A GTPsynthesizing ribozyme chosen by simply metabolism coupling to a RNA polymerase ribozyme

SignificanceMany gram-positive organisms have evolved an elegant solution to sense and resist antimicrobial peptides that inhibit cell-wall synthesis. These organisms express an unusual "Bce-type" adenosine triphosphate-binding cassette (ABC) transporter that recognizes complexes formed between antimicrobial peptides and lipids involved in cell-wall biosynthesis. In this work, we provide the first structural snapshots of a Bce-type ABC transporter trapped in different conformational states. Our structures and associated biochemical data provide key insights into the novel target protection mechanism that these unusual ABC transporters use to sense and resist antimicrobial peptides. The studies described herein set the stage to begin developing a comprehensive molecular understanding of the diverse interactions between antimicrobial peptides and conserved resistance machinery found across most gram-positive organisms.SignificanceBiochemical reactions often occur in small volumes within a cell, restricting the number of molecules to the hundreds or even tens. At this scale, reactions are discrete and stochastic, making reliable signaling difficult. This paper shows that the transition between discrete, stochastic reactions and macroscopic reactions can be exploited to make a self-regulating switch. This constitutes a previously unidentified kind of reaction network that may be present in small structures, such as synapses.SignificanceIn marine ecosystems, transmission of microbial symbionts between host generations occurs predominantly through the environment. Yet, it remains largely unknown how host genetics, symbiont competition, environmental conditions, and geography shape the composition of symbionts acquired by individual hosts. To address this question, we applied population genomic approaches to four species of deep-sea hydrothermal vent snails that live in association with chemosynthetic bacteria. Our analyses show that environment is more important to strain-level symbiont composition than host genetics and that symbiont strains show genetic variation indicative of adaptation to the distinct geochemical conditions at each vent site. This corroborates a long-standing hypothesis that hydrothermal vent invertebrates affiliate with locally adapted symbiont strains to cope with the variable conditions characterizing their habitats.Importance Three-dimensional planning software is not standardized in facial gender-affirming surgery. Objective To develop and validate surgical planning software to create cutting guides to contour the lower jaw border. Design, Setting, and Participants A 3-year prospective case series study done in three phases software development, validation, and surgical guide application. Ethics committee approval was obtained to enroll the patients (Clinical Research Ethics Committee, Hospital Costa del Sol, Marbella, Spain). Main Outcomes and Measures Validation phase degree of agreement between the planned and obtained results, modification of cephalometric parameters, and surgical times. Application phase surgical technique description, complications, and patient-reported outcome measures. Results The degree of agreement between the planned and obtained results was inframillimetric (0.31 ± 0.70 mm). The guides reduced the mandible to within feminine parameters (p  less then  0.05). Surgical times decreased by 10.96% with chin ostectomies (p  less then  0.05) and 23.06% with lower jaw border (angle-to-angle) surgeries (p  less then  0.001). In the application phase, revision surgery was required for 11 patients out of 260 (4.23%). Conclusions and Relevance The use of cutting guides on the lower jaw border is effective, helps reach standard feminine parameters, and decreases surgical times.
High allelic ratio (HAR)
/ITD (AR > 0.4) mutations confer poor prognosis in pediatric acute myeloid leukemia (AML). COG AAML1031 studied the feasibility and efficacy of adding sorafenib, a multikinase tyrosine kinase inhibitor to standard chemotherapy and as single-agent maintenance therapy in this population.
Patients were treated in three cohorts. The initial safety phase defined the maximum tolerated dose of sorafenib starting in induction 2. Cohorts 2 and 3 added sorafenib in induction and as single-agent maintenance. Clinical outcome analysis was limited to n = 72 patients in cohorts 2/3 and compared with n = 76 HAR
/ITD+ AML patients who received identical chemotherapy without sorafenib. Sorafenib pharmacokinetics and plasma inhibitory activity were measured in a subset of patients.
The maximum tolerated dose of sorafenib was 200 mg/m
once daily; dose-limiting toxicities included rash (n = 2; 1 grade 3 and 1 grade 2), grade 2 hand-foot syndrome, and grade 3 fever. Pharmacokinetics/plasma hemotherapy and may improve outcomes in pediatric HAR FLT3/ITD+ AML.Objectives. To characterize the effects of the onset of the COVID-19 pandemic on the risk environment of people who use drugs (PWUD) in Tijuana, Mexico. Methods. We used intensive participant-observation ethnography among street-based PWUD and key informants, such as frontline physicians and harm reductionists. Results. PWUD described an unprecedented cessation of police violence and extortion during the initial pandemic-related lockdown, though this quickly reversed and police violence worsened. Government-provided housing and medical treatment with methadone were temporarily provided to PWUD in a dedicated clinic, yet only for PWUD with COVID-19 symptoms. Concurrently, non‒COVID-19‒related hospital care became virtually inaccessible, and many PWUD died of untreated, chronic illnesses, such as hepatitis C, and soft-tissue infections. Border closures, decreases in social interaction, and reduced drug and sex tourism resulted in worsening food, income, and housing insecurity for many PWUD. By contrast, potent illicit drugs remained easily accessible in open-air drug markets. MK-5108 clinical trial Conclusions. The pandemic exacerbated health risks for PWUD but also offered profound glimpses of beneficial structural changes. Efforts are needed in Tijuana and elsewhere to institutionalize positive pandemic-related shifts and ameliorate novel harms for PWUD. (Am J Public Health. 2022;112(S2)S199-S202. https//doi.org/10.2105/AJPH.2022.306796).Objectives. To identify key gaps in overdose prevention interventions for mothers who use drugs and the paradoxical impact of institutional practices that can increase overdose risk in the context of punitive drug policies and a toxic drug supply. Methods. Semistructured interviews were conducted with 40 women accessing 2 women-only, low-barrier supervised consumption sites in Greater Vancouver, British Columbia, Canada, between 2017 and 2019. Our analysis drew on intersectional understandings of structural, everyday, and symbolic violence. Results. Participants' substance use and overdose risk (e.g., injecting alone) was shaped by fear of institutional and partner scrutiny and loss (or feared loss) of child custody or reunification. Findings indicate that punitive policies and institutional practices that frame women who use drugs as unfit parents continue to negatively shape the lives of women, most significantly among Indigenous participants. Conclusions. Nonpunitive policies, including access to safe, nontoxic drug supplies, are critical first steps to decreasing women's overdose risk alongside gender-specific and culturally informed harm-reduction responses, including community-based, peer-led initiatives to maintain parent-child relationships. (Am J Public Health. 2022;112(S2)S191-S198. https//doi.org/10.2105/AJPH.2022.306776).Drug consumption rooms (DCRs) have the potential to have a positive impact on the opioid overdose crisis. DCRs could also potentially change the political environment for public health because they can affect the distribution of responsibility for harm reduction between the individual and society by collectivizing responsibility for harm reduction through welfare regimes. The methodology is based on 2 case studies-1 in Copenhagen, Denmark, and 1 in Paris, France-about residents, people who inject drugs (PWID), and politicians' experiences of DCRs involving semidirective interviews. Denmark has a long history of harm-reduction policy, and the implementation of DCRs in Copenhagen has happened through close collaboration between local authorities and the local community. France is far more centralized and paternalistic in terms of the distribution of authority and decision-making in welfare and drug policy. Difficulties in cohabitation between local residents and PWID happened in both countries and can sometimes make public authorities hesitate to implement DCRs because of the NIMBY ("not in my backyard") phenomenon. However, the Danish and French case studies show that DCRs have the potential to become an instrument for civic cohabitation as well as to contribute to the destigmatization and health of PWID. (Am J Public Health. 2022;112(S2)S159-S165. https//doi.org/10.2105/AJPH.2022.306808).Objectives. To determine how harm reduction should be applied in low-resource countries such as Vietnam by exploring the perspectives of people who use drugs (PWUD), health care professionals, and policymakers regarding methadone treatment and harm reduction strategies. Methods. We conducted 2 qualitative studies in Vietnam between 2016 and 2021. We interviewed 62 PWUD and 22 experts in drug policy development and drug treatment programs, conducted observations at methadone clinics and harm reduction program meetings, and analyzed drug policy documents. Results. PWUD considered methadone treatment only as a transition to a drug-free life. Policymakers deemed harm reduction ineffective and continued to enforce arrest and incarceration of PWUD. Drug intervention programs are not yet geared to providing specialized services. Effective communication strategies and information on evidence-based harm reduction models are inadequate to help policymakers make the right decisions. Conclusions. Harm reduction principles have not been fully adopted in Vietnam. A harm reduction strategy based on a more humanistic approach that goes beyond a biomedicalized approach is urgently needed in Vietnam and other countries in the Global South. (Am J Public Health. 2022;112(S2)S182-S190. https//doi.org/10.2105/AJPH.2022.306764).Objectives. To elucidate a structurally oriented theoretical framework that considers legacies of racism, trauma, and social exclusion and to interrogate the "unmet obligations" of the institutionalization of the harm reduction infrastructure to provide equitable protections to Black and Latinx people who use drugs (PWUD) in Maryland. Methods. In 2019, we conducted a rapid ethnographic assessment of and qualitative interviews with PWUD (n = 72) and stakeholders (n = 85) in 5 Maryland counties. We assessed PWUD's experiences, service gaps in as well as barriers and facilitators to accessing services, and the potential to expand harm reduction programs. Results. The unmet obligations we found included enforcement and punitive governance of syringes, naloxone, and other drug use equipment; racism and racialization, social exclusion, and legacies of trauma; and differential implications of harm reduction for populations experiencing racialized criminalization. Conclusions. The implementation of harm reduction policies are a first step, but assessment of structural dynamics are needed for diverse communities with unique histories.