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We developed a dataset consisting of outbreak data collected from official, open-source surveillance reports representing more than 170 pathogens, 237 countries and territories, and more than 3300 events that occurred primarily between 1963 and 2023. Here we present and analyze a subset of these data, comprising a dataset of human epidemic events with onset between 2015 and 2020. Structuring of epidemiological data in the dataset follows a specific methodology to ensure consistency across all events. This methodology has been designed to produce the most reliable spatiotemporal view of an outbreak as possible. To ensure data are true-to-source, the structured data undergoes multiple rounds of both manual and automated review and validation. The extensive and standardized nature of the dataset makes it well-suited for both descriptive epidemiology and exploring outbreak dynamics and disease emergence. [ABSTRACT FROM AUTHOR]

Purpose of Review: This review summarizes recent evidence linking experiences of discrimination and anticipated discrimination with cardiovascular health outcomes. Recent Findings: Experiences of discrimination were consistently associated with increased risk of nicotine exposure, poor sleep health, obesity, diabetes, hypertension, and subclinical cardiovascular disease. Evidence is mixed for cardiovascular disease diagnoses and cardiovascular mortality. Although research is limited, anticipated discrimination is an independent risk factor for poor sleep health and subclinical cardiovascular disease. Key methodological limitations included the limited use of gold-standard objective measures of health behaviors and well-validated self-report measures, inadequate consideration of intersectionality, and lack of robust examinations of psychological, behavioral, and physiological mechanisms linking discrimination with cardiovascular health outcomes. Summary: There is substantial evidence linking experiences of discrimination with cardiovascular outcomes. Yet, before translating these findings into clinical practice, more rigorous studies are needed to address methodological limitations and uncover mechanisms by which discrimination influences cardiovascular health. There is a need for studies to inform the development of evidence-based interventions focused on reducing the influence of discrimination-related stressors on cardiovascular health outcomes. Findings have important implications for future work to advance cardiovascular health equity. [ABSTRACT FROM AUTHOR]

Background: Transgender and gender diverse (TGD) adults in the U.S. experience health disparities, including in anogenital sexually transmitted infections (STI). Gender-affirming hormone therapy (GAHT) is known to be medically necessary and improve health. Few studies have assessed the effect of GAHT on STI diagnoses. Objective: To evaluate the effect of GAHT delivered in primary care as an intervention to improve STI outcomes for TGD adults. Design: LEGACY is a longitudinal, multisite cohort study of adult TGD primary care patients from two federally qualified community health centers in Boston, MA, and New York, NY. Participants: Electronic health record data for eligible adult TGD patients contributed to the LEGACY research data warehouse (RDW). A total of 6330 LEGACY RDW patients were followed from 2016 to 2019, with 2555 patients providing STI testing data. Main Measures: GAHT exposure was being prescribed hormones, and the clinical outcome was anogenital gonorrhea or chlamydia diagnoses. Log-Poisson generalized estimating equations assessed the effect of prescription GAHT on primary outcomes, adjusting for age, race, ethnicity, gender identity, poverty level, health insurance, clinical site, and cohort years. Key Results: The median age was 28 years (IQR = 13); the racial breakdown was 20.4% Black, 8.1% Multiracial, 6.9% Asian/Pacific Islander, 1.8% Other; 62.8% White; 21.3% Hispanic/Latinx; 47.0% were assigned female at birth, and 16.0% identified as nonbinary. 86.3% were prescribed hormones. Among those tested, the percentage of patients with a positive anogenital STI diagnosis ranged annually from 10.0 to 12.5% between 2016 and 2019. GAHT prescription was associated with a significant reduction in the risk of anogenital STI diagnosis (aRR = 0.75; 95% CI = 0.59–0.96) over follow-up. Conclusions: GAHT delivered in primary care was associated with less STI morbidity in this TGD cohort over follow-up. Patients may benefit from individualized and tailored clinical care alongside GAHT to optimize STI outcomes. [ABSTRACT FROM AUTHOR]

The design of cereblon-binding molecular glues (MGs) that selectively recruit a desired protein while excluding teratogenic SALL4 is an area of significant interest when designing therapeutic agents. Previous studies show that SALL4 is degraded in the presence of IKZF1 degraders pomalidomide, and to a lesser extent by CC-220. To expand our understanding of the molecular basis for the interaction of SALL4 with cereblon, we performed biophysical and structural studies demonstrating that SALL4 zinc finger domains one and two (ZF1-2) interact with cereblon (CRBN) in a unique manner. ZF1 interacts with the N-terminal domain of cereblon and ZF2 binds as expected in the C-terminal IMiD-binding domain. Both ZF1 and ZF2 contribute to the potency of the interaction of ZF1-2 with CRBN:MG complexes and the affinities of SALL4 ZF1-2 for the cereblon:CC-220 complex are less potent than for the corresponding pomalidomide complex. Structural analysis provides a rationale for understanding the reduced affinity of SALL4 for cereblon in the presence of CC-220, which engages both ZF1 and ZF2. These studies further our understanding of the molecular glue-mediated interactions of zinc finger-based proteins with cereblon and may provide structural tools for the prospective design of compounds with reduced binding and degradation of SALL4. [ABSTRACT FROM AUTHOR]

Acute lymphoblastic leukemia (ALL) is an aggressive bone marrow cancer with disparate outcomes. Data on patient outcomes in real world settings outside of clinical trials is limited. The current study reports on outcomes for 137 ALL patients who received an adult induction and consolidation regimen derived from the CALGB 10102 trial modified without alemtuzumab. Of the 137 patients, 32 were < 40 years old, 52 were between 40 and 59, and 53 were ≥ 60 years old. Overall, 109 (79.6%) patients achieved a complete remission (< 40: 96.1%, 40–59: 86.5%, and 62.3% ≥ 60 (p = 0.0002)). Progression free survival for the entire cohort was 13.5 months and by age was 19.8 months for less than 40, 23.4 months for 40 to 59 and 6.7 months for ≥ 60; p = 0.0002. Median survival was 22.1 months for the entire cohort (32.9 months for ages < 40, 26.6 months ages 40–59, 7.8 months ≥ 60, p < 0.001). [ABSTRACT FROM AUTHOR]

Nucleic acid sensing powered by the sequence recognition of CRIPSR technologies has enabled major advancement toward rapid, accurate and deployable diagnostics. While exciting, there are still many challenges facing their practical implementation, such as the widespread need for a PAM sequence in the targeted nucleic acid, labile RNA inputs, and limited multiplexing. Here we report FACT (Functionalized Amplification CRISPR Tracing), a CRISPR-based nucleic acid barcoding technology compatible with Cas12a and Cas13a, enabling diagnostic outputs based on cis- and trans-cleavage from any sequence. Furthermore, we link the activation of CRISPR-Cas12a to the expression of proteins through a Reprogrammable PAIRing system (RePAIR). We then combine FACT and RePAIR to create FACTOR (FACT on RePAIR), a CRISPR-based diagnostic, that we use to detect infectious disease in an agricultural use case: honey bee viral infection. With high specificity and accuracy, we demonstrate the potential of FACTOR to be applied to the sensing of any nucleic acid of interest. Nucleic acid sensing involving CRISPR technologies is powerful but has certain limitations, such as PAM sequence requirements and limited multiplexing. Here, authors report a CRISPR-based barcoding technology which enables multiple outputs from any target sequence, based on cis- and trans-cleavage. [ABSTRACT FROM AUTHOR]

The sexual partnerships of transmasculine (TM) adults—those assigned female at birth who identify as transgender men or a masculine spectrum gender identity—and characteristics associated with STI/HIV risk behavior remains understudied. Participants in the current study were TM adults (n = 141) receiving care at a community health center in Boston, Massachusetts between March 2015 and September 2016. Using generalized estimating equations, we examined individual- and partnership-level factors associated with TM adults' odds of engaging in sexual behavior with a sexual partner of unknown STI/HIV status in the past 12 months. TM adults with casual sexual partnerships (vs. monogamous partnerships) and those in partnerships with cisgender men, other TM individuals, or transfeminine partners (vs. cisgender women) had statistically significantly higher odds of engaging in sexual behavior with a partner of unknown STI/HIV status in the past 12 months. Findings may inform future efforts to improve sexual health communication and STI/HIV disclosure between TM adults and their sexual partners. [ABSTRACT FROM AUTHOR]

Devimistat is a TCA cycle inhibitor. A previously completed phase I study of devimistat in combination with cytarabine and mitoxantrone in patients with relapsed or refractory AML showed promising response rates. Here we report the results of a single arm phase II study (NCT02484391). The primary outcome of feasibility of maintenance devimistat following induction and consolidation with devimistat in combination with high dose cytarabine and mitoxantrone was not met, as maintenance devimistat was only administered in 2 of 21 responders. The secondary outcomes of response (CR + CRi) and median survival were 44% (21/48) and 5.9 months respectively. There were no unexpected toxicities observed. An unplanned, post-hoc analysis of the phase I and II datasets suggests a trend of a dose response in older but not younger patients. RNA sequencing data from patient samples reveals an age-related decline in mitochondrial gene sets. Devimistat impairs ATP synthesis and we find a correlation between mitochondrial membrane potential and sensitivity to chemotherapy. Devimistat also induces mitochondrial reactive oxygen species and turnover consistent with mitophagy. We find that pharmacological or genetic inhibition of mitochondrial fission or autophagy sensitizes cells to devimistat. These findings suggest that an age related decline in mitochondrial quality and autophagy may be associated with response to devimistat however this needs to be confirmed in larger cohorts with proper trial design. Combining cytarabine and mitoxantrone with the tricarboxylic acid cycle inhibitor devimistat has been reported in a phase I clinical trial with relapsed or refractory acute myeloid leukaemia (AML). Here, the authors report the outcomes of a phase II study, analyse samples from both phases and perform preclinical analyses that show mitochondrial fission or autophagy inhibition sensitizes AML cells to devimistat. [ABSTRACT FROM AUTHOR]

Growth rate, longevity, and maturity were estimated for four commonly targeted species of surgeonfish in Hawai'i: ringtail surgeonfish/pualu Acanthurus blochii, eyestripe surgeonfish/palani Acanthurus dussumieri, orange-band surgeonfish/na'ena'e Acanthurus olivaceus, and yellowfin surgeonfish/pualu Acanthurus xanthopterus. All species demonstrated rapid growth with long life spans. The maximum observed ages were 26 years for A. blochii, 30 years for A. dussumieri, 14 years for A. olivaceus, and 29 years for A. xanthopterus. Females reached maturity at a greater size and age for all four species. All species reached maturity within the first 3 years of life and approximately 59–67% of maximum size. All four surgeonfish species demonstrated a biphasic mortality schedule with a higher total mortality rate occurring earlier part of life. This study provides a comprehensive study of the age, growth, and maturity for four large-bodied surgeonfish species which are commonly targeted throughout Hawai'i and the rest of the Indo-Pacific. [ABSTRACT FROM AUTHOR]

We have previously developed and validated a one-step assay based on reverse transcription loop-mediated isothermal amplification (RT-LAMP) for rapid detection of the Zika virus (ZIKV) from mosquito samples. Patient diagnosis of ZIKV is currently carried out in centralized laboratories using the reverse transcription-quantitative polymerase chain reaction (RT-qPCR), which, while the gold standard molecular method, has several drawbacks for use in remote and low-resource settings, such as high cost and the need of specialized equipment. Point-of-care (POC) diagnostic platforms have the potential to overcome these limitations, especially in low-resource countries where ZIKV is endemic. With this in mind, here we optimized and validated our RT-LAMP assay for rapid detection of ZIKV from patient samples. We found that the assay detected ZIKV from diverse sample types (serum, urine, saliva, and semen) in as little as 20 min, without RNA extraction. The RT-LAMP assay was highly specific and up to 100 times more sensitive than RT-qPCR. We then validated the assay using 100 patient serum samples collected from suspected cases of arbovirus infection in the state of Pernambuco, which was at the epicenter of the last Zika epidemic. Analysis of the results, in comparison to RT-qPCR, found that the ZIKV RT-LAMP assay provided sensitivity of 100%, specificity of 93.75%, and an overall accuracy of 95.00%. Taken together, the RT-LAMP assay provides a straightforward and inexpensive alternative for the diagnosis of ZIKV from patients and has the potential to increase diagnostic capacity in ZIKV-affected areas, particularly in low and middle-income countries. [ABSTRACT FROM AUTHOR]

This study presents age-based life history information on three small-bodied species targeted in the American Samoan fishery: Chlorurus japanensis palecheek parrotfish/fuga-alosama, Lethrinus rubrioperculatus spotcheek emperor/fiola pa'o'omumu, and Naso lituratus orangespine unicornfish/ili'ilia. Age and reproductive information were derived from sagittal otoliths and gonads. Maximum observed ages were 7 years for C. japanensis, 10 years for L. rubrioperculatus, and 25 years for N. lituratus. Due to a limited numbers of immature samples, a proxy for size at 50% maturity (L50) was derived from the relationship between asymptotic fork length (L∞) and L50 based on data published for species from similar geographic regions and respective families. L50 was estimated at 20.9 cm for C. japanensis, 20.4 cm for L. rubrioperculatus, and 17.5 cm for N. lituratus. Derived estimates were within 1 % of the L50 calculated for C. japanensis and N. lituratus from the limited number of immature samples collected in this study, indicating that for regions where sampling ability is limited, derived relationships between L∞ and L50 can be used to calculate an appropriate proxy. Naso lituratus demonstrated a biphasic mortality schedule with a higher than expected total mortality rate in the first 7 years of life. The age-based demographic information presented here can be used for future stock assessments and ecosystem models, which should facilitate improved management. [ABSTRACT FROM AUTHOR]

Introduction: Open reduction and internal fixation has long been accepted as optimal treatment for displaced olecranon fractures based on poor results seen with conservative management. With the presence of comminution, tension-band wiring constructs are contraindicated due to tendency to compress through fragments, thereby shortening the articular segment. Therefore, plate fixation is typically employed. Our hypothesis was that in a comminuted fracture model, 2.7 mm reconstruction plating without locking screws will perform equally to 3.5 mm locked plating in terms of fracture displacement and rotation (shear).Materials and Methods: A three-part comminuted olecranon fracture pattern was created in nine matched pairs of cadaveric specimen using an oscillating saw in standardized, reproducible fashion. Each matched pair was then randomized to receive either 2.7 mm reconstruction plating or 3.5 mm proximal ulna locked plating. Random allocation software was used to assign the 2.7 mm plate construct to either the right or left side of each pair with the contralateral receiving the 3.5 mm plate construct. Specimens were cyclically loaded simulating passive range of motion exercises commonly performed during rehabilitation. Displacement and rotation in relation to the long axis of the ulna were measured through motion capture. Fragment gapping and rotation was quantified following 100 cycles at 10 N and again following 100 cycles at 500 N.Results: No significant differences were detected between the 2.7 and 3.5 mm plates in fracture rotation or gapping following loads at 10 N (0.5° and 0.7°; 0.6 and 1.2 mm; respectively; p > 0.05) or 500 N (2.3° and 1.6°; 3.8 and 3.1 mm; respectively; p > 0.05) loading. Fragment rotation and gapping were positively correlated within each plate construct (R 2 > 0.445; p < 0.05).Conclusions: 2.7 mm plating is an alternative to 3.5 mm locked plating with decreased plate prominence without significantly sacrificing displacement and rotational control. This is beneficial in fracture patterns where the traditional dorsal plating does not offer optimal screw trajectory. [ABSTRACT FROM AUTHOR]

Some transgender men who have sex with men (trans MSM) are vulnerable to HIV infection and face stigma from sexual partners. We evaluated a brief 4-item measure of gender non-affirmation from cisgender male partners. A non-probability sample of American trans MSM (n = 843) reporting past 6-month sexual contact with a cisgender male completed a cross-sectional survey. Psychometric analyses assessed the scale and modeled HIV risk associations. Overall, 78% experienced past 6-month gender non-affirmation from cisgender male partners. The scale demonstrated good reliability (α = 0.78). Convergent validity was supported in associations with psychological distress and anxiety (p < 0.05). Lower frequency of cisgender male partner stigma was associated with increased odds of past 6-month HIV testing and decreased odds of past 6-month condomless receptive sex (all p < 0.01). The gender non-affirmation from cisgender male sexual partners scale found negative associations with protective health behaviors and can be used to better understand the context of trans MSM risk behavior. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the impact of hyperglycemia and glycemic variability during intensive acute myeloid leukemia therapy (AML) on outcomes by age.Methods: Retrospective study of 262 consecutive patients with newly diagnosed AML hospitalized for intensive induction. Hyperglycemia was assessed by mean blood glucose (BG) (mg/dL) during hospitalization and glycemic variability was determined by the standard deviation (SD) of mean BG. Outcomes were complete remission ± incomplete count recovery (CR + CRi), and overall survival (OS). We used logistic regression to evaluate CR + CRi, and Cox proportional hazard models for OS, stratified by age (< 60 vs ≥ 60 years).Results: Older patients (N = 138, median age 70) had higher baseline comorbidity (CCI > 1 60.1% vs 25.8%) and prevalence of diabetes (20.3% vs 7.3%) compared to younger (N = 124, median age 47). The mean ± SD number of BG values obtained per patient during hospitalization was 61 ± 71. The mean (± SD) glucose (mg/dL) during hospitalization was 121.7 (25.9) in older patients (≥ 60 years) versus 111.6 (16.4) in younger. In older patients, higher mean glucose and greater glycemic variability were associated with lower odds of remission (OR 0.80, 95% CI 0.69-0.93 and OR 0.73, 95% CI 0.61-0.88 respectively, per 10-unit increase) and higher mortality rates (HR 1.13, 95% CI 1.05-1.21 and HR 1.17, 95% CI 1.09-1.26, respectively, per 10-unit increase) in multivariate analyses.Conclusions: Our observations that hyperglycemia and increased glycemic variability were associated with lower remission rates and increased mortality in older patients suggest glycemic control may be a potentially modifiable factor to improve AML outcomes. [ABSTRACT FROM AUTHOR]

An estimated one- to two-thirds of incident HIV infections among U.S. men who have sex with men (MSM) occur within the context of a primary relationship. The existing, yet limited, literature on sexual risk behavior among same-sex couples suggests that MSM with main partners are more often to report having lower perceived HIV risk, higher unrecognized HIV infection, and increased frequency of condomless anal intercourse with their primary partner. Furthermore, numerous studies document the strong relationship between polydrug use and binge drinking with HIV infection among MSM. However, more research is needed that identifies how individual- and relationship-level factors are related to polydrug use and binge drinking in the context of same-sex male relationships. We used baseline data collected as part of a prospective randomized controlled trial of 160 same-sex male couples (total N = 320 individuals). In 2015, recruitment commenced in three U.S. cities: Atlanta, GA, Boston, MA, and Chicago, IL. Participants completed a self-report assessment using an audio-computer-assisted self-interview system during their baseline enrollment visit. We collected information on participants' sociodemographic characteristics, drug and alcohol use, individual- and relationship-level variables of interest, as well as relationship quality. Multinomial logistic regression models were fit for three different categories of polydrug use and of binge drinking for which (1) both partners exhibited the behavior, (2) only the respondent exhibited the behavior, or (3) only the partner exhibited the behavior. Participants' age ranged from 18 to 69 (M = 35.9). The sample majority (77.5%) was White (248/320), with 12.2% Black (39/320) and 10.3% Multiracial (33/320); 68.4% had completed a college degree; and 9.6% were unemployed. A high proportion (62.2%) reported any drug use, including marijuana; 45% reported using drugs other than marijuana; and 18.1% reported polydrug use. Overall, 22.2% reported current binge drinking. Age discordance and being in a long-term relationship (6 or more years) were associated with a decreased odds of polydrug use among couples; being in an interracial dyad, recent history of arrest, living with HIV, and self-reported clinically significant depressive symptoms were associated with an increased odds of polydrug use. Additionally, being the older partner and reporting higher levels of internalized homophobia decreased odds for binge drinking, while recent history of arrest, living with HIV, and feeling more loved in their relationship were associated with an increased odds of binge drinking. Findings have implications for developing interventions to reduce substance use and promote health among same-sex male couples. Future research would benefit by using longitudinal study designs to understand the individual-, relationship-, and structural-level factors that potentiate polydrug use and binge drinking among same-sex male couples. [ABSTRACT FROM AUTHOR]

Purpose: Recent anatomic studies have suggested that the dominant arterial supply of the patella enters through the inferior pole. Based upon these findings, we hypothesized that bone-patellar tendon-bone graft harvest can significantly diminish patellar vascularity.Methods: Nine matched pair cadaveric knee specimens (mean age 47.4 years) were dissected and cannulated. A single knee was selected to undergo routine graft harvest, and the contralateral knee was left intact to serve as a control. Gadolinium was injected, and magnetic resonance imaging (MRI) signal enhancement was quantified to determine differences in uptake. Each matched pair was subsequently injected with a urethane polymer compound and dissected to correlate vessel disruption with MRI findings.Results: We identified two predominating patterns of vessel entry. In one pattern, the vessel entered the inferomedial aspect (five o'clock/right, seven o'clock/left) of the patella and was disrupted by graft harvest in 2/9 (22.2 %) pairs. In the second pattern, the vessel entered further medial (four o'clock/right, eight o'clock/left) and was not disrupted (7/9, 78.8 %). The mean decrease in gadolinium uptake following disruption of the predominant vessel measured 56.2 % (range 42.6-69.5 %) compared to an average decrease of 18.3 % (range 7.1-29.1 %) when the dominant arterial supply to the inferior pole remained intact (p < 0.04).Conclusion: Medial entry of the predominant vessel precluded vessel disruption. Disruption of the dominant arterial supply can result in a significant decrease in patellar vascularity. Modification of graft harvest techniques and areas of surgical dissection should be explored to minimize vascular insult. Further correlation with clinical studies/outcomes is necessary to determine a potential association between vascular insult and anterior knee pain. [ABSTRACT FROM AUTHOR]

Young adult transgender men who have sex with men (TMSM) engage in sexual behaviors that place them at risk of sexually transmitted infections (STIs) including HIV. To date, no HIV and STI prevention interventions have been developed specifically for young adult TMSM. To address this gap, the current study aimed to (1) adapt a small group-based behavioral HIV prevention intervention designed for young transgender women ("LifeSkills") to address the unique HIV and STI prevention needs of young TMSM ages 18-29 years and (2) conduct a pilot evaluation of the intervention ("LifeSkills for Men"; LS4M). LS4M was carried out in an iterative approach with community input along the way, which allowed for refinement of the intervention manual and enhanced participant acceptability. A LS4M Task Force was convened to guide intervention development/adaptation and study implementation. Initially, focus groups were conducted to examine the sexual health needs, concerns, and stressors facing young TMSM (n = 12; mean age = 23.8 years; 16.7% people of color). Next, LS4M was pilot tested (n = 17; mean age = 24.3 years; 23.5% people of color) to assess acceptability with the study population and feasibility of all study procedures. Overall attendance, participation rates, and positive feedback from participants demonstrate that LS4M is highly acceptable and feasible to carry out with young TMSM. Trends in outcome measures across 4 months of follow-up suggest that participation in the intervention may improve mental health, reduce internalized stigma, and reduce HIV- and STI-related risk behaviors. Further testing of the intervention enrolling young TMSM with recent sexual risk behavior at baseline and with a control group is warranted. Lessons learned for future work with young TMSM are discussed. [ABSTRACT FROM AUTHOR]

Guidelines for cervical cancer screening have evolved rapidly over the last several years, with a trend toward longer intervals between screenings and an increasing number of screening options, such as Pap/HPV co-testing and HPV testing as a primary screening. However, gynecological recommendations often do not include clinical considerations specific to patients on the female-to-male (FTM) spectrum. Both patients and providers may not accurately assess risk for HPV and other sexually transmitted infections, understand barriers to care, or be aware of recommendations for cervical cancer screening and other appropriate sexual and reproductive health services for this patient population. We review the evidence and provide guidance on minimizing emotional discomfort before, during, and after a pelvic exam, minimizing physical discomfort during the exam, and making adaptations to account for testosterone-induced anatomical changes common among FTM patients. [ABSTRACT FROM AUTHOR]

The article discusses a study focusing on gender identity disparities among transmasculine adults using a Pap test. Topics discussed include the screening of transmasculine adults for cervical cancer, its comparison with the screening for cisgender women, and the use of testosterone by transmasculine adults. Also mentioned is their sexual activity with cisgender people.

In an effort to increase the efficacy of several antineoplastic alkylating agents (CDDP, L-PAM, CTX, or BCNU), we examined the effect of the modulator Fluosol-DA/carbogen in combination with a second modulator, either lonidamine or pentoxifylline, on the survival of FSaIIC tumor cells and of bone marrow CFU-GM from tumor-bearing C3H mice. Fluosol-DA/carbogen increased the tumor-cell killing activity of each alkylating agent by about 10 times. In contrast, lonidamine alone did not significantly increase the cytocidal activity of any of the alkylating agents tested. However, in combination with Fluosol-DA/carbogen, the use of lonidamine produced about a 100-fold increase in the tumor cell kill achieved with CDDP as compared with CDDP alone. No increase in tumor cell kill over that produced with the single modulator Fluosol-DA/carbogen was seen following the addition of lonidamine to the combination treatment with L-PAM, CTX, or BCNU. Unfortunately, although neither lonidamine nor Fluosol-DA/carbogen alone significantly increased alkylator toxicity to bone marrow CFU-GM, the combination of modulators increased the toxicity of each alkylating agent to bone marrow by about 10 times. Pentoxifylline caused an increase in alkylator activity against the FSaIIC fibrosarcoma only when used with BCNU; this effect was further augmented by the addition of Fluosol-DA/carbogen. The combination of modulators pentoxifylline plus Fluosol-DA/carbogen was more effective than Fluosol-DA/carbogen alone only when the former was used with BCNU, whereas only minimal increases in tumor-cell killing activity were obtained with this modulator combination and CDDP, L-PAM, or CTX. Pentoxifylline increased the bone marrow CFU-GM toxicity of L-PAM by about 10 times. The bone marrow CFU-GM toxicity was further increased by Fluosol-DA/carbogen, as was the toxicity of each of the other alkylating agents. Lonidamine plus Fluosol-DA/carbogen may be useful in increasing the therapeutic efficacy of CDDP, and the combination of pentoxifylline plus Fluosol-DA/carbogen might improve the antitumor activity of BCNU. [ABSTRACT FROM AUTHOR]

Pluripotent stem cells (PSCs) are capable of dynamic interconversion between distinct substates; however, the regulatory circuits specifying these states and enabling transitions between them are not well understood. Here we set out to characterize transcriptional heterogeneity in mouse PSCs by single-cell expression profiling under different chemical and genetic perturbations. Signalling factors and developmental regulators show highly variable expression, with expression states for some variable genes heritable through multiple cell divisions. Expression variability and population heterogeneity can be influenced by perturbation of signalling pathways and chromatin regulators. Notably, either removal of mature microRNAs or pharmacological blockage of signalling pathways drives PSCs into a low-noise ground state characterized by a reconfigured pluripotency network, enhanced self-renewal and a distinct chromatin state, an effect mediated by opposing microRNA families acting on the Myc/Lin28/let-7 axis. These data provide insight into the nature of transcriptional heterogeneity in PSCs. [ABSTRACT FROM AUTHOR]

Cells rely on autophagy to clear misfolded proteins and damaged organelles to maintain cellular homeostasis. In this study we use the new autophagy inhibitor PIK-III to screen for autophagy substrates. PIK-III is a selective inhibitor of VPS34 that binds a unique hydrophobic pocket not present in related kinases such as PI(3)Kα. PIK-III acutely inhibits autophagy and de novo lipidation of LC3, and leads to the stabilization of autophagy substrates. By performing ubiquitin-affinity proteomics on PIK-III-treated cells we identified substrates including NCOA4, which accumulates in ATG7-deficient cells and co-localizes with autolysosomes. NCOA4 directly binds ferritin heavy chain-1 (FTH1) to target the iron-binding ferritin complex with a relative molecular mass of 450,000 to autolysosomes following starvation or iron depletion. Interestingly, Ncoa4−/− mice exhibit a profound accumulation of iron in splenic macrophages, which are critical for the reutilization of iron from engulfed red blood cells. Taken together, the results of this study provide a new mechanism for selective autophagy of ferritin and reveal a previously unappreciated role for autophagy and NCOA4 in the control of iron homeostasis in vivo. [ABSTRACT FROM AUTHOR]

Urban gardens may support bees by providing resources in otherwise resource-poor environments. However, it is unclear whether urban, backyard gardens with native plants will support more bees than gardens without native plants. We examined backyard gardens in northwestern Ohio to ask: 1) Does bee diversity, abundance, and community composition differ in backyard gardens with and without native plants? 2) What characteristics of backyard gardens and land cover in the surrounding landscape correlate with changes in the bee community? 3) Do bees in backyard gardens respond more strongly to local or landscape factors? We sampled bees with pan trapping, netting, and direct observation. We examined vegetation characteristics and land cover in 500 m, 1 km, and 2 km buffers surrounding each garden. Abundance of all bees, native bees, and cavity-nesting bees (but not ground-nesting bees) was greater in native plant gardens but only richness of cavity-nesting bees differed in gardens with and without native plants. Bee community composition differed in gardens with and without native plants. Overall, bee richness and abundance were positively correlated with local characteristics of backyard gardens, such as increased floral abundance, taller vegetation, more cover by woody plants, less cover by grass, and larger vegetable gardens. Differences in the amount of forest, open space, and wetlands surrounding gardens influenced abundance of cavity- and ground-nesting bees, but at different spatial scales. Thus, presence of native plants, and local and landscape characteristics might play important roles in maintaining bee diversity within urban areas. [ABSTRACT FROM AUTHOR]

A correction to the article "Factors associated with transmasculine adults recently engaging in sexual behavior with partners of unknow STI and HIV status" that was published in the April 21, 2022 issue is presented.