and dissolve pre-existing stress granules. These effects are consistent across multiple cell types and a variety of initiating stressors. Thus, these compounds represent powerful tools to probe the biology of stress granules and hold promise for therapeutic interventions designed to modulate stress granule formation.

First archaeological evidence for ginger consumption as a potential medicinal ingredient in a late medieval leprosarium at St Leonard, Peterborough, England.

Leprosy was one of the most outwardly visible diseases in the European Middle Ages, a period during which leprosaria were founded to provide space for the sick. The extant documentary evidence for leprosy hospitals, especially in relation to diet, therapeutic, and medical care, is limited. However, human dental calculus stands to be an important source of information as it provides insight into the substances people were exposed to and accumulated in their bodies during their lives. In the present study, microremains and DNA were analysed from the calculus of individuals buried in the late medieval cemetery of St Leonard, a leprosarium located in Peterborough, England. The results show the presence of ginger (Zingiber officinale), a culinary and medicinal ingredient, as well as evidence of consumption of cereals and legumes. This research suggests that affected individuals consumed ingredients mentioned in medieval medical textbooks that were used to treat regions of the body typically impacted by leprosy. To the authors' knowledge, this is the first study which has identified Zingiber officinale in human dental calculus in England or on the wider European continent.

Technical and relational process in MI sessions with a sample of Hispanic/Latinx adults who engage in heavy drinking: A latent growth mediation model.

The current study tests the Motivational Interviewing (MI) technical and relational hypotheses in a sample of Hispanic/Latinx adults (N = 276) who engage in heavy alcohol consumption. MI causal theory hypothesizes that therapist use of MI consistent skills (i.e., technical hypothesis) and embodiment of the MI Spirit (i.e., relational hypothesis) will elicit client change talk, which is a putative mechanism of positive client outcome after the session. We tested these associations in a rigorous parallel process latent growth curve mediation modeling framework. The data are from a completed randomized clinical trial of a culturally-adapted (CAMI) versus un-adapted MI targeting hazardous alcohol use and consequences. Results. The unconditional growth models for the mediator (i.e., proportion of change talk relative to sustain talk) and two study outcomes (i.e., percent of heavy drinking days; alcohol-related consequences) showed a linear effect over a 12-month period with a slower rate of growth at later timepoints. Contrary to expectations, the latent growth mediation models did not show relationships between MI-consistent skills (i.e., technical predictor) or latent MI Spirit (i.e., relational indicator) and the slope factor for proportion change talk. The slope factor for proportion change talk was also not associated with the slope factors for percent heavy drinking and consequences over follow-up. Conclusions. In this novel population for MI process analysis, the technical and relational hypotheses were not supported. Studies that are exploratory may be needed to further investigate the causal model in populations that are not often represented in MI process research.

Salmonella Vitkin Outbreak Associated with Bearded Dragons, Canada and United States, 2020-2022.

We identified 2 cases of Salmonella enterica serovar Vitkin infection linked by whole-genome sequencing in infants in Ontario, Canada, during 2022. Both households of the infants reported having bearded dragons as pets. The outbreak strain was also isolated from an environmental sample collected from a patient's bearded dragon enclosure. Twelve cases were detected in the United States, and onset dates occurred during March 2021-September 2022 (isolates related to isolates from Canada within 0-9 allele differences by core-genome multilocus sequence typing). Most US patients (66.7%) were <1 year of age, and most (72.7%) had reported bearded dragon exposure. Hospitalization was reported for 5 (38.5%) of 13 patients. Traceback of bearded dragons identified at least 1 potential common supplier in Southeast Asia. Sharing rare serovar information and whole-genome sequencing data between Canada and the United States can assist in timely identification of outbreaks, including those that might not be detected through routine surveillance.

Examining the Intersection of Ethnoracial Disparities and HIV Status in Substance Use Risks among U.S. Adults.

Black/African American and Hispanic Americans experience significant HIV-related disparities. Substance use might be a contributing factor to these disparities, but there is limited research on this topic. This study investigated various substance use risks by HIV status and race/ethnicity (Black, Hispanic, White) among U.S. adults. We used data from the 2005-2019 National Survey on Drug Use and Health (N = 541,921). In each racial/ethnic group, the prevalence rates of past-year and past-month tobacco, alcohol, cannabis, and cocaine use, and past-year alcohol and illicit drug use disorders were estimated by HIV status. A series of logistic regressions with the interaction term of HIV x race/ethnicity were performed to examine race/ethnicity's moderating effect on the HIV-substance use associations, while controlling for sociodemographic factors and survey year. Moderation analysis showed that HIV status's association with the risks of past-year tobacco use (AOR = 1.67, 95% CI = 1.01-2.75), past-year cocaine use (AOR = 3.80, 95% CI = 1.91-7.57), past-month cocaine use (AOR = 5.34, 95% CI = 2.10-13.60), and past-year alcohol use disorder (AOR = 2.52, 95% CI = 1.29-4.92) differed significantly between Black and White adults. Between the Hispanic and White groups, HIV status's association with the risks of past-year alcohol use (AOR = 2.00, 95% CI = 1.09-3.69), past-year cocaine use (AOR = 2.40, 95% CI = 1.06-5.39), and past-month cocaine use (AOR = 3.69, 95% CI = 1.36-10.02) also differed significantly. It is well-established that individuals with HIV face an elevated risk of substance use. Our study added valuable insights by highlighting that this phenomenon is particularly more significant among Black and Hispanic adults for several substances when compared to White adults. Implications for practice are discussed.

The relationship between discrimination, alcohol use severity, and PTSD symptoms among Latinx heavy drinkers.

INTRODUCTION: Discrimination is linked to alcohol use severity among Latinx adults, who also show high prevalence rates of PTSD compared to non-Latinx adults. We know little about whether PTSD symptoms affects the relationship between discrimination and alcohol use severity. We hypothesized that the association between discrimination and alcohol use severity might differ by level of PTSD symptom severity. METHODS: This is a secondary cross-sectional analysis of data collected at baseline from a completed randomized clinical trial testing the relative efficacy of a culturally adapted motivational interview designed to address discrimination and drinking behavior against an unadapted motivational interview for Latinx adults. Eligible participants screened positive for the NIAAA Single Alcohol Screening Question for heavy drinking days, identified as Latinx, and were 18-65 years old. We assessed the Everyday Discrimination Scale, Primary Care PC-PTSD screener, Alcohol Use Disorder Identification Test, and the Short Acculturation Scale for Hispanics. The study analyzed the main and interactive effects of discrimination and PTSD symptoms on alcohol use severity, while controlling for age, sex, household income, and acculturation. RESULTS: After controlling for covariates in model 2, the interaction of discrimination and PTSD symptoms was significantly related to alcohol use severity. Simple slopes analysis indicated that discrimination was positively related to alcohol use severity among those with high (1 SD above the mean) but not low (1 SD below the mean) levels of PTSD symptoms. CONCLUSIONS: Evidence suggests that the experiences of discrimination were associated with alcohol use severity among those who reported more PTSD symptoms. Specifically, discrimination may have a stronger effect on alcohol use severity among Latinx adults who report more PTSD symptoms. Screening Latinx adults for heavy drinking days, discrimination, and PTSD symptoms is clinically important. Culturally adapted alcohol interventions that target discrimination may be particularly effective for Latinx individuals with more PTSD symptoms.

Serial troponin-I and long-term outcomes in subjects with suspected acute coronary syndrome.

BACKGROUND AND AIMS: It is unclear how serial high-sensitivity troponin-I (hsTnI) concentrations affect long-term prognosis in individuals with suspected acute coronary syndrome (ACS). METHODS: Subjects who underwent two hsTnI-measurements (Siemens TnI Flex® Reagent) separated by 1-7 hours, during a first-time hospitalization for myocardial infarction, unstable angina, observation for suspected myocardial infarction, or chest pain from 2012 through 2019, were identified through Danish national registries. Individuals were stratified per their hsTnI-concentration pattern (normal, rising, persistently elevated, or falling) and the magnitude of hsTnI-concentration change (<20%, > 20 to 50%, or >50% in either direction). We calculated absolute and relative mortality risks standardized to the distributions of risk factors for the entire study population. RESULTS: A total of 20,609 individuals were included of whom 2.3% had died at 30 days, and an additional 4.7% had died at 365 days. The standardized risk of death was highest among persons with a persistently elevated hsTnI-concentration (0-30 days: 8.0%, 31-365 days: 11.1%) and lowest among those with two normal hsTnI-concentrations (0-30 days: 0.5%, 31-365 days: 2.6%). In neither case did relative hsTnI-concentration changes between measurements clearly affect mortality risk. Among persons with a rising hsTnI-concentration pattern, 30-day mortality was higher in subjects with a > 50% rise compared with those with a less pronounced rise (2.2% versus <0.1%). CONCLUSIONS: Among individuals with suspected ACS, those with a persistently elevated hsTnI-concentration consistently had the highest risk of death. In subjects with two normal hsTnI-concentrations, mortality was very low and not affected by the magnitude of change between measurements.

In this Danish study of more than 20,000 individuals with suspected heart attack, we confirmed the clinical importance of drawing two consecutive blood samples for measurement of high-sensitivity troponin-I concentrations (a marker of damage to the heart): The risk of death was highest in persons with two elevated high-sensitivity troponin-I concentrations and lowest in those with two normal concentrations Among persons who had a first normal and a subsequently elevated high-sensitivity troponin-I concentration, a > 50% relative rise was associated with significantly higher risk of death at 30 days.

Sleep improvements following atopic dermatitis management in young children.

OBJECTIVES: The purpose of this pilot study was to assess improvements in associated sleep and caregiver mood following treatment of atopic dermatitis in young children. METHODS: Participants included children (n = 23; Mage = 22.0 months) and their caregivers. Topical management of atopic dermatitis was conducted for 2 weeks, with measures of skin, sleep (child, caregiver), and mood (caregiver) at baseline and day 14. RESULTS: Topical management resulted in significant improvements in child skin, with associated increases in sleep consolidation. There were similar improvements in caregiver nightwakings, with nighttime sleep duration improving by over an hour. Caregivers also reported more energy to engage with their family and feeling better rested. CONCLUSIONS: Overall, topical management significantly improved atopic dermatitis. There were concomitant improvements in sleep outcomes for children and their caregivers, as well as caregiver mood. Daily management of atopic dermatitis may result in improvements in not just skin health but also sleep and family well-being.

Discovery of KB-0742, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of CDK9 for MYC-Dependent Cancers.

Transcriptional deregulation is a hallmark of many cancers and is exemplified by genomic amplifications of the MYC family of oncogenes, which occur in at least 20% of all solid tumors in adults. Targeting of transcriptional cofactors and the transcriptional cyclin-dependent kinase (CDK9) has emerged as a therapeutic strategy to interdict deregulated transcriptional activity including oncogenic MYC. Here, we report the structural optimization of a small molecule microarray hit, prioritizing maintenance of CDK9 selectivity while improving on-target potency and overall physicochemical and pharmacokinetic (PK) properties. This led to the discovery of the potent, selective, orally bioavailable CDK9 inhibitor 28 (KB-0742). Compound 28 exhibits in vivo antitumor activity in mouse xenograft models and a projected human PK profile anticipated to enable efficacious oral dosing. Notably, 28 is currently being investigated in a phase 1/2 dose escalation and expansion clinical trial in patients with relapsed or refractory solid tumors.

Vascular Reconstruction and Limb Loss in Military Tibial Artery Injuries.

BACKGROUND: Selective operative management of injuries to the tibial arteries is controversial, with the necessity of revascularization in the face of multiple tibial arteries debated. Tibial artery injuries are frequently encountered in military trauma, but revascularization practices and outcomes are poorly defined. We aimed to investigate associations between the number of injured vessels and reconstruction and limb loss rates in military casualties with tibial arterial trauma. METHODS: A US military database of lower extremity vascular injuries from Iraq and Afghanistan (2004-2012) was queried for limbs sustaining at least 1 tibial artery injury. Injury, intervention characteristics, and limb outcomes were analyzed by the number of tibial arteries injured (1, T1; 2, T2; 3, T3). RESULTS: Two hundred twenty one limbs were included (194 T1, 22 T2, 5 T3). The proportions with concomitant venous, orthopedic, nerve, or proximal arterial injuries were similar between groups. Arterial reconstruction (versus ligation) was performed in 29% of T1, 63% of T2, and universally in T3 limbs (P < 0.001). Arterial reconstruction was via vein graft (versus localized repair) in 62% of T1, 54% of T2, and 80% of T3 (P = 0.59). T3 received greater blood transfusion volume (P = 0.02), and fasciotomy was used universally (versus 34% T1 and 14% T2, P = 0.05). Amputation rates were 23% for T1, 26% for T2, and 60% for T3 (P = 0.16), and amputation was not significantly predicted by arterial ligation in T1 (P = 0.08) or T2 (P = 0.34) limbs. Limb infection was more common in T3 (80%) than in T1 (25%) or T2 (32%, P = 0.02), but other limb complication rates were similar. CONCLUSIONS: In this series of military lower extremity injuries, an increasing number of tibial arteries injured was associated with the increasing use of arterial reconstruction. Limbs with all 3 tibial arteries injured had high rates of complex vascular reconstruction and eventual amputation. Limb loss was not predicted by arterial ligation in 1-vessel and 2-vessel injuries, suggesting that selective reconstruction in these cases is advisable.

Reversible histone deacetylase activity catalyzes lysine acylation.

Starvation and low carbohydrate diets lead to the accumulation of the ketone body, ß-hydroxybutyrate (BHB), whose blood concentrations increase more than 10-fold into the millimolar range. In addition to providing a carbon source, BHB accumulation triggers lysine ß-hydroxybutyrylation (Kbhb) of proteins via unknown mechanisms. As with other lysine acylation events, Kbhb marks can be removed by histone deacetylases (HDACs). Here, we report that class I HDACs unexpectedly catalyze protein lysine modification with ß-hydroxybutyrate (BHB). Mutational analyses of the HDAC2 active site reveal a shared reliance on key amino acids for classical deacetylation and non-canonical HDAC-catalyzed ß-hydroxybutyrylation. Also consistent with reverse HDAC activity, Kbhb formation is driven by mass action and substrate availability. This reverse HDAC activity is not limited to BHB but also extends to multiple short-chain fatty acids. The reversible activity of class I HDACs described here represents a novel mechanism of PTM deposition relevant to metabolically-sensitive proteome modifications.

Computed tomography dose index determination in dose modulation prospectively involving the third-generation iterative reconstruction and noise index.

PURPOSE: Optimizing CT protocols is challenging in the presence of automatic dose modulation because the CT dose index (CTDIvol ) at different patient sizes is unknown to the operator. The task is more difficult when both the image quality index and iterative reconstruction prospectively affect the dose determination. It is of interest in practice to be informed of the CTDIvol during the protocol initialization and evaluation. It was our objective to obtain a predictive relationship between CTDIvol , the image quality index, and iterative reconstruction strength at various patient sizes. METHODS: Dose modulation data were collected on a GE Revolution 256-slice scanner utilizing a Mercury phantom and selections of the noise index (NI) from 8 to 17, the third generation iterative reconstruction (ASIR-V) from 0% to 80%, and phantom diameters from 16 to 36 cm. The fixed parameters were 120 kVp, a pitch of .984, and a collimation of 40 mm with a primary slice width of 2.5 mm. The CTDIvol per diameter was based on the average tube current over three adjacent slices (same or similar diameter) multiplied by a conversion factor between the average mA of the series and the reported CTDIvol . The relationship between CTDIvol , NI, and ASIR-V for each diameter was fitted with a 2nd order polynomial of ASIR-V multiplied by a power law of NI. RESULTS: The ASIR-V fit parameters versus diameter followed a Lorentz function while the NI exponent versus diameter followed an exponential growth function. The CTDIvol predictions were accurate within 15% compared to phantom results on a separate GE Revolution. For clinical relevance, the phantom diameter was converted to an abdomen or chest equivalent diameter and was well matched to patient data. CONCLUSION: The fitted relationship for CTDIvol . for given values of NI and ASIR-V blending for a range of phantom sizes was a good match to phantom and patient data. The results can be of direct help for selecting adequate parameters in CT protocol development.

Piconewton Forces Mediate GAIN Domain Dissociation of the Latrophilin-3 Adhesion GPCR.

Latrophilins are adhesion G-protein coupled receptors (aGPCRs) that control excitatory synapse formation. Most aGPCRs, including latrophilins, are autoproteolytically cleaved at their GPCR-autoproteolysis inducing (GAIN) domain, but the two resulting fragments remain noncovalently associated on the cell surface. Force-mediated dissociation of the fragments is thought to activate G-protein signaling, but how this mechanosensitivity arises is poorly understood. Here, we use magnetic tweezer assays to show that physiologically relevant forces in the 1-10 pN range lead to dissociation of the latrophilin-3 GAIN domain on the seconds-to-minutes time scale, compared to days in the absence of force. In addition, we find that the GAIN domain undergoes large changes in length in response to increasing mechanical load. These data are consistent with a model in which a force-sensitive equilibrium between compact and extended GAIN domain states precedes dissociation, suggesting a mechanism by which latrophilins and other aGPCRs may mediate mechanically induced signal transduction.

Curved adhesions mediate cell attachment to soft matrix fibres in three dimensions.

Integrin-mediated focal adhesions are the primary architectures that transmit forces between the extracellular matrix (ECM) and the actin cytoskeleton. Although focal adhesions are abundant on rigid and flat substrates that support high mechanical tensions, they are sparse in soft three-dimensional (3D) environments. Here we report curvature-dependent integrin-mediated adhesions called curved adhesions. Their formation is regulated by the membrane curvatures imposed by the topography of ECM protein fibres. Curved adhesions are mediated by integrin ɑvß5 and are molecularly distinct from focal adhesions and clathrin lattices. The molecular mechanism involves a previously unknown interaction between integrin ß5 and a curvature-sensing protein, FCHo2. We find that curved adhesions are prevalent in physiological conditions, and disruption of curved adhesions inhibits the migration of some cancer cell lines in 3D fibre matrices. These findings provide a mechanism for cell anchorage to natural protein fibres and suggest that curved adhesions may serve as a potential therapeutic target.

Targeted Lysosomal Degradation of Secreted and Cell Surface Proteins through the LRP-1 Pathway.

Protein dysregulation has been characterized as the cause of pathogenesis in many different diseases. For proteins lacking easily druggable pockets or catalytically active sites, targeted protein degradation is an attractive therapeutic approach. While several methods for targeted protein degradation have been developed, there remains a demand for lower molecular weight molecules that promote efficient degradation of their targets. In this work, we describe the synthesis and validation of a series of heterobifunctional molecules that bind a protein of interest through a small molecule ligand while targeting them to the lysosome using a short gluten peptide that leverages the TG2/LRP-1 pathway. We demonstrate that this approach can be used to effectively endocytose and degrade representative secreted, cell surface, and transmembrane proteins, notably streptavidin, the vitamin B12 receptor, cubilin, and integrin αvß5. Optimization of these prototypical molecules could generate pharmacologically relevant LYTAC agents.