Structure of the human inner kinetochore CCAN complex and its significance for human centromere organization.

Centromeres are specialized chromosome loci that seed the kinetochore, a large protein complex that effects chromosome segregation. A 16-subunit complex, the constitutive centromere associated network (CCAN), connects between the specialized centromeric chromatin, marked by the histone H3 variant CENP-A, and the spindle-binding moiety of the kinetochore. Here, we report a cryo-electron microscopy structure of human CCAN. We highlight unique features such as the pseudo GTPase CENP-M and report how a crucial CENP-C motif binds the CENP-LN complex. The CCAN structure has implications for the mechanism of specific recognition of the CENP-A nucleosome. A model consistent with our structure depicts the CENP-C-bound nucleosome as connected to the CCAN through extended, flexible regions of CENP-C. An alternative model identifies both CENP-C and CENP-N as specificity determinants but requires CENP-N to bind CENP-A in a mode distinct from the classical nucleosome octamer.

Dynamics of circulating lymphocytes responding to human experimental enterotoxigenic Escherichia coli infection.

Enterotoxigenic Escherichia coli (ETEC) is an important cause of children's and travelers' diarrhea, with no licensed vaccine. This study aimed to explore the role of cellular immunity in protection against human ETEC infection. Nine volunteers were experimentally infected with ETEC, of which six developed diarrhea. Lymphocytes were collected from peripheral blood buffy coats, before and 3, 5, 6, 7, 10, and 28 days after dose ingestion, and 34 phenotypic and functional markers were examined by mass cytometry. Thirty-three cell populations, derived by manually merging 139 cell clusters from the X-shift unsupervised clustering algorithm, were analyzed. Initially, the diarrhea group responded with increased CD56dim CD16+ natural killer cells, dendritic cells tended to rise, and mucosal-associated invariant T cells decreased. On day 5-7, an increase in plasmablasts was paralleled by a consistent rise in CD4+ Th17-like effector memory and regulatory cell subsets. CD4+ Th17-like central memory cells peaked on day 10. All Th17-like cell populations showed increased expression of activation, gut-homing, and proliferation markers. Interestingly, in the nondiarrhea group, these same CD4+ Th17-like cell populations expanded earlier, normalizing around day 7. Earlier development of these CD4+ Th17-like cell populations in the nondiarrhea group may suggest a recall response and a potential role in controlling ETEC infections.

A simple scoring algorithm based on intrinsic capacity for functional ability in community-dwelling older adults in Taiwan.

BACKGROUND: Intrinsic capacity (IC) is a comprehensive indicator of the overall well-being of older adults, and assessing of IC can help identify early stage of disability and tailor intervention to individual needs. However, there is a lack of effective and simple IC assessment tools. This study aimed to establish predictive scoring algorithms of IC to identify older adults at high risk of impaired functional ability. METHODS: We conducted a cross-sectional study in Southern Taiwan, measuring IC using 7 subitems: cognition, locomotion, vitality, vision, hearing, psychological well-being, and medication usage were measured. Functional ability outcomes included frailty, basic activities of daily living, and instrumental activities of daily living (IADL). The capability of 7 domains of IC in predicting functional ability was assessed by multivariable logistic regression. The prediction of capability of scoring algorithms was indicated by receiver operating characteristic (AUC) curves and measures of sensitivity and specificity. RESULTS: A total of 1,152 older adults were recruited and analyzed. Locomotion emerged as a significant predictor of IADL disability and worsening frailty. The IC-based weighted scoring algorism for predicting IADL demonstrated satisfactory capability (AUC: 0.80), as did the algorithm for predicting worsening frailty (AUC: 0.90). The optimal cutoff points for predicting IADL disability and frailty worse were estimated respectively at 13 and 16, with sensitivity/specificity values of 0.74/0.75 for the IADL prediction algorithm and 0.92/0.77 for the frailty prediction algorithm. CONCLUSION: Our 7-domain IC screening tool proves to be sensitive and practical for early identification of functional disability and frailty among community-dwelling older adults in Taiwan.

Inter-rater variability and repeatability in the assessment of the Tanner-Whitehouse classification of hand radiographs for the estimation of bone age.

OBJECTIVE: To determine which bones and which grades had the highest inter-rater variability when employing the Tanner-Whitehouse (T-W) method. MATERIALS AND METHODS: Twenty-four radiologists were recruited and trained in the T-W classification of skeletal development. The consistency and skill of the radiologists in determining bone development status were assessed using 20 pediatric hand radiographs of children aged 1 to 18 years old. Four radiologists had a poor concordance rate and were excluded. The remaining 20 radiologists undertook a repeat reading of the radiographs, and their results were analyzed by comparing them with the mean assessment of two senior experts as the reference standard. Concordance rate, scoring, and Kendall's W were calculated to evaluate accuracy and consistency. RESULTS: Both the radius, ulna, and short finger (RUS) system (Kendall's W = 0.833) and the carpal (C) system (Kendall's W = 0.944) had excellent consistency, with the RUS system outperforming the C system in terms of scores. The repeatability analysis showed that the second rating test, performed after 2 months of further bone age assessment (BAA) practice, was more consistent and accurate than the first. The capitate had the lowest average concordance rate and scoring, as well as the lowest overall concordance rate for its D classification. Moreover, the G classifications of the seven carpal bones all had a concordance rate less than 0.6. The bones with lower Kendall's W were likewise those with lower scores and concordance rates. CONCLUSION: The D grade of the capitate showed the highest variation, and the use of the Tanner-Whitehouse 3rd edition (T-W3) to determine bone age (BA) was frequently inconsistent. A more comprehensive description with a focus on inaccuracy bones or ratings and a modification to the T-W3 approach would significantly advance BAA.

Reliability of the Assessment of Tooth Wear Severity on Dental Hard Tissues and Dental Restorations, Using the TWES 2.0, by Nonexperts.

BACKGROUND: Tooth wear is a multifactorial process resulting in the loss of dental hard tissues. For its assessment, the tooth wear evaluation system (TWES) 2.0 has been published. Previous studies on the TWES involved well-trained practitioners, rather than nonexperts. OBJECTIVE: The first aim of this study was to investigate the reliability of the assessment of tooth wear severity on dental hard tissues, using the TWES 2.0, by nonexperts. The second aim was to investigate the reliability of assessment of wear severity on dental restorations, using a third scale. METHODS: Forty-seven dental students evaluated at least 9 of 14 possible patient cases on dental casts and intraoral photographs. Cohen's kappa (agreement with sample solution) and Fleiss' kappa (Inter-rater reliability) were calculated. RESULTS: The agreements of the operators' ratings compared to the sample-solution resulted in Cohen's kappa between 0.02 and 0.9. The agreements were 0.34 for occlusal; 0.43 for vestibular; 0.57 for oral surfaces. Inter-rater reliability (Fleiss' kappa) was 0.35 for occlusal, 0.17 for vestibular and 0.24 for oral assessment. The inter-rater reliability of the ratings on tooth surfaces with restorations was lower with 0.21 (occlusal), 0.14 (vestibular) and 0.39 (oral). The agreement on different restorations differed tremendously. CONCLUSIONS: The ability to correctly assess the cases varied considerably between individual examiners. Within the limits of this study, assessment of restorations was slightly more challenging compared to natural teeth, particularly in occlusal regions or when the restorative material is gold. Subsequent studies should address whether enhanced training and improved definition of tooth wear grades result in higher reliability scores.

Novel citrinin derivatives from fungus Penicillium sp. TW131-64 and their antimicrobial activities.

Six new citrinin derivatives (1, 2, 4, 10, 11, and 16), along with fourteen known analogues, were acquired from Penicillium sp. TW131-64, a marine-derived fungus strain. The chemical structures of new compounds were identified through adopting various spectroscopic methods in combination with X-ray diffraction technology and comparison of the experimental electronic circular dichroism (ECD) with calculated ones. Among them, compounds 1-4 were nitrogen-containing citrinin derivatives existing in enantiomers which were resolved by chiral chromatography. A putative biosynthetic pathway for compounds 1-4 was proposed. Additionally, the antimicrobial activities of these compounds were detected by the broth microdilution assays. Citrinin derivatives 1, 2, 4 and their corresponding enantiomers (1a, 2a, 4a, 1b, 2b, and 4b) exhibited potent antimicrobial activities towards Helicobacter pylori standard strains and multidrug-resistant strains (MIC values ranging from 0.25 to 8 µg/mL), which were comparable or even better than metronidazole. Moreover, compounds 1a and 1b also showed remarkable broad antimicrobial effects towards Staphylococcus aureus, Enterococcus faecalis, methicillin-resistant Staphylococcus aureus (MRSA), Bacillus subtilis, vancomycin-resistant Enterococcus faecium (VRE), and Candida albicans. In summary, our studies demonstrated that citrinin enantiomers 1a-4a and 1b-4b, especially 1a and 1b, can be lead compounds in the research and development (R & D) of novel antimicrobial drugs. KEY POINTS: • 3 novel nitrogen-containing citrinin derivatives (1, 2, 4) were isolated. • citrinin derivatives 1-4 in enantiomers were resolved by chiral chromatography. • citrinin derivatives 1a and 1b showed broad and significant antimicrobial effects.

Non-uptake of HIV testing among trans men and trans women: cross-sectional study of client records from 2017 to 2019 in a community-based transgender health center in Metro Manila, Philippines.

BACKGROUND: Transgender individuals are considered at high risk of contracting HIV infection. Integrating HIV testing and counseling (HTC) services into current transgender health programs is necessary to increase its uptake. Our study aimed to describe the characteristics of trans men (TM) and trans women (TW) who accessed HTC services in a community-based transgender health center in Metro Manila, Philippines, and to examine the relationship between gender identity and their non-uptake of HIV testing.  METHODS: We conducted a cross-sectional study of TM and TW seeking care from 2017 to 2019. Medical records of clients were reviewed to ascertain their age, gender identity, year and frequency of clinic visits, lifestyle factors, and non-uptake of HIV testing. The effect of gender identity on the non-uptake of HIV testing was estimated using a generalized linear model with Poisson distribution, log link function, and a robust variance, adjusted for confounding variables.  RESULTS: Five hundred twenty-five clients were included in the study, of which about 82.3% (432/525) of the clients declined the HTC services being offered. In addition, the prevalence of non-uptake of HIV testing was 48% higher (Adjusted Prevalence Ratio: 1.48; 95% Confidence Interval: 1.31-1.67) among TM compared to TW. Approximately 3.7% (1/27) and 10.6% (7/66) of the TM and TW, respectively, who accessed the HTC services were reactive. Moreover, most reactive clients were on treatment 87.5% (7/8); three were already virally suppressed, four were on ART but not yet virally suppressed, and one TW client was lost to follow up. CONCLUSION: The non-uptake of HTC service of TM and TW is high. HIV program implementers should strategize solutions to reach this vulnerable population for increased and better HTC service uptake and linkage to care.

Two New Prenylated Glycine Derivatives from the Marine-Derived Fungus Fusarium sp. TW56-10.

Two new prenylated glycine derivatives N-({4-[(3-methylbut-2-en-1-yl)oxy]phenyl}acetyl)glycine (1) and methyl N-({4-[(3-methylbut-2-en-1-yl)oxy]phenyl}acetyl)glycinate (2), along with nine known compounds (3-11) were purified from the marine-derived fungus Fusarium sp. TW56-10. Their chemical structures were determined by spectroscopic evidence, including extensive nuclear magnetic resonance (NMR), high-resolution electrospray ionization mass spectroscopy (HR-ESI-MS) data, infrared radiation (IR) and Ultraviolet spectra (UV). Compound 4 (8-O-methylfusarubin) exhibited cytotoxic activity with IC50 value of 11.45 µM for A549 cells.

Melatonin Is Neuroprotective in Escherichia coli Meningitis Depending on Intestinal Microbiota.

Avian meningitis Escherichia coli (E. coli) can cause acute bacterial meningitis which threatens poultry health, causes great economic losses in the poultry industry, and has recently been speculated as a potential zoonotic pathogen. Melatonin can counteract bacterial meningitis-induced disruption of the blood-brain barrier (BBB), neuroinflammation, and reduce mortality. There are increasing data showing that melatonin's beneficial effects on bacterial meningitis are associated with intestinal microbiota. In this study, our data showed that melatonin alleviated neurological symptoms, enhanced survival rate, protected the integrity of the BBB, reduced the bacterial load in various tissues and blood, and inhibited inflammation and neutrophil infiltration of brain tissue in an APEC TW-XM-meningitis mice model. The results of 16S rRNA showed that melatonin pretreatment significantly maintained the composition of intestinal microbiota in APEC-meningitis mice. The abundance and diversity of intestinal microbiota were disturbed in APEC TW-XM-meningitis mice, with a decreased ratio of Firmicutes to Bacteroides and an increased the abundance of Proteobacteria. Melatonin pretreatment could significantly improve the composition and abundance of harmful bacteria and alleviate the decreased abundance of beneficial bacteria. Importantly, melatonin failed to affect the meningitis neurologic symptoms caused by APEC TW-XM infection in antibiotic-pretreated mice. In conclusion, the results suggest that melatonin can effectively prevent meningitis induced by APEC TW-XM infection in mice, depending on the intestinal microbiota. This finding is helpful to further explore the specific target mechanism of melatonin-mediated intestinal microbiota in the prevention of and protection against Escherichia coli meningitis.

METCAM/MUC18 Plays a Tumor Suppressor Role in the Development of Nasopharyngeal Carcinoma Type I.

From previous studies of negatively correlating the expression of human METCAM/MUC18 with the pathology of nasopharyngeal carcinoma (NPC), we have suggested that human METCAM/MUC18 (huMETCAM/MUC18) might play a tumor suppressor role in the development of nasopharyngeal carcinoma. To scrutinize this hypothesis, we investigated the effects of huMETCAM/MUC18's over-expression on in vitro cellular behavior and on the in vivo tumorigenesis of one NPC cell line (NPC-TW01). HuMETCAM/MUC18 cDNA was first transfected into the NPC-TW01 cell line, which was established from NPC type I, and many G418-resistant clones were obtained. Then, two NPC-TW01 clones, which expressed high and medium levels of huMETCAM/MUC18, respectively, and one empty vector (control) clone were used to test the effects of huMETCAM/MUC18's over-expression on in vitro behaviors and on in vivo tumorigenesis (via subcutaneous injection) in athymic nude mice (Balb/cAnN.Cg-Foxnlnu/Cr1Nar1). The time course of tumor proliferation and the final tumor weights were determined. Tumor sections were used for the histology and immunohistochemistry (IHC) studies. Tumor lysates were used for determining the expression levels of huMETCAM/MUC18 and various downstream key effectors. HuMETCAM/MUC18's over-expression reduced in vitro motility and invasiveness and altered growth behaviors in 3D basement membrane culture assays, and it decreased the in vivo tumorigenicity of the NPC-TW01 cells. The tumor cells from a high-expressing clone were clustered and confined in small areas, whereas those from a vector control clone were more spread out, suggesting that the tumor cells from the high-expressing clone appeared to stay dormant in micro-clusters. Expression levels of the proliferation index, an index of the metabolic switch to aerobic glycolysis, angiogenesis indexes, and survival pathway indexes were reduced, whereas the pro-apoptosis index increased in the corresponding tumors. The over-expression of huMETCAM/MUC18 in the NPC-TW01 cells decreased the epithelial-to-mesenchymal transition and the in vitro and in vitro tumorigenesis, suggesting that it plays a tumor suppressor role in the development of type I NPC, perhaps by increasing apoptosis and decreasing angiogenesis, proliferation, and the metabolic switch to aerobic glycolysis.

Effect of trickling filter on carbon and nitrogen removal in vertical flow treatment wetlands: A full-scale investigation.

Vertical Flow Treatment Wetland (VF-TW) systems achieve high efficiencies in terms of carbon related parameters removals from domestic wastewaters. Nitrogen removal is also efficient but optimisations are still needed. This article reports and discusses experimental data collected from 24-h monitoring campaigns of 29 full-scale VF-TWs, having different configurations and operation time up to 13 years. All monitored systems gathered 1 or 2 stage(s) of unsaturated or partially saturated VF-TW. Additionally, some of those included an aerobic biological Tricking Filter (TF) prior to TW stage(s). Results firstly showed that the implementation of a TF improved TSS, COD and BOD5 removal rates in the monitored systems. Regarding nitrogen removal, the association of TF with one stage of partially saturated vertical TW was found to achieve around 79% of nitrification in average and up to 92% in some cases. In the configurations where TF was associated to 2 successive stages of TW, almost all total nitrogen removal by nitrification/denitrification was achieved at the outlet of the first-stage TW. The contribution of the second-stage TW in denitrification was found very low due to limited availability of organic carbon to support heterotrophic denitrification. Specific solutions to enhance the contribution of the second stage in the denitrification process are discussed.

Application of Quality by Design to the robust preparation of a liposomal GLA formulation by DELOS-susp method.

Fabry disease is a lysosomal storage disease arising from a deficiency of the enzyme α-galactosidase A (GLA). The enzyme deficiency results in an accumulation of glycolipids, which over time, leads to cardiovascular, cerebrovascular, and renal disease, ultimately leading to death in the fourth or fifth decade of life. Currently, lysosomal storage disorders are treated by enzyme replacement therapy (ERT) through the direct administration of the missing enzyme to the patients. In view of their advantages as drug delivery systems, liposomes are increasingly being researched and utilized in the pharmaceutical, food and cosmetic industries, but one of the main barriers to market is their scalability. Depressurization of an Expanded Liquid Organic Solution into aqueous solution (DELOS-susp) is a compressed fluid-based method that allows the reproducible and scalable production of nanovesicular systems with remarkable physicochemical characteristics, in terms of homogeneity, morphology, and particle size. The objective of this work was to optimize and reach a suitable formulation for in vivo preclinical studies by implementing a Quality by Design (QbD) approach, a methodology recommended by the FDA and the EMA to develop robust drug manufacturing and control methods, to the preparation of α-galactosidase-loaded nanoliposomes (nanoGLA) for the treatment of Fabry disease. Through a risk analysis and a Design of Experiments (DoE), we obtained the Design Space in which GLA concentration and lipid concentration were found as critical parameters for achieving a stable nanoformulation. This Design Space allowed the optimization of the process to produce a nanoformulation suitable for in vivo preclinical testing.

Status Set Sequential Pattern Mining Considering Time Windows and Periodic Analysis of Patterns.

The traditional sequential pattern mining method is carried out considering the whole time period and often ignores the sequential patterns that only occur in local time windows, as well as possible periodicity. Therefore, in order to overcome the limitations of traditional methods, this paper proposes status set sequential pattern mining with time windows (SSPMTW). In contrast to traditional methods, the item status is considered, and time windows, minimum confidence, minimum coverage, minimum factor set ratios and other constraints are added to mine more valuable rules in local time windows. The periodicity of these rules is also analyzed. According to the proposed method, this paper improves the Apriori algorithm, proposes the TW-Apriori algorithm, and explains the basic idea of the algorithm. Then, the feasibility, validity and efficiency of the proposed method and algorithm are verified by small-scale and large-scale examples. In a large-scale numerical example solution, the influence of various constraints on the mining results is analyzed. Finally, the solution results of SSPM and SSPMTW are compared and analyzed, and it is suggested that SSPMTW can excavate the laws existing in local time windows and analyze the periodicity of the laws, which solves the problem of SSPM ignoring the laws existing in local time windows and overcomes the limitations of traditional sequential pattern mining algorithms. In addition, the rules mined by SSPMTW reduce the entropy of the system.

Cryptotanshinone chemosensitivity potentiation by TW-37 in human oral cancer cell lines by targeting STAT3-Mcl-1 signaling.

BACKGROUND: Despite being one of the leading cancer types in the world, the diagnosis of oral cancer and its suitable therapeutic options remain limited. This study aims to investigate the single and chemosensitizing effects of TW-37, a BH3 mimetic in oral cancer, on human oral cancer cell lines. METHODS: We assessed the single and chemosensitizing effects of TW-37 in vitro using trypan blue exclusion assay, Western blotting, DAPI staining, Annexin V-FITC/PI double staining, and quantitative real-time PCR. Mcl-1 overexpression models were established by transforming vector and transient transfection was performed to test for apoptosis. RESULTS: TW-37 enhanced the cytotoxicity of human oral cancer cell lines by inducing caspase-dependent apoptosis, which correlates with the reduction of the myeloid cell leukemia-1 (Mcl-1) expression via transcriptional and post-translational regulation. The ectopic expression of Mcl-1 partially attenuated the apoptosis-inducing capacity of TW-37 in human oral cancer cell lines. Besides, TW-37 decreased the phosphorylation of signal transducer and activator of transcription 3 (STAT3) at Tyr705 and nuclear translocation in human oral cancer cell lines at the early time points. Furthermore, TW-37 potentiated chemosusceptibility of cryptotanshinone in human oral cancer cell lines by suppressing STAT3-Mcl-1 signaling compared with either TW-37 or cryptotanshinone alone, resulting in potent apoptosis. CONCLUSIONS: This study not only unravels the single and chemosensitizing effects of TW-37 for treatment of human oral cancer but also highlights the likelihood of TW-37 as a good therapeutic strategy to enhance the prognosis of patients with oral cancer in the future.

Evaluation of the reproductive system development and egg-laying performance of hens infected with TW I-type infectious bronchitis virus.

The prevalence of TW I-type infectious bronchitis virus (IBV) has been increasing rapidly, and it has become the second most common genotype of IBV in China threatening the poultry industry. In this study, 1-day-old specific-pathogen-free (SPF) chickens infected with TW I-type IBV were continuously observed for 200 days. TW I-type IBV affected the respiratory, urinary, and female reproductive systems, resulting in a mortality rate of 10% as well as a decrease in egg quantity and an increase in inferior eggs. During the monitoring period, serious lesions occurred in the female reproductive system, such as yolk peritonitis, a shortened oviduct, and cysts of different sizes with effusion in the degenerated right oviduct. The infective viruses persisted in vivo for a long time, and due to the stress of laying, virus shedding was detected again after the onset of egg production. Our findings suggest that TW I-type IBV is deadly to chickens and could cause permanent damage to the oviduct, resulting in the poor laying performance of female survivors and decreasing the breeding value and welfare of the infected flock.

Intimate Partner Violence Against Transgender Women: Prevalence and Correlates in Lima, Peru (2016-2018).

Limited data exists on intimate partner violence (IPV) among transgender women (TW), though global trends suggest IPV is associated with HIV risk in this population. We describe the prevalence of verbal, physical, and/or sexual violence as well as participant- and partner-level correlates of IPV among TW in Lima, Peru. Among 389 respondents, 15.2% reported IPV with one or more of their last three sexual partners: 9.2% verbal, 8.2% physical, and 2.3% sexual violence. Physical and verbal violence were more common with stable partners (aPR 3.46, 95% CI 1.17-10.25, aPR 2.46, 95% CI 1.14-5.28, respectively). Physical violence was associated with condomless receptive anal intercourse (cRAI) (aPR 2.22, 95% CI 1.19-4.13) and partner alcohol use (aPR 4.38, 95% CI 1.56-12.33) while verbal violence correlated with participant inebriation (aPR 4.86, 95% CI 1.63-14.46). Our results link IPV with stable partnerships, alcohol use, and cRAI, suggesting TW in Peru may benefit from multidimensional IPV prevention strategies to foster supportive relationships and reduce HIV transmission.

Personalized Cognitive Counseling Reduces Drinking Expectancy Among Men Who Have Sex with Men and Transgender Women in Lima, Peru: A Pilot Randomized Controlled Trial.

Personalized cognitive counseling (PCC) is an evidence-based intervention designed to modify HIV-related risk behavior. We assessed the impact of PCC on sexual behavior, drinking expectancy, and incidence of sexually transmitted infections (STIs) in a 6-month randomized controlled trial among 153 HIV-uninfected men who have sex with men (MSM) and transgender women (TW) in Peru. Study retention was ≥ 90%, with three HIV infections (3 Control) and 19 cases of GC/CT (10 Control, 9 PCC) at 6 months. There was a decline in condomless receptive anal intercourse in the Control (0.74, 95% CI 0.60-0.91; p < 0.01) and PCC arms (0.72, 0.55-0.94; p = 0.02) at 6-month follow-up. There was a decrease in drinking expectancy at 6 months among participants endorsing alcohol use in the PCC arm (0.89, 0.83-0.96; p < 0.01), versus no change in the Control arm (0.98, 0.92-1.04; p = 0.54). PCC was efficacious in reducing drinking expectancy and HIV risk among MSM and TW in Peru.

RESUMEN: La consejería cognitiva personalizada (CCP) es una intervención basada en evidencia diseñada para poder modificar el comportamiento asociado con el riesgo de contraer VIH. Evaluamos el impacto de CCP en el compartimiento sexual, el drinking expectancy, y la incidencia de infecciones de transmisión sexual (ITS) a través de un estudio controlado aleatorio que duró seis meses e incluyó 153 hombres sin VIH que tienen relaciones sexuales con hombres (HSH) y mujeres transgéneros (MT) en Perú. La retención en el estudio fue ≥90%, con tres infecciones de VIH (3 Control) y 19 casos de GC/CT (10 Control, 9 CCP) a los seis meses. Hubo una disminución de las relaciones sexuales receptivas sin preservativos dentro del grupo Control (0.74, 95% CI: 0.60-0.91; p<0.01) y el grupo CCP (0.72, 0.55-0.94; p=0.02) a los seis meses. También hubo una disminución en el drinking expectancy a los seis meses dentro de los participantes quienes tomaban alcohol dentro del grupo CCP (0.89, 0.83-0.96; p<0.01), versus ningún cambio dentro del grupo Control (0.98, 0.92-1.04; p=0.54). La CCP fue eficaz en disminuir el drinking expectancy y el riesgo de contraer VIH dentro de HSH y MT en Perú.

High-Risk, but Hidden: Binge Drinking among Men Who Have Sex with Men and Transgender Women in Lima, Peru, 2012-2014.

Background: Binge drinking (BD) is common in Peru, but may not be routinely detected by standard assessments of hazardous drinking. Objectives: We describe prevalence and risk behaviors of men who have sex with men (MSM) and transgender women (TW) in Peru who met criteria for BD as compared with those who met criteria for hazardous drinking. Methods: In a cross-sectional sample of MSM and TW from Lima (2012-2014), we calculated prevalence of BD (consuming ≥6 alcoholic drinks per occasion by AUDIT-3 criteria), conducted bivariate analyses of associations of BD with demographic and behavioral characteristics, and compared prevalence and behaviors of BD to those of hazardous drinkers (identified by AUDIT-10 criteria). Results: Of 1,520 MSM (n = 1,384) and TW (n = 137) with median age 27 years, 74.4% of MSM and 86.9% of TW met criteria for BD. Among MSM, BD was associated with a greater likelihood of using alcohol (41.6% vs. 13.8%; p < .01) or drugs (7.8% vs. 2.8%; p < .01) prior to a recent sexual contact. Among TW, BD was associated with greater frequency of alcohol use (44.9% vs. 11.1%; p < .01) or unprotected anal intercourse (58.8% vs. 33.3%; p = .04) during ≥1 of their three most recent sexual contacts. There was a higher prevalence of BD (75.5%) than hazardous drinking (53.2%) in our sample, with binge drinkers exhibiting similar sexual risk behaviors to hazardous drinkers. Conclusions: Binge drinking is common among MSM and TW in Lima, associated with risky sexual behavior, and may not be adequately captured by AUDIT-10 criteria.

The small molecule Bcl-2/Mcl-1 inhibitor TW-37 shows single-agent cytotoxicity in neuroblastoma cell lines.

BACKGROUND: High-risk neuroblastoma with N-Myc amplification remains a therapeutic challenge in paediatric oncology. Antagonism of pro-death Bcl-2 homology (BH) proteins to pro-survival BH members such as Mcl-1 and Bcl-2 has become a treatment approach, but previous studies suggest that a combined inhibition of Bcl-2 and Mcl-1 is necessary. TW-37 inhibits Mcl-1 and Bcl-2 with almost the same affinity. However, single-agent cytotoxicity of TW-37 in neuroblastoma cell lines has not been investigated. METHODS: Cell viability, apoptosis, proliferation and changes in growth properties were determined in SKNAS, IMR-5, SY5Y and Kelly cells after treatment with TW-37. After transfection with Mcl-1 or Bcl-2 siRNA, apoptosis and proliferation were investigated in Kelly cells. Mice with Kelly cell line xenografts were treated with TW-37 and tumor growth, survival and apoptosis were determined. RESULTS: Cell lines with N-Myc amplification were more sensitive to TW-37 treatment, IC50 values for IMR-5 and Kelly cells being 0.28 µM and 0.22 µM, compared to SY5Y cells and SKNAS cells (IC50 0.96 µM and 0.83 µM). Treatment with TW-37 resulted in increased apoptosis and reduced proliferation rates, especially in IMR5 and Kelly cells. Bcl-2 as well as Mcl-1 knockdown induced apoptosis in Kelly cells. TW-37 led to a decrease in tumor growth and a favorable survival (p = 0.0379) in a Kelly neuroblastoma xenografts mouse model. CONCLUSION: TW-37 has strong single-agent cytotoxicity in vitro and in vivo. Therefore, combined inhibition of Bcl-2/Mcl-1 by TW-37 in N-Myc amplified neuroblastoma may represent an interesting therapeutic strategy.

Antibacterial activity against drug-resistant microbial pathogens of cytochalasan alkaloids from the arthropod-associated fungus Chaetomium globosum TW1-1.

By feeding 1-methyl-l-tryptophan (1-MT) into cultures of the arthropod-associated fungus Chaetomium globosum TW1-1, three novel cytochalasan alkaloids, termed as armochaetoglosins A-C (1-3), together with five known analogues, namely prochaetoglobosin I (4), chaetoglobosin T (5), chaetoglobosin C (6), armochaetoglobin Y (7), and chaetoglobosin Vb (8), were isolated and characterized. Their structures including absolute configurations were elucidated by means of NMR spectroscopy, single-crystal X-ray crystallography, and comparison of the experimental electronic circular dichroism (ECD) spectra. Structurally, compounds 1-3 represented the first examples of 1'-N-methyl-chaetoglobosins, which were possibly biosynthesized from the additive 1-MT rather than tryptophan. Additionally, compound 3 showed the highest antibacterial activity against K. pneumoniae and ESBL-E. coli with MIC values of 4.0 µg/mL and 16.0 µg/mL, respectively, wherein the inhibitory effect of 3 against K. pneumoniae was stronger than that of the clinically used antibiotic meropenem, with an MIC value of 8 µg/mL. Our findings may provide new chemical templates for the development of new antibacterial agents against drug-resistant microbial pathogens.