IL-10 indirectly modulates functional activity of CD4+CD28null T-lymphocytes through LFA-3 and HLA class II inhibition.

Expansion of CD4+CD28null T-lymphocytes is common in chronic heart failure (CHF) patients. Its ability to produce high levels of proinflammatory cytokines is probably the key role of these cells in CHF. IL-10 is a candidate for limiting CD4+CD28null T-lymphocyte responses, whereas tumour necrosis factor (TNF) is the cytokine most closely involved in the loss of CD28 expression. Serum levels of TNF and IL-10 were measured in 65 CHF patients (mean age, 65.2 ± 13.84 years). Patients with an IL-10/TNF ratio ≥1 had significantly lower levels of CD4+CD28null T-lymphocytes than those with a ratio <1. In vitro, IL-10 reduced the frequency of proliferative CD4+CD28null T-lymphocytes stimulated with anti-CD3. Pre-treatment with IL-10 before anti-CD3 stimulation was required for the cytokine to inhibit TNF production by CD4+CD28null T-lymphocytes. In addition to the previously described effect of IL-10 on HLA-DR and ICAM-1 expression, LFA-3 protein and mRNA levels were reduced in the presence of the cytokine in monocytes. IL-10 inhibition on CD4+CD28null T-lymphocytes may be mediated by a reduction in HLA class II and LFA-3 expression because blocking interactions with these costimulators has similar effects to those of IL-10 treatment. Moreover, costimulation through CD2/LFA-3 interaction is enough to induce proliferation and cytokine production in CD4+CD28null T-lymphocytes.

Peroxisomes during postnatal development of mouse endocrine and exocrine pancreas display cell-type- and stage-specific protein composition.

Peroxisomal dysfunction unhinges cellular metabolism by causing the accumulation of toxic metabolic intermediates (e.g. reactive oxygen species, very -chain fatty acids, phytanic acid or eicosanoids) and the depletion of important lipid products (e.g. plasmalogens, polyunsaturated fatty acids), leading to various proinflammatory and devastating pathophysiological conditions like metabolic syndrome and age-related diseases including diabetes. Because the peroxisomal antioxidative marker enzyme catalase is low abundant in Langerhans islet cells, peroxisomes were considered scarcely present in the endocrine pancreas. Recently, studies demonstrated that the peroxisomal metabolism is relevant for pancreatic cell functionality. During the postnatal period, significant changes occur in the cell structure and the metabolism to trigger the final maturation of the pancreas, including cell proliferation, regulation of energy metabolism, and activation of signalling pathways. Our aim in this study was to (i) morphometrically analyse the density of peroxisomes in mouse endocrine versus exocrine pancreas and (ii) investigate how the distribution and the abundance of peroxisomal proteins involved in biogenesis, antioxidative defence and fatty acid metabolism change during pancreatic maturation in the postnatal period. Our results prove that endocrine and exocrine pancreatic cells contain high amounts of peroxisomes with heterogeneous protein content indicating that distinct endocrine and exocrine cell types require a specific set of peroxisomal proteins depending on their individual physiological functions. We further show that significant postnatal changes occur in the peroxisomal compartment of different pancreatic cells that are most probably relevant for the metabolic maturation and differentiation of the pancreas during the development from birth to adulthood.

Facemask analyses for the non-invasive detection of chronic and acute P. aeruginosa lung infections using nanoparticle-based immunoassays.

Pseudomonas aeruginosa (P. aeruginosa) is a pathogen that persistently colonizes the respiratory tract of patients with chronic lung diseases. The risk of acquiring a chronic P. aeruginosa infection can be minimized by rapidly detecting the pathogen in the patient's airways and promptly administrating adequate antibiotics. However, the rapid detection of P. aeruginosa in the lungs involves the analysis of sputum, which is a highly complex matrix that is not always available. Here, we propose an alternative diagnosis based on analyzing breath aerosols. In this approach, nanoparticle immunosensors identify bacteria adhered to the polypropylene layer of a surgical facemask that was previously worn by the patient. A polypropylene processing protocol was optimized to ensure the efficient capture and analysis of the target pathogen. The proposed analytical platform has a theoretical limit of detection of 105 CFU mL-1 in aerosolized mock samples, and a dynamic range between 105 and 108 CFU mL-1. When tested with facemasks worn by patients, the biosensors were able to detect chronic and acute P. aeruginosa lung infections, and to differentiate them from respiratory infections caused by other pathogens. The results shown here pave the way to diagnose Pseudomonas infections at the bedside, as well as to identify the progress from chronic to acute infection.

IGHG3 hinge length variation was associated with the risk of critical disease and death in a Spanish COVID-19 cohort.

IgG3 would play an important role in the immune adaptive response against SARS-CoV-2, and low plasma levels might increase the risk of COVID-19 severity and mortality. The IgG3 hinge sequence has a variable repeat of a 15 amino acid exon with common 4-repeats (M) and 3-repeats (S). This length IGHG3 polymorphism might affect the IgG3 effector functions. The short hinge length would reduce the IgG3 flexibility and impairs the neutralization and phagocytosis compared to larger length-isoforms. We genotyped the IGHG3 length polymorphism in patients with critical COVID-19 (N = 516; 107 death) and 152 moderate-severe but no-critical cases. Carriers of the S allele had an increased risk of critical ICU and mortality (p < 0.001, OR = 2.79, 95% CI = 1.66-4.65). This adverse effect might be explained by a less flexibility and reduced ability to induce phagocytosis or viral neutralization for the short length allele. We concluded that the IgG3 hinge length polymorphism could be a predictor of critical COVID-19 and the risk of death. This study was based on a limited number of patients from a single population, and requires validation in larger cohorts.

The FCGR2A rs1801274 polymorphism was associated with the risk of death among COVID-19 patients.

Polymorphisms of Fcγ receptors have been associated with variable responses to infections. We determined the association of functional polymorphisms rs1801274 in the FCGR2A and rs396991 in the FCGR3A with COVID-19 severity. This study involved 453 patients with severe COVID-19, in which the FCGR2A rs1801274 G-allele (131-Arg) was significantly associated with death (p = 0.02, OR = 1.47). This effect was independent of age and increased IL6 and D-Dimer levels. This study suggests that the FCGR2A gene might be associated with the risk of death among COVID-19 patients. Our study has several limitations, mainly the limited number of patients and the inclusion of a single population. It is thus necessary to confirm this result in larger cohorts from different populations.

p120-catenin regulates WNT signaling and EMT in the mouse embryo.

Epithelial-to-mesenchymal transitions (EMTs) require a complete reorganization of cadherin-based cell-cell junctions. p120-catenin binds to the cytoplasmic juxtamembrane domain of classical cadherins and regulates their stability, suggesting that p120-catenin may play an important role in EMTs. Here, we describe the role of p120-catenin in mouse gastrulation, an EMT that can be imaged at cellular resolution and is accessible to genetic manipulation. Mouse embryos that lack all p120-catenin, or that lack p120-catenin in the embryo proper, survive to midgestation. However, mutants have specific defects in gastrulation, including a high rate of p53-dependent cell death, a bifurcation of the posterior axis, and defects in the migration of mesoderm; all are associated with abnormalities in the primitive streak, the site of the EMT. In embryonic day 7.5 (E7.5) mutants, the domain of expression of the streak marker Brachyury (T) expands more than 3-fold, from a narrow strip of posterior cells to encompass more than one-quarter of the embryo. After E7.5, the enlarged T+ domain splits in 2, separated by a mass of mesoderm cells. Brachyury is a direct target of canonical WNT signaling, and the domain of WNT response in p120-catenin mutant embryos, like the T domain, is first expanded, and then split, and high levels of nuclear ß-catenin levels are present in the cells of the posterior embryo that are exposed to high levels of WNT ligand. The data suggest that p120-catenin stabilizes the membrane association of ß-catenin, thereby preventing accumulation of nuclear ß-catenin and excessive activation of the WNT pathway during EMT.

Association of high-risk human papillomavirus with ocular surface squamous neoplasia: a case-control study in Mexico.

OBJECTIVE: To investigate the association of high-risk hu-man papilloma virus (HR-HPV) and other risk factors with ocular surface squamous cell neoplasia (OSSN). MATERIALS AND METHODS: We obtained DNA from 22 fresh frozen OSSN tissues and 22 pterygia as controls, we used a broad-spectrum HPV DNA amplification short PCR fragment to identify HPV infection in all specimens and then genotyped HPV by a reverse hybridization line probe assay. We also obtained demographic, sun exposure, and tobacco consump-tion information. RESULTS: HR-HPV frequency was 40.9% in the OSSN group and 4.5% in the pterygia group (p=0.009). After covariate adjustment, OSSN was associated with HR-HPV (OR=16.3, 95%CI=1.2,218.1, p=0.03) and sunburn (OR=10.8, 95%CI=1.8,86.0, p=0.02). CONCLUSIONS: Ocular surface squamous cell neoplasia is a multifactorial disease. The strong association between HR-HPV and OSSN, suggests that HR-HPV could play an etiological role in OSSN development.

ß-Pix directs collective migration of anterior visceral endoderm cells in the early mouse embryo.

Collective epithelial migration is important throughout embryonic development. The underlying mechanisms are poorly understood but likely involve spatially localized activation of Rho GTPases. We previously reported that Rac1 is essential for generating the protrusive activity that drives the collective migration of anterior visceral endoderm (AVE) cells in the early mouse embryo. To identify potential regulators of Rac1, we first performed an RNAi screen of Rho family exchange factors (guanine nucleotide exchange factor [GEF]) in an in vitro collective epithelial migration assay and identified ß-Pix. Genetic deletion of ß-Pix in mice disrupts collective AVE migration, while high-resolution live imaging revealed that this is associated with randomly directed protrusive activity. We conclude that ß-Pix controls the spatial localization of Rac1 activity to drive collective AVE migration at a critical stage in mouse development.

Health risk assessment of gaseous elemental mercury (GEM) in Mexico City.

Emissions of gaseous elemental mercury (GEM or Hg0) from different sources in urban areas are important subjects for environmental investigations. In this study, atmospheric Hg measurements were conducted to investigate air pollution in the urban environment by carrying out several mobile surveys in Mexico City. This work presents atmospheric concentrations of GEM in terms of diurnal variation trends and comparisons with criteria for pollutant concentrations such as CO, SO2, NO2, PM2.5, and PM10. The concentration of GEM was measured during the pre-rainy period by using a high-resolution active air sampler, the Lumex RA 915 M mercury analyzer. In comparison with those for other cities worldwide, the GEM concentrations were similar or slightly elevated, and they ranged from 0.20 to 30.23 ng m-3. However, the GEM concentration was significantly lower than those in contaminated areas, such as fluorescent lamp factory locations and gold mining zones. The GEM concentrations recorded in Mexico City did not exceed the WHO atmospheric limit of 200 ng m-3. We performed statistical correlation analysis which suggests equivalent sources between Hg and other atmospheric pollutants, mainly NO2 and SO2, emitted from urban combustion and industrial plants. The atmospheric Hg emissions are basically controlled by sunlight radiation, as well as having a direct relationship with meteorological parameters. The area of the city studied herein is characterized by high traffic density, cement production, and municipal solid waste (MSW) treatment, which constantly release GEM into the atmosphere. In this study, we included the simulation with the HYSPLIT dispersion model from three potential areas of GEM release. Emissions from industrial corridors and volcanic plumes localized outside the urban area contribute to the pollution of Mexico City and mainly affect the northern area during specific periods and climate conditions. Using the USEPA model, we assessed the human health risk resulting from exposure to inhaled GEM among residents of Mexico City. The results of the health risk assessment indicated no significant noncarcinogenic risk (hazard quotient (HQ) < 1) or consequent adverse effects for children and adults living in the sampling area over the study period. GEM emissions inventory data is necessary to improve our knowledge about the Hg contribution and effect in urban megacity areas with the objective to develop public safe policy and implementing the Minamata Convention.

Seasonal and Diurnal Variations of BTEX in Ambient Air from a Site Impacted by the Oil Industry in Southeast Mexico.

Atmospheric concentrations of BTEX were measured in an urban site located in the vicinity of an oil storage-distribution facility in Paraiso, Tabasco, Mexico. Samples were collected during two seasons (nortes 2018 and dry 2019). The relative abundance of BTEX mean concentrations was: toluene (5.24 µg m-3) > ethylbenzene (3.92 µg m-3) > m, p-xylene (3.89 µg m-3) > benzene (2.43 µg m-3). BTEX concentrations had a clear diurnal and seasonal pattern, showing higher levels during the dry season due to differences in wind conditions, rainfall patterns and temperature. Statistical analysis showed significant positive correlations among BTEX, indicating that these compounds had common sources. Interspecies ratios revealed that BTEX were originated from sources beyond vehicular traffic and that they were influenced by the transport of local air masses. The assessment of lifetime cancer risk showed that the population in the study area is at possible risk of developing cancer.

High prevalence of human papillomavirus type 66 in low-grade cervical lesions of Mexican women.

Our aim was to analyze the prevalence of high-risk human papillomavirus (HR-HPV) and its association with risk factors related to cervical lesions. We used 362 cervical samples from a transversal study to detect nineteen types from the high-risk HPV clade by highly sensitive PCR. Unexpectedly, we found a very high prevalence of HPV type 66 (32.8%), particularly in low-grade squamous intraepithelial lesions. A significant association of HPV66 with previously sexually transmitted disease was observed (p < 0.05). Our results strongly suggest that HPV66 might be indicative of cervical lesions that will not progress to cancer. HPV genotyping by methods that grouped type 66 with other HR-HPV clade types should be interpreted with caution.

High prevalent human papillomavirus infections of the oral cavity of asymptomatic HIV-positive men.

BACKGROUND: Incidence of anal and oral infections with Human Papillomavirus (HPV) is increasing, particularly among Human Immunodeficiency Virus-positive (HIV+) men. HPV type 16 has exhibited the highest incidence and only limited data is available on other prevalent types, variants of HPV16, as well as associated factors. We were interested in identifying prevalent HPV types, variants of type 16, as well as factors associated with HPV16 infections in the oral cavity of HIV+ men who have sex with men (MSM). METHODS: A cross-sectional study of oral cavity samples from HIV+ MSM, that in a previous study were identified as positive for HPV16 in the anal canal. Cells from the oral cavity (102 samples, paired with 102 from the anal canal of same patient) were used to extract DNA and detect HPV infections using INNO-LiPA HPV Genotyping Extra II, and PCR. From these, 80 samples (paired, 40 anal and 40 oral) were used to identify variants of type 16 by sequencing. Statistical differences were estimated by the X2 test, and p values equal to or less than 0.05 were considered significant. SPSS ver. Twenty-four statistical software (IBM Corp) was used. RESULTS: We found a high prevalence of High-Risk HPV (HR-HPV) and Low-Risk HPV (LR-HPV). Patients were positive in the oral cavity for HR types; 16, 39 and 18 (80.4, 61.8 and 52.9% respectively) and LR types 11 and 6 (53.9 and 34.3% respectively). Surprisingly, only European variants of type 16 were found in the oral cavity, although American Asian (22.5%) and African (2.5%) variants were identified in the anal canal. The analysis showed that CD4 counts could be the most important risk factor associated with HR-HPV infections in the oral cavity, anal canal or both anatomical regions. The risk of infection of the oral cavity with type 18 increased in men diagnosed with HIV for more than 6 years. CONCLUSIONS: Prevalence of both HR and LR HPV's in the oral cavity of Mexican HIV+ MSM is very high. The fact that only European variants of HPV16 were found in the oral cavity suggest a possible tropism not previously described.

Use of inhibitors of the renin-angiotensin system in hypertensive patients and COVID-19 severity: A systematic review and meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Controversy has arisen in the scientific community on whether the use of renin-angiotensin system (RAS) inhibitors in the context of COVID-19 would be beneficial or harmful. A meta-analysis of eligible studies comparing the occurrence of severe and fatal COVID-19 in infected hypertensive patients who were under treatment with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) vs no treatment or other antihypertensives was conducted. METHODS: PubMed, Google Scholar, the Cochrane Library, medRxiv and bioRxiv were searched for relevant studies. Fixed-effects models or random-effects models were used depending on the heterogeneity between estimates. RESULTS AND DISCUSSION: A total of eighteen studies with 17 311 patients were included. The use of RAS inhibitors was associated with a significant 16% decreased risk of the composite outcome (death, admission to intensive care unit, mechanical ventilation requirement or progression to severe or critical pneumonia): RR: 0.84 (95% CI: 0.73-0.95), P = .007, I2  = 65%. WHAT IS NEW AND CONCLUSION: The results of this pooled analysis suggest that the use of ACEI/ARB does not worsen the prognosis of COVID-19, and could even be protective in hypertensive subjects. Hypertensive patients should continue these drugs even if they become infected with SARS-CoV-2.

Prevalence and related factors of office and home hypotension in older treated hypertensive patients.

BACKGROUND: Older hypertensive adults under treatment are especially susceptible to hypotensive episodes, which entail an elevated risk. However, data on this subject are very scarce. AIM: The purpose of this study was to determine the prevalence and predictors of office and home hypotension in older (≥ 65 years) treated hypertensive adults. METHODS: Blood pressure (BP) was measured at the office and at home, using a validated oscillometric device. Office and home hypotension were defined as systolic BP (SBP) < 110 and/or diastolic BP (DBP) < 70 mmHg, and SBP < 105 and/or DBP < 65 mmHg, respectively. Masked hypotension was considered when office BP ≥ 110/70 and home BP < 105 and/or < 65 mmHg. We evaluated factors associated with hypotension both at the office and at home through multivariable models. RESULTS: The prevalence of hypotension among the 302 patients included in the study was 29.8% at the office and 23.9% at home, whereas the prevalence of masked hypotension was 10.4%. Older age, lower body mass index and use of calcium channel blockers were associated with office hypotension, while older age, diabetes and ischemic heart disease were predictors for home hypotension. CONCLUSION: Hypotension is frequent in older hypertensive adults under treatment. The presence of diabetes, ischemic heart disease and older age should alert for screening of hypotension at home to avoid overtreatment.

Animalizing the disadvantaged, mechanizing the wealthy: The convergence of socio-economic status and attribution of humanity.

Differences between groups in socio-economic status (SES) are becoming more salient nowadays. In this context, we examined the animalistic and mechanistic dehumanization that both low and high-SES groups may experience respectively by conducting three studies. In study 1, we manipulated the SES of two fictitious groups (low vs. high-SES) and measured the humanity ascribed to them. Results showed that the low-SES group was animalized in comparison with the high-SES group, which was mechanized. In study 2, we manipulated the humanity of two fictitious groups by describing them as animals or machines and measured the perceived SES of the groups. Participants tended to attribute lower SES to the group described as animals and higher SES to the group described as machines. Finally, in study 3, we used an Implicit Association Test to replicate the results of studies 1 and 2. Taken together, these studies show that low-SES groups are considered as animal-like whereas high-SES groups are seen as robot-like. We discuss the implications of these findings in relation to the justification of income inequality within our society.

Global Study of Social Odor Awareness.

Olfaction plays an important role in human social communication, including multiple domains in which people often rely on their sense of smell in the social context. The importance of the sense of smell and its role can however vary inter-individually and culturally. Despite the growing body of literature on differences in olfactory performance or hedonic preferences across the globe, the aspects of a given culture as well as culturally universal individual differences affecting odor awareness in human social life remain unknown. Here, we conducted a large-scale analysis of data collected from 10 794 participants from 52 study sites from 44 countries all over the world. The aim of our research was to explore the potential individual and country-level correlates of odor awareness in the social context. The results show that the individual characteristics were more strongly related than country-level factors to self-reported odor awareness in different social contexts. A model including individual-level predictors (gender, age, material situation, education, and preferred social distance) provided a relatively good fit to the data, but adding country-level predictors (Human Development Index, population density, and average temperature) did not improve model parameters. Although there were some cross-cultural differences in social odor awareness, the main differentiating role was played by the individual differences. This suggests that people living in different cultures and different climate conditions may still share some similar patterns of odor awareness if they share other individual-level characteristics.

Cloning, overexpression, and purification of glucose-6-phosphate dehydrogenase of Pseudomonas aeruginosa.

Glucose-6-phosphate dehydrogenase (G6PDH) (EC 1.1.1.363) plays an important role in the human pathogen Pseudomonas aeruginosa because it generates NADPH, an essential cofactor for several biosynthetic pathways and antioxidant enzymes. P. aeruginosa G6PDH is also a key enzyme in the metabolism of various carbon sources, such as glucose, glycerol, fructose, and mannitol. Understanding the kinetic characteristics and mechanisms that control the activity of this enzyme is crucial for future studies in this context. However, one of the impediments to achieving this goal is the limited amount of protein obtained when current purification protocols are implemented, a factor curtailing its biochemical characterization. In this study, we report a fast, efficient and reproducible procedure for the purification of P. aeruginosa G6PDH that can be implemented in a short period (2 days). In order to establish this protocol, the zwf gene, which encodes for this enzyme, was cloned and overexpressed in Escherichia coli cells. In contrast to other procedures, our method is based on protein precipitation with CaCl2 and further purification by ion exchange chromatography. Using this protocol, we were able to obtain 31 mg/L of pure protein that manifested specific activity of 145.7 U/mg. The recombinant enzyme obtained in this study manifested similar physicochemical and kinetic properties to those reported in previous works for this molecule. The large quantities of active enzyme obtained using this procedure will facilitate its structural characterization and identify differences between P. aeruginosa- and human G6PDH, thus contributing to the search for selective inhibitors against the bacterial enzyme.

High frequency of HPV16 European variant E350G among Mexican women from Sinaloa.

BACKGROUND & OBJECTIVES: Human papillomavirus (HPV) infections play a crucial role in the aetiology of cervical cancer (CC), and HPV16 is the primary viral genotype associated with CC. A number of variants of the HPV16 E6 gene are involved in the progression of CC, differing in their prevalence and biological and biochemical properties. This study was designed to determine the frequency of HPV types 16/18 and to identify the presence of HPV16 E6-variants in asymptomatic Mexican women. METHODS: A total of 189 cervical Pap smears were collected from women attending public health services in three different cities in Sinaloa, Mexico. Viral DNA was identified by amplification of E6 viral gene fragments using polymerase chain reaction (PCR). Identification of variants was done by sequencing a DNA fragment (321bp) of the HPV16 E6 gene. RESULTS: More than half of the women tested were HPV-positive (52.38%), with HPV16 being the most frequent genotype (21.16%), followed by HPV18 (8.99%). Sequence analysis of the E6-HPV16 PCR products showed that in all cases, the viruses corresponded to European variants. It was further observed that the E350G intra-variant was the most common (>76%). INTERPRETATION & CONCLUSIONS: This study showed a predominance of European lineage variants of HPV16 among asymptomatic women from Sinaloa, Mexico, predominantly with of the E350G variant. This variant has been shown to be associated with an increased risk of early development of CC. The use of molecular identification of carcinogenic HPV and Pap test screening may be a good strategy for monitoring women to prevent CC.

Hemodynamic characterization of hypertensive patients with an exaggerated orthostatic blood pressure variation.

Exaggerated orthostatic blood pressure variation (EOV) is a poorly understood phenomenon related to high cardiovascular risk. We aimed to determine whether hypertensive patients with EOV have a distinct hemodynamic pattern, assessed through impedance cardiography. METHODS: In treated hypertensive patients, we measured the cardiac index (CI), systemic vascular resistance index (SVRI), blood pressure (BP), and heart rate (HR) in the supine and standing (after 3 minutes) positions, defining three groups according to BP variation: 1) Normal orthostatic BP variation (NOV): standing systolic BP (stSBP)-supine systolic BP (suSBP) between -20 and 20 mmHg and standing diastolic BP (stDBP)-supine diastolic BP (suDBP) between -10 and 10 mmHg; 2) orthostatic hypotension (OHypo): stSBP-suSBP≤-20 or stDBP-suDBP≤-10 mmHg; 3) orthostatic hypertension (OHyper): stSBP-suSBP≥20 or stDBP-suDBP≥10 mmHg. We performed multivariable analyses to determine the association of hemodynamic variables with EOV. RESULTS: We included 186 patients. Those with OHyper had lower suDBP and higher orthostatic SVRI variation compared to NOV. In multivariable analyses, orthostatic HR variation (OR = 1.06 (95%CI 1.01-1.13), p = 0.03) and orthostatic SVRI variation (OR = 1.16 (95%CI 1.06-1.28), p = 0.002) were independently related to OHyper. No variables were independently associated with OHypo. CONCLUSION: Patients with OHyper have a distinct hemodynamic pattern, with an exaggerated increase in SVRI and HR when standing.