Molecular Challenges and Opportunities in Climate Change-Induced Kidney Diseases.

As temperatures continue to modify due to weather changes, more regions are being exposed to extreme heat and cold. Physiological distress due to low and high temperatures can affect the heart, blood vessels, liver, and especially, the kidneys. Dehydration causes impaired cell function and heat itself triggers cellular stress. The decline in circulating plasma volume by sweat, which stresses the renal and cardiovascular systems, has been related to some molecules that are crucial players in preventing or provoking cellular damage. Hypovolemia and blood redistribution to cutaneous blood vessels reduce perfusion to the kidney triggering the activation of the renin-angiotensin-aldosterone system. In this review, we expose a deeper understanding of the modulation of molecules that interact with other proteins in humans to provide significant findings in the context of extreme heat and cold environments and renal damage reversal. We focus on the molecular changes exerted by temperature and dehydration in the renal system as both parameters are heavily implicated by weather change (e.g., vasopressin-induced fructose uptake, fructogenesis, and hypertension). We also discuss the compensatory mechanisms activated under extreme temperatures that can exert further kidney injury. To finalize, we place special emphasis on the renal mechanisms of protection against temperature extremes, focusing on two important protein groups: heat shock proteins and sirtuins.

Marfan Syndrome Incorrectly Diagnosed as Autism.

Marfan syndrome is a pleiotropic genetic connective tissue disorder most commonly involving the cardiovascular, skeletal, and ocular systems, which have abundant connective tissue. It is not known to affect the central nervous system, therefore developmental delays or cognitive involvement are not typically associated. We present a case of a 2-year-old Hispanic male who was diagnosed with autism spectrum disorder (ASD) because of poor social interaction, lack of eye contact, and speech delays. Several months after the ASD diagnosis and receiving therapies without improvement, he was unexpectedly found to have severe myopia and bilateral ectopia lentis. These findings prompted further evaluation that subsequently led to a clinical and molecular diagnosis of Marfan syndrome. After correction of his refractive error, his social skills and eye contact had significantly improved and his speech gradually caught up and resolved to a normal level for his age. This report emphasizes the need for comprehensive investigation of children with delays to include ocular assessments before determining ASD in the context of developmental delays.

HSP60-Derived Peptide as an LPS/TLR4 Modulator: An in silico Approach.

As a part of innate immunity mechanisms, the Toll-like receptor (TLR) signaling pathway serves as one of the mainstay lines of defense against pathogenic microorganisms and cell dysfunction. Nevertheless, TLR overactivation induces a systemic proinflammatory environment compromising organ function or causing the patient's death. TLRs modulators, specially those focused for TLR4, remain a promising approach for inflammatory diseases treatment, being peptide-based therapy a trendy approach. Heat shock protein 60 (HSP60) not only plays a pivotal role in the development of several maladies with strong inflammatory components but also HSP60 peptides possess anti-inflammatory properties in TLR4-mediated diseases, such as diabetes, arthritis, and atherosclerosis. The experimental treatment using HSP60 peptides has proven to be protective in preclinical models of the heart by hampering inflammation and modulating the activity of immune cells. Nonetheless, the effect that these peptides may exert directly on cells that express TLR and its role to inhibit overactivation remain elusive. The aim of this study is to evaluate by molecular docking, a 15 amino acid long-HSP60 peptide (Peptide-2) in the lipopolysaccharide (LPS) binding site of TLR4/MD2, finding most Peptide-2 resulting conformations posed into the hydrophobic pocket of MD2. This observation is supported by binding energy obtained for the control antagonist Eritoran, close to those of Peptide-2. This last does not undergo drastic structural changes, moving into a delimited space, and maintaining the same orientation during molecular dynamics simulation. Based on the two computational techniques applied, interaction patterns were defined for Peptide-2. With these results, it is plausible to propose a peptidic approach for TLR4 modulation as a new innovative therapy to the treatment of TLR4-related cardiovascular diseases.

Improved yield, stability, and cleavage reaction of a novel tobacco etch virus protease mutant.

The protease catalytic subunit of the nuclear inclusion protein A from tobacco etch virus (TEVp) is widely used to remove tags and fusion proteins from recombinant proteins. Some intrinsic drawbacks to its recombinant production have been studied for many years, such as low solubility, auto-proteolysis, and instability. Some point mutations have been incorporated in the amino acid protease sequence to improve its production. Here, a comprehensive review of each mutation reported so far has been made to incorporate them into a mutant called TEVp7M with a total of seven changes. This mutant with a His7tag at N-terminus was produced with remarkable purification yields (55 mg/L of culture) from the soluble fraction in a single step affinity purification. The stability of His7-TEVp7M was analyzed and compared with the single mutant TEVp S219V, making evident that His7-TEVp7M shows very constant thermal stability against pH variation, whereas TEVp S219V is highly sensitive to this change. The cleavage reaction was optimized by determining the amount of protease that could cleave a 100-fold excess substrate in the shortest possible time at 30 °C. Under these conditions, His7-TEVp7M was able to cleave His-tag in the buffers commonly used for affinity purification. Finally, a structural analysis of the mutations showed that four of them increased the polarity of the residues involved and, consequently, showed increased solubility of TEVp and fewer hydrophobic regions exposed to the solvent. Taken together, the seven changes studied in this work improved stability, solubility, and activity of TEVp producing enough protease to digest large amounts of tags or fusion proteins. KEY POINTS: • Production of excellent yields of a TEVp (TEVp7M) by incorporation of seven changes. • His-tag removal in an excess substrate in the common buffers used for purification. • Incorporated mutations improve polarity, stability, and activity of TEVp7M.

Lateral cut as management of late voiding dysfunction syndrome post sling: 'more than a cut' - video article.

INTRODUCTION AND HYPOTHESIS: The mid-urethral sling (MUS) is considered the gold standard for stress urinary incontinence (SUI). Nevertheless, this procedure is not excluded from postsurgical complications, which can be challenging for most clinicians. Hence, one of the main concerns about this procedure is late postoperative voiding dysfunction (LDS), defined as obstructive symptoms 6 weeks after surgery. Primary medical management regularly includes expectant management and rehabilitation, including the mid-urethral cut sling (MUCS) as an alternative when it fails. This video provides an anatomical illustration and detailed description of the surgical steps of the J-cut of the lateral sling. MATERIALS AND METHODS: We set up a step-by-step surgical process and provided some advice for MUCS in a video; this material included how to position the sling, dissect, isolate the synthetic material, release adhesions and make a lateral cut of the MUS. Additionally, a case series of 30 patients from our institution is described to confirm the effectiveness of MUCS to manage delayed voiding dysfunction syndrome. RESULTS: MUCS in LDS was beneficial for our patients. Obstructive symptoms improved clinically from 75% to 100%, and urgency-related symptoms decreased from 57.9% to 26.3%, evidencing 20% SUI post-MUCS surgery. CONCLUSIONS: The lateral cut of the mid-urethral tape should be considered a surgical alternative for the resolution of post-sling late voiding dysfunction syndrome in patients who do not improve with expectant management.

Reinforcement of Alginate-Gelatin Hydrogels with Bioceramics for Biomedical Applications: A Comparative Study.

This study states the preparation of novel ink with potential use for bone and cartilage tissue restoration. 3Dprint manufacturing allows customizing prostheses and complex morphologies of any traumatism. The quest for bioinks that increase the restoration rate based on printable polymers is a need. This study is focused on main steps, the synthesis of two bioceramic materials as WO3 and Na2Ti6O13, its integration into a biopolymeric-base matrix of Alginate and Gelatin to support the particles in a complete scaffold to trigger the potential nucleation of crystals of calcium phosphates, and its comparative study with independent systems of formulations with bioceramic particles as Al2O3, TiO2, and ZrO2. FT-IR and SEM studies result in hydroxyapatite's potential nucleation, which can generate bone or cartilage tissue regeneration systems with low or null cytotoxicity. These composites were tested by cell culture techniques to assess their biocompatibility. Moreover, the reinforcement was compared individually by mechanical tests with higher results on synthesized materials Na2Ti6O13 with 35 kPa and WO3 with 63 kPa. Finally, the integration of these composite materials formulated by Alginate/Gelatin and bioceramic has been characterized as functional for further manufacturing with the aid of novel biofabrication techniques such as 3D printing.

Hydroxyapatite Nanoparticles in Drug Delivery: Physicochemistry and Applications.

Hydroxyapatite (HAP) has been the gold standard in the biomedical field due to its composition and similarity to human bone. Properties such as shape, size, morphology, and ionic substitution can be tailored through the use of different synthesis techniques and compounds. Regardless of the ability to determine its physicochemical properties, a conclusion for the correlation with the biological response it is yet to be found. Hence, a special focus on the most desirable properties for an appropriate biological response needs to be addressed. This review provides an overview of the fundamental properties of hydroxyapatite nanoparticles and the characterization of physicochemical properties involved in their biological response and role as a drug delivery system. A summary of the main chemical properties and applications of hydroxyapatite, the advantages of using nanoparticles, and the influence of shape, size, functional group, morphology, and crystalline phase in the biological response is presented. A special emphasis was placed on the analysis of chemical and physical interactions of the nanoparticles and the cargo, which was explained through the use of spectroscopic and physical techniques such as FTIR, Raman, XRD, SEM, DLS, and BET. We discuss the properties tailored for hydroxyapatite nanoparticles for a specific biomolecule based on the compilation of studies performed on proteins, peptides, drugs, and genetic material.

Isotretinoin and Thalidomide Down-Regulate c-MYC Gene Expression and Modify Proteins Associated with Cancer in Hepatic Cells.

Hepatocellular carcinoma (HCC) is the most common form of liver cancer. The number of cases is increasing and the trend for the next few years is not encouraging. HCC is usually detected in the advanced stages of the disease, and pharmacological therapies are not entirely effective. For this reason, it is necessary to search for new therapeutic options. The objective of this work was to evaluate the effect of the drugs isotretinoin and thalidomide on c-MYC expression and cancer-related proteins in an HCC cellular model. The expression of c-MYC was measured using RT-qPCR and western blot assays. In addition, luciferase activity assays were performed for the c-MYC promoters P1 and P2 using recombinant plasmids. Dose-response-time analyses were performed for isotretinoin or thalidomide in cells transfected with the c-MYC promoters. Finally, a proteome profile analysis of cells exposed to these two drugs was performed and the results were validated by western blot. We demonstrated that in HepG2 cells, isotretinoin and thalidomide reduced c-MYC mRNA expression levels, but this decrease in expression was linked to the regulation of P1 and P1-P2 c-MYC promoter activity in isotretinoin only. Thalidomide did not exert any effect on c-MYC promoters. Also, isotretinoin and thalidomide were capable of inducing and repressing proteins associated with cancer. In conclusion, isotretinoin and thalidomide down-regulate c-MYC mRNA expression and this is partially due to P1 or P2 promoter activity, suggesting that these drugs could be promising options for modulating the expression of oncogenes and tumor suppressor genes in HCC.

Antiretroviral therapy use in selected countries in Latin America during 2013-2017: results from the Latin American Workshop in HIV Study Group.

OBJECTIVE: To document antiretroviral use in Latin America during the last decade. METHODS: We collected indicators from 79 HIV health care centres in 14 Latin American Spanish-speaking countries for 2013-2017. Indicators were analysed by age, sex and other characteristics and weighted by the estimated people under care (PUC) population in each country. RESULTS: We gathered information on 116 299 PUC. One-third belonged to centres reporting a shortage of at least one antiretroviral therapy (ART) drug for >30 days during 2017. At end 2017, 95.1% of PUC were receiving ART. During 2013-2017, 45 329 people living with HIV were admitted to 39 centres. ART initiated during the first year after admission increased from 76.7% in 2013 to 83.8% in 2017. In 35 centres across the study period, 71.7% of PUC started ART with tenofovir disoproxil fumarate and lamivudine, and zidovudine use decreased. The third most common ART drug, EFV, reached 64.8%. Raltegravir and other alternatives increased annually to almost 10% of total use in 2017. CONCLUSIONS: Initial ART in Latin America is not based on the most recent scientific evidence and recommendations; use of drugs with higher efficacy and safety profiles and guarantee of ART availability continues to be a public health challenge.

Fear of COVID-19 among Peruvian People Living in Disadvantaged Communities: A Cross-Sectional Study.

BACKGROUND: The COVID-19 crisis is fuelling a state of fear among the human population at global level. Especially, those living in informal settlements and slums worldwide have been profoundly impacted by this pandemic. Individuals living in these places are already leading underprivileged lives. Thus, the economic and mental health problems caused by the COVID-19 crisis have further exacerbated their living standards, which has resulted, for instance, in tragedies such as suicides. OBJECTIVE: In this study, we have sought to identify those individuals most at risk of displaying high levels of fear of COVID-19 in an informal settlement located in the capital city of Peru. METHODS: A questionnaire was administered to 449 inhabitants living in the Carmen Alto informal settlement. The questionnaire was made up of two parts: the first one inquired about demographic data and the second part consisted of the Fear of COVID-19 Scale. RESULTS: The demographic variables of age, gender, marital status, educational level, occupation, whether a relative from the household was infected with COVID-19, and whether one of them died of this showed significant differences. It could be observed as well that the groups of females, stable workers, unemployed and those having completed a workforce education are at higher odds of displaying high levels of fear of COVID-19. As expected, the groups that had either a relative infected with COVID-19 or a relative death by this had the highest levels of fear towards the virus. CONCLUSION: The female participants are more likely to display higher levels of fear of COVID-19 due to the terrible effect that unfavorable events have on them. In the cases of the unemployed and stable workers, their proneness to show high levels of fear towards the virus is because they have lost their incomes, due to the loss of their jobs, and because of fear of infection, respectively. Hence, we hope that this work serves Peruvian (and other) health authorities to develop strategies that help individuals living in informal settlements and are in urgent need of mitigating mental health problems.

Vaccines against components of the renin-angiotensin system.

Even though effective drugs for treating hypertension are available, a great percentage of patients have inadequate control of their blood pressure. Unwanted side effects and inappropriate oral drug adherence are important factors that contribute to the global problem of uncontrolled hypertension. Vaccination could provide a revolutionary therapy with long-lasting effects, increasing patient compliance and therefore better control of high blood pressure. Nowadays, current immunization approaches against hypertension target renin, angiotensin I, angiotensin II, and angiotensin II type 1 receptor, key elements of the renin-angiotensin system. This article reviews the different vaccination attempts with proteins and peptides against the different molecules of the renin-angiotensin system in the last two decades, safety issues, and other novel prospects biomarkers in hypertension, and summarizes the potential of this immunomodulatory approach in clinical practice.

Peptidic vaccines: The new cure for heart diseases?

Cardiovascular disease continues to be the most common cause of death worldwide. The global burden is so high that numerous organizations are providing counseling recommendations and annual revisions of current pharmacological and non-pharmacological treatments as well as risk prediction for disease prevention and further progression. Although primary preventive interventions targeting risk factors such as obesity, hypertension, smoking, and sedentarism have led to a global decline in hospitalization rates, the aging population has overwhelmed these efforts on a global scale. This review focuses on peptidic vaccines, with the known and not well-known autoantigens in atheroma formation or acquired cardiac diseases, as novel potential immunotherapy approaches to counteract harmful heart disease continuance. We summarize how cancer immunomodulatory strategies started novel approaches to modulate the innate and adaptive immune responses, and how they can be targeted for therapeutic purposes in the cardiovascular system. Brief descriptions focused on the processes that start as either immunologic or non-immunologic, and the ultimate loss of cardiac muscle cell contractility as the outcome, are discussed. We conclude debating how novel strategies with nanoparticles and nanovaccines open a promising therapeutic option to reduce or prevent cardiovascular diseases.

HIV-1 resistance patterns to integrase inhibitors in Chilean patients with virological failure on raltegravir-containing regimens.

In this viewpoint we would like to describe our results in terms of resistance pattern in Chilean patients with virological failure (VF) on raltegravir (RAL)-containing-regimens and highlight the need for the concomitant availability of genotypic resistance testing to integrase strand transfer inhibitors (INSTIs) introduction in antiretroviral regimens, particularly in countries in South America. Indeed we found in our study the presence of two or more primary mutations in some of the participants which is associated with cross-resistance to all INSTIs. By using timely genotyping, we could optimally manage these patients, early after detection of VF.

Awareness of predatory publishing for Peruvian university professors and lecturers doing research.

Predatory open access journals and predatory conferences' main purpose is to make profit rather than promoting good science. In Peru, the University Law 30220 asks that professors and lecturers undertake research duties at universities. Hence, nowadays part of this academic staff is required to write scientific articles. However, not all of them are experienced on how to write a scholarly paper. Thus, in the rush to comply with the publication requirements that their individual institutions demand from them, a great number of these professors and lecturers are likely to fall prey of predatory publishing, which already is happening in other developing nations. This publishing method is not only unethical because it produces low-quality articles but also is an egregious mismanagement of the resources that universities allocate to fund research. Moreover, the time and effort that the academic staff put to the production of low-quality papers also completely go to waste. Professors and lecturers who follow these bad practices should be penalized; this also avoids the emergence of fraudulent research authorities. Thus, vice-rectorates for research in Peruvian universities should take corrective or preventive measures to promote the production of high-quality papers by part of their academic staff.

Cationic Dendrimer G2-S16 Inhibits Herpes Simplex Type 2 Infection and Protects Mice Vaginal Microbiome.

The G2-S16 polyanionic carbosilane dendrimer is a promising microbicide that inhibits HSV-2 infection in vitro and in vivo in mice models. This G2-S16 dendrimer inhibits HSV-2 infection even in the presence of semen. Murine models, such as BALB/c female mice, are generally used to characterize host-pathogen interactions within the vaginal tract. However, the composition of endogenous vaginal flora remains largely undefined with modern microbiome analyses. It is important to note that the G2-S16 dendrimer does not change healthy mouse vaginal microbiome where Pseudomonas (10.2-79.1%) and Janthinobacterium (0.7-13%) are the more abundant genera. The HSV-2 vaginally infected female mice showed a significant microbiome alteration because an increase of Staphylococcus (up to 98.8%) and Escherichia (30.76%) levels were observed becoming these bacteria the predominant genera. BALB/c female mice vaginally-treated with the G2-S16 dendrimer and infected with the HSV-2 maintained a healthy vaginal microbiome similar to uninfected female mice. Summarizing, the G2-S16 polyanionic carbosilane dendrimer inhibits the HSV-2 infection in the presence of semen and prevents the alteration of mice female vaginal microbiome.

The algorithm used for the interpretation of doravirine transmitted drug resistance strongly influences clinical practice and guideline recommendations.

OBJECTIVES: We report the results of the reverse transcriptase (RT)/protease (PR) transmitted drug resistance (TDR) prevalence study in 2018, focusing on doravirine resistance-associated mutations and the differences observed when Stanford or French National Agency for AIDS Research (ANRS)/Spanish Network of AIDS Research (RIS)/IAS-USA resistance interpretation algorithms are used to describe clinically relevant resistance. METHODS: We used the WHO 2009 list to investigate the prevalence of NNRTI, NRTI and PI TDR, in treatment-naive HIV-1-infected patients, adding mutations E138A/G/K/Q/R, V106I, V108I, V179L, G190Q, H221Y, F227C/L/V, M230IDR, L234I, P236L and Y318F in RT. The prevalence of doravirine resistance-associated mutations, as described by Soulie et al. in 2019, was evaluated. Clinically relevant TDR was investigated using the latest versions of ANRS, RIS, IAS-USA and Stanford algorithms. RESULTS: NNRTI mutations were detected in 82 of 606 (13.5%) patients. We found 18 patients (3.0%) with NRTI mutations and 5 patients (0.8%) with PI mutations. We detected 11 patients harbouring doravirine resistance-associated mutations (prevalence of 1.8%). Furthermore, we observed important differences in clinically relevant resistance to doravirine when ANRS/RIS (0.7%), IAS-USA (0.5%) or Stanford algorithms (5.0%) were used. V106I, which was detected in 3.8% of the patients, was the main mutation driving these differences. V106I detection was not associated with any of the clinical, demographic or virological characteristics of the patients. CONCLUSIONS: The prevalence of NRTI and PI TDR remains constant in Spain. Doravirine TDR is very infrequent by RIS/ANRS/IAS-USA algorithms, in contrast with results using the Stanford algorithm. Further genotype-phenotype studies are necessary to elucidate the role of V106I in doravirine resistance.

Combination of G2-S16 dendrimer/dapivirine antiretroviral as a new HIV-1 microbicide.

Aim: To research the synergistic activity of G2-S16 dendrimer and dapivirine (DPV) antiretroviral as microbicide candidate to prevent HIV-1 infection. Materials & methods: We assess the toxicity of DPV on cell lines by MTT assay, the anti-HIV-1 activity of G2-S16 and DPV alone or combined at several fixed ratios. Finally, their ability to inhibit the bacterial growth in vitro was assayed. The analysis of combinatorial effects and the effective concentrations were performed with CalcuSyn software. Conclusion: Our results represent the first proof-of-concept study of G2-S16/DPV combination to develop a safe microbicide.

Número de cigarrillos en las cajetillas, cigarrillos sueltos y caducidad de la cajetilla: ¿un juego? / Number of cigarettes in the packs, individual cigarettes and shelf life of the cigarette pack: is it a game?

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New anionic poly(alkylideneamine) dendrimers as microbicide agents against HIV-1 infection.

Acquired immune deficiency syndrome (AIDS) due to human immunodeficiency virus type-1 (HIV-1) represents one of the most important sexually transmitted infections (STI) worldwide. Great international efforts have been made to stop new infections but, to date, several compounds failed as microbicides at different stages of clinical trials. The quest to design new molecules that could prevent these infections is essential. In this work, we synthesized the first, second and third generations of anionic dendrimers having carboxylate and sulfonate terminal groups, respectively named G1C, G2C, G3C and G1S, G2S, and G3S, starting from a family of poly(alkylideneamine) dendrimers with nitrile termini. The anionic terminal groups of these dendrimers were expected to prompt them to act against HIV-1 infection. All dendrimers were fully characterized by 1H- and 13C-NMR, FTIR, MS and zeta potential techniques. Importantly, they were able to remain stable in the solid state and aqueous solutions at least for one and a half years. Screening of these six new dendrimers was then performed to shed light on their potential anti-HIV-1 activity and their mechanism of action. Results showed that the dendrimers were cytocompatible and that G1C and G1S dendrimers had important activity against R5-HIV-1NLAD8 and X4-HIV-1NL4.3 isolates by acting directly on viral particles and blocking their entry in host cells. Additionally, G1C and G1S dendrimers maintained their inhibitory effect at different pH values. Through a vaginal irritation assay carried out in BALB/c mice, the safety of these new dendrimers for topical application was also shown. Taken together, our results clearly show that G1C and G1S dendrimers are strong candidates for developing an effective microbicide to prevent HIV-1 new infections.