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Glucosamine-6-phosphate synthase (GlcN-6-P synthase) is known as a promising target for antimicrobial agents and antidiabetics. Several compounds of natural or synthetic origin have been identified as inhibitors of this enzyme. This set comprises highly selective l-glutamine, amino sugar phosphate or transition state intermediate cis-enolamine analogues. Relatively low antimicrobial activity of these inhibitors, poorly penetrating microbial cell membranes, has been improved using the pro-drug approach. On the other hand, a number of heterocyclic and polycyclic compounds demonstrating antimicrobial activity have been presented as putative inhibitors of the enzyme, based on the results of molecular docking to GlcN-6-P synthase matrix. The most active compounds of this group could be considered promising leads for development of novel antimicrobial drugs or antidiabetics, provided their selective toxicity is confirmed.

The CRISPR/Cas9 system is a powerful tool for studying gene function. Here, we describe a method that allows temporal control of CRISPR/Cas9 activity based on conditional Cas9 destabilization. We demonstrate that fusing an FKBP12-derived destabilizing domain to Cas9 (DD-Cas9) enables conditional Cas9 expression and temporal control of gene editing in the presence of an FKBP12 synthetic ligand. This system can be easily adapted to co-express, from the same promoter, DD-Cas9 with any other gene of interest without co-modulation of the latter. In particular, when co-expressed with inducible Cre-ER T2 , our system enables parallel, independent manipulation of alleles targeted by Cas9 and traditional recombinase with single-cell specificity. We anticipate this platform will be used for the systematic characterization and identification of essential genes, as well as the investigation of the interactions between functional genes. CRISPR/Cas9-based genome editing enables specific deletion of target genes. Here, Senturk et al . develop an inducible editing system by fusing a conditional destabilization domain to Cas9 and demonstrate temporal control of gene editing in response to a synthetic ligand.

Male circumcision has been shown to reduce the acquisition of the human immunodeficiency virus (HIV) in circumcised men. In two studies in Uganda involving 3393 adolescent boys and men who were seronegative for HIV and for herpes simplex virus type 2 (HSV-2), circumcision reduced the acquisition of HSV-2 and the prevalence of high-risk human papillomavirus (HPV) infection but not the acquisition of syphilis. In two studies in Uganda, circumcision reduced the acquisition of herpes simplex virus type 2 (HSV-2) and the prevalence of high-risk human papillomavirus (HPV) infection but not the acquisition of syphilis. Herpes simplex virus type 2 (HSV-2) and human papillomavirus (HPV) infections and syphilis are common sexually transmitted infections. HSV-2 infection and syphilis are two of the main causes of genital ulceration 1 – 3 and have been associated with an increased risk of human immunodeficiency virus (HIV) infection in observational studies. 1 , 2 , 4 The prevalence of HPV is significantly increased in developing nations. 5 HPV infection can cause genital warts, and high-risk HPV genotypes are associated with penile and anal cancer, as well as with cervical cancer in female partners. 5 , 6 Three randomized trials and multiple observational studies showed that male circumcision significantly . . .

Flexible intracerebral probes for neural recording and electrical stimulation have been the focus of many research works to achieve better compliance with the surrounding tissue while minimizing rejection. Strategies have been explored to find the best way to insert flexible probes into the brain while maintaining their flexibility once positioned. Here, we present a novel and versatile scalable batch fabrication approach to deliver ultrathin and flexible probes consisting of a silk-parylene bilayer. The biodegradable silk layer, whose degradation time is programmable, provides a temporary and programmable stiffener to allow the insertion of ultrathin parylene-based flexible devices. Our innovative and robust batch fabrication technology allows complete freedom over probe design in terms of materials, size, shape, and thickness. We demonstrate successful ex vivo insertion of the probe with acute high-fidelity recordings of epileptic seizures in field potentials as well as single-unit action potentials in mouse brain slices. Our novel technological solution for implanting ultraflexible devices in the brain while minimizing rejection risks shows high potential for use in both brain research and clinical therapies.

HIV pre-exposure prophylaxis (PrEP) significantly reduces the risk of HIV acquisition. However, studies have demonstrated discordance between self-reported measures and biomedical benchmarks of PrEP adherence. We estimated the correlation between self-reported PrEP adherence and PrEP biomarkers and explored factors associated with adherence among men who have sex with men (MSM) in Nigeria. TRUST-PrEP, an open-label, prospective study; conducted in Abuja between April 2018 and May 2019. MSM ≥ 18 years with substantial HIV risk were enrolled. Participants reported PrEP adherence in the last month using a 4-point scale from \"poor\" to \"perfect\" and serum samples for PrEP biomarkers were collected at months 3 and 9. Serum tenofovir concentration was measured by liquid chromatography-tandem mass spectrometry and considered protective for adherence if ≥ 4.2 ng/ml. Spearman's rank correlation was used to estimate correlation between self-reported adherence and measured tenofovir levels. Generalized estimating equations with a logit link was used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for associations between self-reported adherence and laboratory-measured adherence. A total of 219 MSM with median age 23 (interquartile range 20-27) years had at least one PrEP biomarker assay. Only 66/219 (30%) had at least one record of protective tenofovir concentration. Correlation between tenofovir and self-reported adherence at 3 and 9 months were 0.1 and 0.02 respectively. Furthermore, 17/219 (8%,) and 49/219 (22%) had serum tenofovir of 4.2-35.4 ng/mL and ≥ 35.5 ng/mL, corresponding to at least 4 and 7 days' PrEP use in a week, respectively. PrEP adherence was higher among participants introduced to PrEP in the clinics compared with communities (aOR: 8.35, 95%CI: [3.24, 21.5]) and those with same-sex practices family disclosure (aOR: 3.60 95% CI: [1.73, 7.51]). Self-reported PrEP adherence poorly correlated with biomarkers. Facilitating clinic-based PrEP introduction and disclosure of same-sex practices to family among MSM may improve PrEP adherence.

Controlling the electrical properties of SiC requires knowledge of the nature and properties of extended defects. We have employed orthodox defect-selective etching and photo-etching methods to reveal typical and new structural defects in commercial SiC wafers. For photo-etching, the etch rate increases as the free carrier concentration decreases. The etch rate can be used to estimate the free carrier concentration with higher precision, and over a larger lateral and depth range than that accessed by Raman scattering. The logarithmic dependence of the etch rate on the free carrier concentration has been characterized.

Psychiatrists play an important role in providing access to psychiatric electrical interventions (PEIs) such as electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS). As such, their views on these procedures likely influence whether they refer or provide these types of treatments for their clinically depressed patients. Despite this, scholars have too infrequently examined psychiatrists’ views about specific PEIs and have not yet examined their views across different PEIs. To gain insight into psychiatrists’ views about PEIs, we conducted a qualitative study based on semi-structured interviews with 16 psychiatrists in Michigan. The majority of psychiatrists had a positive attitude towards PEIs in general. One-third reported cautionary attitudes towards PEIs; they did not reject the interventions but were skeptical of their effectiveness or felt they needed further development. The majority of psychiatrists consider ECT and TMS to be viable therapies that they would discuss with their patients after several failed medication trials. There was a lack of knowledge about surgical PEIs, such as deep brain stimulation. This study provides insights into how psychiatrists perceive PEIs. While broadly positive attitudes exist, this research highlights certain challenges, particularly lack of knowledge and ambiguity about the use of PEIs.

Men who have sex with men (MSM) and transgender women (TGW) are at risk for sexually transmitted infections (STIs), including those of the oropharynx. We estimated the prevalence and factors associated with oral sex practices and characterized oropharyngeal STIs among a cohort of MSM and TGW in Nigeria. From 2013 to 2018, TRUST/RV368 recruited MSM and TGW into HIV/STI diagnosis and treatment at community-based clinics in Nigeria. Participants who completed HIV testing and oral sex questions at enrollment were selected. Cross-sectional analyses with bivariate and multivariable logistic regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs). Oropharyngeal swab testing for Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) began in 2014 and for those with diagnostic results at enrollment, the unadjusted association of oral sex practices with oropharyngeal STIs was conducted. A total of 1342 participants had a median age of 25 years (interquartile range: 22-29), 58% were living with HIV, and 69% reported oral sex practices. Factors associated with increased odds of engaging in oral sex included living with HIV (adjusted [a]OR: 1.4, 95% CI: 1.1-1.8), self-identifying as a woman (aOR:1.8, 95% CI: 1.1-2.8), mobile phone ownership (aOR:2.3, 95% CI: 1.3-3.9), receptive anal sex (aOR:1.7, 95% CI:1.3-2.3) and multiple male sexual partners (2 to 4 vs. ≤1, aOR:1.5, 95% CI: 1.0-2.2; 5+ vs ≤1, aOR:2.9, 95% CI:1.9-4.3). Oropharyngeal STI prevalence was 7% (52/752) and higher among those who engaged in oral sex compared to those who did not (unadjusted OR: 2.5, 95% CI:1.2-5.3). Oral sex was common and associated with an increased odds of oropharyngeal STIs among MSM and TGW from Nigeria. In the absence of screening and treatment guidelines, condoms continue to be the mainstay for oral STI prevention. A pre-exposure prophylaxis for bacterial STIs would complement current prevention strategies to curb transmission.

Background Early detection and treatment of anal precancer via high resolution anoscopy (HRA) is paramount to prevent anal cancer, particularly for populations at heightened risk like sexual minority men (SMM) living with HIV. Successful training and sustainability of cancer screening requires attention to local contexts, best captured by qualitative research. Using the Consolidated Framework for Implementation Research (CFIR), this study investigated factors that challenged or fostered learning and implementing HRA across a variety of stakeholder groups in Abuja, Nigeria. Methods Using in-depth qualitative methodology, nineteen semi-structured interviews were conducted in September 2023 with stakeholders - patients who underwent HRA, HRA providers, and health system representatives in Nigeria. Thematic analysis, guided by CFIR, was employed to identify key themes related to the barriers and facilitators to practicing HRA as guided by the International Anal Neoplasia Society. Results Eight themes were identified across three domains. Barriers included low knowledge and understanding of HRA, with participants explicitly noting the need for more research in low resource settings to garner local acceptance. Participants were concerned about financial costs for the clinic and the patients. Facilitators included organizational buy-in, SMM social networks, and a safe clinic environment to support HRA engagement. Facilitators important for sustainability included acceptance of the research evidence for HRA and recognition of the health benefits. Overall, participants from all stakeholder groups welcomed HRA as a new evidence-based intervention as part of HIV care services. Conclusions Our study highlighted the need for localized research, cultural sensitivity, and resource allocation to improve the adoption of HRA in a Nigerian HIV care setting. Organizational buy-in, community engagement, and safe healthcare environments facilitated trust and patient engagement and would promote long term sustainability. Overall, the study provided perspectives from various stakeholders that strengthen clinical proficiency and sustainability of anal cancer screening in Nigeria.

Genetically engineered mouse models (GEMMs) are important immunocompetent models for research into the roles of individual genes in cancer and the development of novel therapies. Here we use inducible CRISPR-Cas9 systems to develop two GEMMs which aim to model the extensive chromosome p3 deletion frequently observed in clear cell renal cell carcinoma (ccRCC). We cloned paired guide RNAs targeting early exons of Bap1 , Pbrm1 , and Setd2 in a construct containing a Cas9 D10A (nickase, hSpCsn1n) driven by tetracycline (tet)-responsive elements (TRE3G) to develop our first GEMM. The founder mouse was crossed with two previously established transgenic lines, one carrying the tet-transactivator (tTA, Tet-Off) and one with a triple-mutant stabilized HIF1A-M3 (TRAnsgenic Cancer of the Kidney, TRACK), both driven by a truncated, proximal tubule-specific γ-glutamyltransferase 1 (ggt or γGT) promoter, to create triple-transgenic animals. Our results indicate that this model (BPS-TA) induces low numbers of somatic mutations in Bap1 and Pbrm1 (but not in Setd2), known tumor suppressor genes in human ccRCC. These mutations, largely restricted to kidneys and testis, induced no detectable tissue transformation in a cohort of 13 month old mice (N = 10). To gain insights into the low frequencies of insertions and deletions (indels) in BPS-TA mice we analyzed wild type (WT, N = 7) and BPS-TA (N = 4) kidneys by RNAseq. This showed activation of both DNA damage and immune response, suggesting activation of tumor suppressive mechanisms in response to genome editing. We then modified our approach by generating a second model in which a ggt-driven, cre-regulated Cas9 WT (hSpCsn1) was employed to introduce Bap1 , Pbrm1 , and Setd2 genome edits in the TRACK line (BPS-Cre). The BPS-TA and BPS-Cre lines are both tightly controlled in a spatiotemporal manner with doxycycline (dox) and tamoxifen (tam), respectively. In addition, whereas the BPS-TA line relies on paired guide RNAs (gRNAs), the BPS-Cre line requires only single gRNAs for gene perturbation. In the BPS-Cre we identified increased Pbrm1 gene-editing frequencies compared to the BPS-TA model. Whereas we did not detect Setd2 edits in the BPS-TA kidneys, we found extensive editing of Setd2 in the BPS-Cre model. Bap1 editing efficiencies were comparable between the two models. Although no gross malignancies were observed in our study, this is the first reported GEMM which models the extensive chromosome 3p deletion frequently observed in kidney cancer patients. Further studies are required (1) to model more extensive 3p deletions, e.g. impacting additional genes, and (2) to increase the cellular resolution, e.g. by employing single-cell RNAseq to ascertain the effects of specific combinatorial gene inactivation.