Paternal Incarceration and Adolescent Delinquency: Role of Father Engagement and Early Child Behavior Problems.

Paternal incarceration is an important predictor of teen delinquency, but the factors that may explain this relationship-such as early child problem behaviors and level of father engagement-have not been adequately explored. The current longitudinal study examined paternal history of incarceration as a predictor of teen self-reported delinquency over a 15-year gap, considering early child problem behaviors and father engagement as mediators. Sex differences in these relationships were also evaluated. This four-wave longitudinal study included an analytic sample of 4897 teens who participated in the birth-cohort Future of Families and Child Well-Being Study. Mothers and fathers were interviewed shortly after the focal child's birth and were then reassessed in follow-up interviews at child ages 1, 3, 5, 9, and 15. The focal children were interviewed at ages 9 and 15. Results showed that paternal prior incarceration at year 1 was associated with greater child behavior problems and father engagement at year 5; however, those relationships disappeared by age 9. Paternal history of incarceration was not related to teen delinquency, but child behavior problems at age 9 were directly related to subsequent engagement in delinquent behaviors. Paternal current incarceration was related to subsequent father engagement but was not associated with later child behaviors. No significant indirect pathways emerged, indicating a lack of support for mediation. No sex differences in these relationships were observed. Overall, the findings underscore the complexity of the relationships between paternal incarceration, child behavior, and father engagement in the emergence of delinquent behaviors.

Talar and Calcaneal Coordinate Axes Definitions across Foot Pathologies.

The understanding of foot and ankle biomechanics is improving as new technology provides more detailed information about the motion of foot and ankle bones with biplane fluoroscopy, as well as the ability to analyze the hindfoot under weightbearing conditions with weightbearing computed tomography. Three-dimensional anatomical coordinate systems are necessary to describe the 3D alignment and kinematics of the foot and ankle. The lack of standard coordinate systems across research study sites can significantly alter experimental data analyses used for pre-surgical evaluation and post-operative outcome assessments. Clinical treatment paradigms are changing based on the expanding knowledge of complex pes planovalgus morphologies or progressive collapsing foot deformity, which is present in both neurologic and non-neurologic populations. Four patient cohorts were created from 10 flexible PCFD, 10 rigid PCFD, 10 adult cerebral palsy, and 10 asymptomatic control patients. Six coordinate systems were tested on both the talus and calcaneus for all groups. The aim of this study was to evaluate axes definitions for the subtalar joint across four different patient populations to determine the influence of morphology on the implementation of previously defined coordinate systems. Different morphologic presentations from various pathologies have a substantial impact on coordinate system definitions, given that numerous axes definitions are defined through geometric fits or manual landmark selection. Automated coordinate systems that align with clinically relevant anatomic planes are preferred. Principal component axes are automatic, but do not align with clinically relevant planes and should not be used for such analysis where anatomic planes are critical.

Patterns of clinical and imaging presentations in patients with spontaneous intracranial hypotension due to spinal cerebrospinal fluid venous fistula: A single-center retrospective cross-sectional study.

OBJECTIVE: To identify distinct clinical or imaging subtypes of spontaneous intracranial hypotension (SIH) due to spinal cerebrospinal fluid (CSF) venous fistula (CVF). BACKGROUND: Spontaneous intracranial hypotension is classically understood to present clinically with an orthostatic headache and stereotyped brain magnetic resonance imaging (MRI) findings; however, most prior literature examining clinical and brain MRI features of SIH has focused on all types of spinal CSF leaks concurrently. This study aimed to evaluate whether data support the possibility of internally consistent subtypes based on brain imaging features and clinical symptoms analogous to those seen in primary headache syndromes. METHODS: This retrospective cross-sectional single-institution study included 48 consecutive patients meeting the International Classification of Headache Disorders, 3rd edition criteria for SIH due to CVF. Clinical symptoms, pre-treatment brain MRI, and symptom duration were analyzed. Clinical and MRI data were analyzed to identify patterns and associations between symptoms and imaging findings. RESULTS: A total of 20 males and 28 females were evaluated, with a mean (standard deviation) age of 61 (10) years. In all, 44/48 (92%) patients experienced headaches, though 18/48 (40%) did not endorse relief when flat, including six of the 48 (13%) with worsening symptoms when flat. In all, 19/48 (40%) patients reported at least one migraine symptom, and six of the 48 (13%) presented with at least one migraine symptom and had no relief when flat. Clinical symptoms clustered primarily into a "classic" presentation consisting of relief when flat, occipital head pain, comorbid neck pain, a pressure/throbbing headache quality, and an "atypical" presentation that was characterized by having several differences: less relief when flat (nine of 22 (41%) vs. 20/23 (87.0%), p = 0.002; odds ratio [OR] 0.110, 95% confidence interval [CI] 0.016-0.53), more frontal head pain (14/22 (64%) vs. one of 23 (4%), p < 0.001; OR 35.0, 95% CI 4.2-1681.0), less neck pain (two of 21 (4.5%) vs. nine of 13 (69.6%), p < 0.001; OR 0.023, 95% CI 0.0005-0.196), and more stabbing/sharp headache quality (nine of 22 (41%) vs. two of 23 (9%), p = 0.017; OR 7.0, 95% CI 1.18-75.9). Brain MRI findings clustered into three groups: those presenting with most imaging findings of SIH concurrently, those with brain sag but less pachymeningeal/venous engorgement, and those with pachymeningeal/venous engorgement but less brain sag. CONCLUSION: This study highlights the clinical and imaging diversity among patients with SIH due to CVF, challenging the reliance on classic orthostatic headache alone for diagnosis. The findings suggest the existence of distinct SIH subtypes based on clinical and imaging presentations, underscoring the need for comprehensive evaluation in patients with suspected CVF. Future research should further elucidate the relationship between clinical symptoms and imaging findings, aiming to refine diagnostic criteria and enhance understanding of SIH's pathophysiology.

A proposed test to determine physical working capacity at pain intensity threshold (PWCPIT).

PURPOSE: This study aimed to establish a new threshold parameter called the physical working capacity at pain intensity threshold (PWCPIT) using a pain intensity scale and mathematical methods similar to those used to develop the physical working capacity at oxygen consumption threshold (PWCVO2) and physical working capacity at heart rate threshold (PWCHRT). The study had two objectives: (i) to examine the relationship between PWCPIT and traditional PWC measures and (ii) to explore the physiological mechanisms underlying the relationship between pain perception and capacity thresholds. METHODS: Fourteen male volunteers (age 21 ± 2 years, height 176 ± 6 cm, weight 76 ± 9 kg, VO2peak 37.8 ± 7.8 ml/kg/min-1) underwent an incremental exhaustion test and four 8-min randomly ordered work bouts on different days at 70-100% peak power output (119-320 W) to establish their PWCPIT, PWCHRT and PWCVO2. One-way repeated-measures ANOVA with Bonferroni post hoc tests and a zero-order correlation matrix were used to analyze these thresholds. RESULTS: PWCPIT significantly correlated with PWCHRT (r = 0.88, P < 0.001), PWCVO2 (r = 0.84, P < 0.001), and gas exchange threshold (GET) (r = 0.7, P = 0.006). CONCLUSION: The model for estimating PWCHRT and PWCVO2 can be applied to determine the PWCPIT. By examining how PWCPIT aligns with, differs from, or complements existing PWC threshold measures, researchers may provide a more comprehensive understanding of the factors that govern endurance performance.

Correction: The Myth of Man the Hunter: Women's contribution to the hunt across ethnographic contexts.

[This corrects the article DOI: 10.1371/journal.pone.0287101.].

The effect of resistance exercise on multimodal pain thresholds in local and systemic muscle sites.

Dynamic resistance exercise may produce reductions in pain locally at the exercising muscle and systemically at non-exercising sites. However, limited research has examined these changes with multiple noxious stimuli. This study examined changes in heat pain threshold (HPT) and pressure pain threshold (PPT) on different musculature after an upper and lower body exercise to compare local and systemic effects. A crossover design with 28 participants (mean age: 21 ± 4 years, 21 female) completed three sessions. Visit one included baseline quantitative sensory testing and 5-repetition maximum (RM) testing for upper (shoulder press) and lower (leg extension) body. In subsequent sessions, participants performed upper or lower body exercises using an estimated 75% 1-RM with pre/post assessment of HPT and PPT at three sites: deltoid, quadriceps, and low back. A significant three-way interaction was observed for HPT (F (1.71, 3.80) = 2.19, p = 0.036, η2p = 0.12) with significant increases in HPT over the quadriceps (p = 0.043) after leg extension and over the deltoid (p = 0.02) after shoulder press. Significant systemic changes were not observed for HPT or PPT. Local but not systemic effects were demonstrated after an acute bout of exercise. Peripheral pain sensitivity may be more responsive to heat stimuli after resistance exercise.

Recommendation of minimal distal tibial length for long axis coordinate system definitions.

Accurate anatomical coordinate systems for the foot and ankle are critical for interpreting their complex biomechanics. The tibial superior-inferior axis is crucial for analyzing joint kinematics, influencing bone motion analysis during gait using CT imaging and biplane fluoroscopy. However, the lack of consensus on how to define the tibial axis has led to variability in research, hindering generalizability. Even as advanced imaging techniques evolve, including biplane fluoroscopy and weightbearing CT, there exist limitations to imaging the entire foot together with the full length of the tibia. These limitations highlight the need to refine axis definitions. This study investigated various superior-inferior axes using multiple distal tibia lengths to determine the minimal field of view for representing the full tibia long-axis. Twenty human cadaver tibias were imaged and segmented to generate 3D bone models. Axes were calculated based on coordinate definitions that required user manual input, and a gold standard mean superior-inferior axis was calculated based on the population's principal component analysis axis. Four manually calculated superior-inferior tibial axes groups were established based on landmarks and geometric fittings. Statistical analysis revealed that geometrically fitting a cylinder 1.5 times the mediolateral tibial width, starting 5 cm above the tibial plafond, yielded the smallest angular deviation from the gold standard. From these findings, we recommend a minimum field of view that includes 1.5 times the mediolateral tibial width, starting 5 cm above the tibial plafond for tibial long-axis definitions. Implementing these findings will help improve foot and ankle research generalizability and impact clinical decisions.

Quantifying Fluid and Function in Suboptimal Responders Switched From an Anti-vascular Endothelial Growth Factor (VEGF) to Faricimab.

Background Anti-vascular endothelial growth factor (VEGF) injections have been successful in reducing vision loss from neovascular age-related macular degeneration, a leading cause of blindness. Due to the high treatment burden and suboptimal responses, switching to bi-specific faricimab treatment may lead to improved outcomes. Methods This retrospective chart review evaluated if suboptimal responders to anti-VEGF injections had better outcomes when switched to faricimab. Suboptimal responders were defined as patients with a history of >3 months of injections and the presence of fluid after ≥3 injections. The primary endpoints were best-corrected visual acuity, treatment interval, and fluid levels. Visual acuity measurements and optical coherence tomography were performed before each injection. The total fluid area (TFA) was measured using MATLAB 2023a (MathWorks, Natick, MA, USA). Results Nineteen eyes were included in the analysis. After three faricimab injections, average letters increased from 54.5 to 59.0 (SD: 15.3; p<0.05), and the injection interval was extended from 7.6 to 9.3 weeks (SD: 3.9; p<0.01) after four injections. Patients also experienced anatomical retinal changes, with a reduction in the TFA to 47.3% (p<0.005) after the second injection and a reduction in pigment epithelial detachment height to 82.3% (p<0.005) after one injection. The central subfield thickness was significantly reduced after the second injection (90.6% (SD: 17.6%) p<0.05). Conclusion Switching to faricimab after a suboptimal anti-VEGF response results in improvements in visual acuity, reduced treatment burden, and reduced fluid levels.

Experience of irreproducibility as a risk factor for poor mental health in biomedical science doctoral students: A survey and interview-based study.

High rates of irreproducibility and of poor mental health in graduate students have been reported in the biomedical sciences in the past ten years, but to date, little research has investigated whether these two trends interact. In this study, we ask whether the experience of failing to replicate an expected finding impacts graduate students' mental health. Using an online survey paired with semi-structured qualitative interviews, we examined how often biomedical science doctoral students at a large American public university experienced events that could be interpreted as failures to replicate and how they responded to these experiences. We found that almost all participants had experience with irreproducibility: 84% had failed to replicate their own results, 70% had failed to replicate a colleague's finding, and 58% had failed to replicate a result from the published literature. Participants reported feelings of self-doubt, frustration, and depression while experiencing irreproducibility, and in 24% of cases, these emotional responses were strong enough to interfere with participants' eating, sleeping, or ability to work. A majority (82%) of participants initially believed that the anomalous results could be attributed to their own error. However, after further experimentation, most participants concluded that the original result was wrong (38%), that there was a key difference between the original experiment and their own (17%), or that there was a problem with the protocol (17%). These results suggest that biomedical science graduate students may be biased towards initially interpreting failures to replicate as indicative of a lack of skill, which may trigger or perpetuate feelings of anxiety, depression, or impostorism.

Association of first primary cancer with risk of subsequent primary cancer among survivors of adult-onset cancers in Kentucky and Appalachian Kentucky.

Background: Appalachia is a region with significant cancer disparities in incidence and mortality compared to Kentucky and the United States. However, the contribution of these cancer health disparities to subsequent primary cancers (SPCs) among survivors of adult-onset cancers is limited. This study aimed to quantify the overall and cancer type-specific risks of SPCs among adult-onset cancer survivors by first primary cancer (FPC) types, residence and sex. Methods: This retrospective cohort study from the Kentucky Cancer Registry included 148,509 individuals aged 20-84 years diagnosed with FPCs from 2000-2014 (followed until December 31, 2019) and survived at least 5 years. Expected numbers of SPC were derived from incidence rates in the Kentucky population; standardized incidence ratio (SIR) compared with those expected in the general Kentucky population. Results: Among 148,509 survivors (50.2% women, 27.9% Appalachian), 17,970 SPC cases occurred during 829,530 person-years of follow-up (mean, 5.6 years). Among men, the overall risk of developing any SPCs was statistically significantly higher for 20 of the 30 FPC types, as compared with risks in the general population. Among women, the overall risk of developing any SPCs was statistically significantly higher for 20 of the 31 FPC types, as compared to the general population. The highest overall SIR were estimated among oral cancer survivors (SIR, 2.14 [95% CI, 1.97-2.33] among men, and among laryngeal cancer survivors (SIR, 3.62 [95% CI, 2.93-4.42], among women. Appalachian survivors had significantly increased risk of overall SPC and different site specific SPC when compared to non-Appalachian survivors. The highest overall SIR were estimated among laryngeal cancer survivors for both Appalachian and non-Appalachian residents (SIR, 2.50: 95%CI, 2.10-2.95; SIR, 2.02: 95% CI, 1.77-2.03, respectively). Conclusion: Among adult-onset cancer survivors in Kentucky, several FPC types were significantly associated with greater risk of developing an SPC, compared with the general population. Risk for Appalachian survivors was even higher when compared to non-Appalachian residents, but was not explained by higher risk of smoking related cancers. Cancers associated with smoking comprised substantial proportions of overall SPC incidence among all survivors and highlight the importance of ongoing surveillance and efforts to prevent new cancers among survivors.

Loss of Progranulin Results in Increased Pan-Cathepsin Activity and Reduced LAMP1 Lysosomal Protein.

Mutations in the progranulin (PGRN) encoding gene, GRN, cause familial frontotemporal dementia (FTD) and neuronal ceroid lipofuscinosis (NCL) and PGRN is also implicated in Parkinson's disease (PD). These mutations result in decreased PGRN expression. PGRN is highly expressed in peripheral immune cells and microglia and regulates cell growth, survival, repair, and inflammation. When PGRN is lost, the lysosome becomes dysfunctional, but the exact mechanism by which PGRN plays a role in lysosome function and how this contributes to inflammation and degeneration is not entirely understood. To better understand the role of PGRN in regulating lysosome function, this study examined how loss of GRN impacts total LAMP1 protein expression and cathepsin activities. Using mouse embryonic fibroblasts (MEFs), immunocytochemistry and immunoblotting assays were performed to analyze fluorescent signal from LAMP1 (lysosomal marker) and BMV109 (marker for pan-cathepsin activity). GRN-/- MEFs exhibit increased expression of pan-cathepsin activity relative to GRN+/+ MEFs, and significantly impacts expression of LAMP1. The significant increase in pan-cathepsin activity in the GRN-/- MEFs confirms that PGRN loss does alter cathepsin expression, which may be a result of compensatory mechanisms happening within the cell. Using NTAP PGRN added to GRN-/- MEFs, specific cathepsin activity is rescued. Further investigations should include assessing LAMP1 and BMV109 expression in microglia from GRN-/- mice, in the hopes of understanding the role of PGRN in lysosomal function in immune cells of the central nervous system and the diseases in which it is implicated.

The Myth of Man the Hunter: Women's contribution to the hunt across ethnographic contexts.

The sexual division of labor among human foraging populations has typically been recognized as involving males as hunters and females as gatherers. Recent archeological research has questioned this paradigm with evidence that females hunted (and went to war) throughout the Homo sapiens lineage, though many of these authors assert the pattern of women hunting may only have occurred in the past. The current project gleans data from across the ethnographic literature to investigate the prevalence of women hunting in foraging societies in more recent times. Evidence from the past one hundred years supports archaeological finds from the Holocene that women from a broad range of cultures intentionally hunt for subsistence. These results aim to shift the male-hunter female-gatherer paradigm to account for the significant role females have in hunting, thus dramatically shifting stereotypes of labor, as well as mobility.

Young Adults' Perspectives of Childhood Food Allergies: Implications for School Nurses.

The primary goal of this study was to examine young adults' perspectives about the effects of their food allergies (FAs) on their social lives from school-age to young adulthood. Young adults aged 18-21 (n = 10) at the University of South Carolina were interviewed. A qualitative descriptive method to find themes and commonalities from transcribed interviews was used for data analysis. Identified themes were (1) feeling different and being isolated, (2) strategies for managing feeling different and being isolated, (3) strategies for managing safety, and (4) acceptance of myself and by others. School-age children attributed the school lunch allergy table as contributing to social isolation. Additionally, participants described feeling different and concerns about safety. Strategies to mitigate those experiences were identified by participants. Implications for children with FAs, their parents, school nurses, and other education and health professionals who work with children are presented.

Molecular Tumor Board-Assisted Care in an Advanced Cancer Population: Results of a Phase II Clinical Trial.

PURPOSE: Multidisciplinary molecular tumor boards (MTBs) interpret next-generation sequencing reports and help oncologists determine best therapeutic options; however, there is a paucity of data regarding their clinical utility. The purpose of this study was to determine if MTB-directed therapy improves progression-free survival (PFS) over immediately prior therapy in patients with advanced cancer. METHODS: This single-arm, prospective phase II clinical trial enrolled patients with advanced cancer with an actionable mutation who received MTB-recommended targeted therapy between January 1, 2017, and October 31, 2020. MTB-recommended both on-label (level 1 evidence) and off-label (evidence levels 2 and 3) therapies. Of the 93 enrolled patients, 43 were treated frontline and 50 received second-line or greater-line therapy. The primary outcome was the probability of patients treated with second-line or greater-line MTB-directed therapy who achieved a PFS ratio ≥ 1.3 (PFS on MTB-directed therapy divided by PFS on the patient's immediately prior therapy). Secondary outcomes included PFS for patients treated frontline and overall survival and adverse effects for the entire study population. RESULTS: The most common disease sites were lung (35 of 93, 38%), gynecologic (17 of 93, 18%), GI (16 of 93, 17%), and head and neck (7 of 93, 8%). The Kaplan-Meier estimate of the probability of PFS ratio ≥ 1.3 was 0.59 (95% CI, 0.47 to 0.75) for patients treated with second-line or greater-line MTB-directed therapy. The median PFS was 449 (range 42-1,125) days for patients treated frontline. The median overall survival was 768 (range 22-1,240) days. There were four nontreatment-related deaths. CONCLUSION: When treated with MTB-directed therapy, most patients experienced improved PFS compared with immediately prior treatment. MTB-directed targeted therapy may be a strategy to improve outcomes for patients with advanced cancer.

Human macrophage-engineered vesicles for utilization in ovarian cancer treatment.

Background: Ovarian cancer is a deadly female malignancy with a high rate of recurrent and chemotherapy-resistant disease. Tumor-associated macrophages (TAMs) are a significant component of the tumor microenvironment and include high levels of M2-protumor macrophages that promote chemoresistance and metastatic spread. M2 macrophages can be converted to M1 anti-tumor macrophages, representing a novel therapeutic approach. Vesicles engineered from M1 macrophages (MEVs) are a novel method for converting M2 macrophages to M1 phenotype-like macrophages. Methods: Macrophages were isolated and cultured from human peripheral blood mononuclear cells. Macrophages were stimulated to M1 or M2 phenotypes utilizing LPS/IFN-γ and IL-4/IL-13, respectively. M1 MEVs were generated with nitrogen cavitation and ultracentrifugation. Co-culture of ovarian cancer cells with macrophages and M1 MEVs was followed by cytokine, PCR, and cell viability analysis. Murine macrophage cell line, RAW264.7 cells were cultured and used to generate M1 MEVs for use in ovarian cancer xenograft models. Results: M1 MEVs can effectively convert M2 macrophages to an M1-like state both in isolation and when co-cultured with ovarian cancer cells in vitro, resulting in a reduced ovarian cancer cell viability. Additionally, RAW264.7 M1 MEVs can localize to ovarian cancer tumor xenografts in mice. Conclusion: Human M1 MEVs can repolarize M2 macrophages to a M1 state and have anti-cancer activity against ovarian cancer cell lines. RAW264.7 M1 MEVs localize to tumor xenografts in vivo murine models.

Molecular Tumor Board Review and Improved Overall Survival in Non-Small-Cell Lung Cancer.

With the introduction of precision medicine, treatment options for non-small-cell lung cancer have improved dramatically; however, underutilization, especially in disadvantaged patients, like those living in rural Appalachian regions, is associated with poorer survival. Molecular tumor boards (MTBs) represent a strategy to increase precision medicine use. UK HealthCare at the University of Kentucky (UK) implemented a statewide MTB in January 2017. We wanted to test the impact of UK MTB review on overall survival in Appalachian and other regions in Kentucky. METHODS: We performed a case-control study of Kentucky patients newly diagnosed with non-small-cell lung cancer between 2017 and 2019. Cases were reviewed by the UK MTB and were compared with controls without UK MTB review. Controls were identified from the Kentucky Cancer Registry and propensity-matched to cases. The primary end point was the association between MTB review and overall patient survival. RESULTS: Overall, 956 patients were included, with 343 (39%) residing in an Appalachian region. Seventy-seven (8.1%) were reviewed by the MTB and classified as cases. Cox regression analysis showed that poorer survival outcome was associated with lack of MTB review (hazard ratio [HR] = 8.61; 95% CI, 3.83 to 19.31; P < .0001) and living in an Appalachian region (hazard ratio = 1.43; 95% CI, 1.17 to 1.75; P = .004). Among individuals with MTB review, survival outcomes were similar regardless of whether they lived in Appalachia or other parts of Kentucky. CONCLUSION: MTB review is an independent positive predictor of overall survival regardless of residence location. MTBs may help overcome some health disparities for disadvantaged populations.

Assignment of local coordinate systems and methods to calculate tibiotalar and subtalar kinematics: A systematic review.

The introduction of biplane fluoroscopy has created the ability to evaluate in vivo motion, enabling six degree-of-freedom measurement of the tibiotalar and subtalar joints. Although the International Society of Biomechanics defines a standard method of assigning local coordinate systems for the ankle joint complex, standards for the tibiotalar and subtalar joints are lacking. The objective of this systematic review was to summarize and appraise the existing literature that (1) defined coordinate systems for the tibia, talus, and/or calcaneus or (2) assigned kinematic definitions for the tibiotalar and/or subtalar joints. A systematic literature search was developed with search results limited to English Language from 2006 through 2020. Articles were screened by two independent reviewers based on title and abstract. Methodological quality was evaluated using a modified assessment tool. Following screening, 52 articles were identified as having met inclusion criteria. Methodological assessment of these articles varied in quality from 61 to 97. Included articles adopted primary methods for defining coordinate systems that included: (1) anatomical coordinate system (ACS) based on individual bone landmarks and/or geometric shapes, (2) orthogonal principal axes, and (3) interactive closest point (ICP) registration. Common methods for calculating kinematics included: (1) joint coordinate system (JCS) to calculate rotation and translation, (2) Cardan/Euler sequences, and (3) inclination and deviation angles for helical angles. The methods each have strengths and weaknesses. This summarized knowledge should provide the basis for the foot and ankle biomechanics community to create an accepted standard for calculating and reporting tibiotalar and subtalar kinematics.

Olaparib Combined with an ATR or Chk1 Inhibitor as a Treatment Strategy for Acquired Olaparib-Resistant BRCA1 Mutant Ovarian Cells.

OBJECTIVE: Despite the promise of PARP inhibitors (PARPi) for treating BRCA1/2 mutated ovarian cancer (OC), drug resistance invariably develops. We hypothesized rationale drug combinations, targeting key molecules in DNA repair pathways and the cell cycle may be synergistic and overcome acquired PARPi resistance. METHODS: Drug sensitivity to PARPi alone and in combination with inhibitors of key DNA repair and cell cycle proteins, including ATR (VE-821), Chk1 (MK-8776), Wee1 (MK-1775), RAD51 (RI-1) was assessed in PARPi-sensitive (UWB1) and -resistant (UWB1-R) gBRCA1 mutant OC cell lines using a cell proliferation assay. The Bliss synergy model was used to estimate the two-drug combination effect and pharmacologic synergy (Bliss score ≥ 0) or antagonistic (Bliss score ≥ 0) response of the PARPi in combination with the inhibitors. RESULTS: IC50 for olaparib alone was 1.6 ± 0.9 µM compared to 3.4 ± 0.6 µM (p = 0.05) for UWB1 and UWB1-R cells, respectively. UWB1-R demonstrated increased sensitivity to ATRi (p = 0.04) compared to UWB1. Olaparib (0.3-1.25 µM) and ATRi (0.8-2.5 µM) were synergistic with Bliss scores of 17.2 ± 0.2, 11.9 ± 0.6 for UWB1 and UWB1-R cells, respectively. Olaparib (0.3-1.25 µM) and Chk1i(0.05-1.25 µM) were synergistic with Bliss scores of 8.3 ± 1.6, 5.7 ± 2.9 for UWB1 and UWB1-R cells, respectively. CONCLUSIONS: Combining an ATRi or Chk1i with olaparib is synergistic in both PARPi-sensitive and -resistant BRCA1 mutated OC cell models, and are rationale combinations for further clinical development.

Factors influencing bird-building collisions in the downtown area of a major North American city.

Bird-building collisions are the largest source of avian collision mortality in North America. Despite a growing literature on bird-building collisions, little research has been conducted in downtown areas of major cities, and no studies have included stadiums, which can be extremely large, often have extensive glass surfaces and lighting, and therefore may cause many bird collisions. Further, few studies have assessed the role of nighttime lighting in increasing collisions, despite the often-cited importance of this factor, or considered collision correlates for different seasons and bird species. We conducted bird collision monitoring over four migration seasons at 21 buildings, including a large multi-use stadium, in downtown Minneapolis, Minnesota, USA. We used a rigorous survey methodology to quantify among-building variation in collisions and assess how building features (e.g., glass area, lighting, vegetation) influence total collision fatalities, fatalities for separate seasons and species, and numbers of species colliding. Four buildings, including the stadium, caused a high proportion of all collisions and drove positive effects of glass area and amount of surrounding vegetation on most collision variables. Excluding these buildings from analyses resulted in slightly different collision predictors, suggesting that factors leading some buildings to cause high numbers of collisions are not the exact same factors causing variation among more typical buildings. We also found variation in collision correlates between spring and fall migration and among bird species, that factors influencing collision fatalities also influence numbers of species colliding, and that the proportion, and potentially area, of glass lighted at night are associated with collisions. Thus, reducing bird collisions at large buildings, including stadiums, should be achievable by reducing glass area (or treating existing glass), reducing light emission at night, and prioritizing mitigation efforts for glass surfaces near vegetated areas and/or avoiding use of vegetation near glass.

Diversity in CO2-Concentrating Mechanisms among Chemolithoautotrophs from the Genera Hydrogenovibrio, Thiomicrorhabdus, and Thiomicrospira, Ubiquitous in Sulfidic Habitats Worldwide.

Members of the genera Hydrogenovibrio, Thiomicrospira, and Thiomicrorhabdus fix carbon at hydrothermal vents, coastal sediments, hypersaline lakes, and other sulfidic habitats. The genome sequences of these ubiquitous and prolific chemolithoautotrophs suggest a surprising diversity of mechanisms for the uptake and fixation of dissolved inorganic carbon (DIC); these mechanisms are verified here. Carboxysomes are apparent in the transmission electron micrographs of most of these organisms but are lacking in Thiomicrorhabdus sp. strain Milos-T2 and Thiomicrorhabdus arctica, and the inability of Thiomicrorhabdus sp. strain Milos-T2 to grow under low-DIC conditions is consistent with the absence of carboxysome loci in its genome. For the remaining organisms, genes encoding potential DIC transporters from four evolutionarily distinct families (Tcr_0853 and Tcr_0854, Chr, SbtA, and SulP) are located downstream of carboxysome loci. Transporter genes collocated with carboxysome loci, as well as some homologs located elsewhere on the chromosomes, had elevated transcript levels under low-DIC conditions, as assayed by reverse transcription-quantitative PCR (qRT-PCR). DIC uptake was measureable via silicone oil centrifugation when a representative of each of the four types of transporter was expressed in Escherichia coli The expression of these genes in the carbonic anhydrase-deficient E. coli strain EDCM636 enabled it to grow under low-DIC conditions, a result consistent with DIC transport by these proteins. The results from this study expand the range of DIC transporters within the SbtA and SulP transporter families, verify DIC uptake by transporters encoded by Tcr_0853 and Tcr_0854 and their homologs, and introduce DIC as a potential substrate for transporters from the Chr family.IMPORTANCE Autotrophic organisms take up and fix DIC, introducing carbon into the biological portion of the global carbon cycle. The mechanisms for DIC uptake and fixation by autotrophic Bacteria and Archaea are likely to be diverse but have been well characterized only for "Cyanobacteria" Based on genome sequences, members of the genera Hydrogenovibrio, Thiomicrospira, and Thiomicrorhabdus have a variety of mechanisms for DIC uptake and fixation. We verified that most of these organisms are capable of growing under low-DIC conditions, when they upregulate carboxysome loci and transporter genes collocated with these loci on their chromosomes. When these genes, which fall into four evolutionarily independent families of transporters, are expressed in E. coli, DIC transport is detected. This expansion in known DIC transporters across four families, from organisms from a variety of environments, provides insight into the ecophysiology of autotrophs, as well as a toolkit for engineering microorganisms for carbon-neutral biochemistries of industrial importance.