The clustered gamma protocadherin PcdhγC4 isoform regulates cortical interneuron programmed cell death in the mouse cortex.

Cortical inhibitory interneurons (cINs) are born in the ventral forebrain and migrate into the cortex where they make connections with locally produced excitatory glutamatergic neurons. Cortical function critically depends on the number of cINs, which is also key to establishing the appropriate inhibitory/excitatory balance. The final number of cINs is determined during a postnatal period of programmed cell death (PCD) when ~40% of the young cINs are eliminated. Previous work shows that the loss of clustered gamma protocadherins (Pcdhgs), but not of genes in the Pcdha or Pcdhb clusters, dramatically increased BAX-dependent cIN PCD. Here, we show that PcdhγC4 is highly expressed in cINs of the mouse cortex and that this expression increases during PCD. The sole deletion of the PcdhγC4 isoform, but not of the other 21 isoforms in the Pcdhg gene cluster, increased cIN PCD. Viral expression of the PcdhγC4, in cIN lacking the function of the entire Pcdhg cluster, rescued most of these cells from cell death. We conclude that PcdhγC4 plays a critical role in regulating the survival of cINs during their normal period of PCD. This highlights how a single isoform of the Pcdhg cluster, which has been linked to human neurodevelopmental disorders, is essential to adjust cIN cell numbers during cortical development.

Multicomponent synthesis and photophysical study of novel α,ß-unsaturated carbonyl depsipeptides and peptoids.

Multicomponent reactions were performed to develop novel α,ß-unsaturated carbonyl depsipeptides and peptoids incorporating various chromophores such as cinnamic, coumarin, and quinolines. Thus, through the Passerini and Ugi multicomponent reactions (P-3CR and U-4CR), we obtained thirteen depsipeptides and peptoids in moderate to high yield following the established protocol and fundamentally varying the electron-rich carboxylic acid as reactants. UV/Vis spectroscopy was utilized to study the photophysical properties of the newly synthesized compounds. Differences between the carbonyl-substituted chromophores cause differences in electron delocalization that can be captured in the spectra. The near UV regions of all the compounds exhibited strong absorption bands. Compounds P2, P5, U2, U5, and U7 displayed absorption bands in the range of 250-350 nm, absorbing radiation in this broad region of the electromagnetic spectrum. A photostability study for U5 showed that its molecular structure does not change after exposure to UV radiation. Fluorescence analysis showed an incipient emission of U5, while U6 showed blue fluorescence under UV radiation. The photophysical properties and electronic structure were also determined by TD-DFT theoretical study.

Comparative Study of the Removal Efficiency of Nalidixic Acid by Poly[(4-vinylbenzyl)trimethylammonium Chloride] and N-Alkylated Chitosan through the Ultrafiltration Technique and Its Approximation through Theoretical Calculations.

Emerging antibiotic contaminants in water is a global problem because bacterial strains resistant to these antibiotics arise, risking human health. This study describes the use of poly[(4-vinylbenzyl) trimethylammonium chloride] and N-alkylated chitosan, two cationic polymers with different natures and structures to remove nalidixic acid. Both contain ammonium salt as a functional group. One of them is a synthetic polymer, and the other is a modified artificial polymer. The removal of the antibiotic was investigated under various experimental conditions (pH, ionic strength, and antibiotic concentration) using the technique of liquid-phase polymer-based retention (LPR). In addition, a stochastic algorithm provided by Fukui's functions is used. It was shown that alkylated N-chitosan presents 65.0% removal at pH 7, while poly[(4-vinylbenzyl)trimethylammonium chloride] removes 75.0% at pH 9. The interaction mechanisms that predominate the removal processes are electrostatic interactions, π-π interactions, and hydrogen bonding. The polymers reached maximum retention capacities of 1605 mg g-1 for poly[(4-vinylbenzyl) trimethylammonium chloride] and 561 mg g-1 of antibiotic per gram for alkylated poly(N-chitosan). In conclusion, the presence of aromatic groups improves the capacity and polymer-antibiotic interactions.

The Clustered Gamma Protocadherin Pcdhγc4 Isoform Regulates Cortical Interneuron Programmed Cell Death in the Mouse Cortex.

Cortical function critically depends on inhibitory/excitatory balance. Cortical inhibitory interneurons (cINs) are born in the ventral forebrain and migrate into cortex, where their numbers are adjusted by programmed cell death. Previously, we showed that loss of clustered gamma protocadherins (Pcdhγ), but not of genes in the alpha or beta clusters, increased dramatically cIN BAX-dependent cell death in mice. Here we show that the sole deletion of the Pcdhγc4 isoform, but not of the other 21 isoforms in the Pcdhγ gene cluster, increased cIN cell death in mice during the normal period of programmed cell death. Viral expression of the Pcdhγc4 isoform rescued transplanted cINs lacking Pcdhγ from cell death. We conclude that Pcdhγ, specifically Pcdhγc4, plays a critical role in regulating the survival of cINs during their normal period of cell death. This demonstrates a novel specificity in the role of Pcdhγ isoforms in cortical development.

Healthiness as a Virtue: The Healthism of mHealth and the Challenges to Public Health.

Mobile health (mHealth) technologies for self-monitoring health-relevant parameters such as heart frequency, sleeping patterns or exercise regimes aim at fostering healthy behavior change and increasing the individual users to promote and maintain their health. We argue that this aspect of mHealth supports healthism, the increasing shift from institutional responsibility for public health toward individual engagement in maintaining health as well as mitigating health risks. Moreover, this healthist paradigm leads to a shift from understanding health as the absence of illness to regarding health as the performance of certain rituals in order to project healthiness. By drawing from the analogy between healthiness and traditional virtues, we evaluate the promises made by proponents of mHealth technologies for self-monitoring. We argue that the implementation and use of mHealth risk entrenching existing inequalities and, more particularly, tend to exclude populations situated at the losing end of those inequalities from participating in the quasi-virtue of healthiness. Consequently, the implementation and use of mHealth technologies not only present challenges for social justice but also undermine their primary societal goal-to promote public health. Finally, we offer several suggestions on how to realize the potential benefit of mHealth.

[Acute cardiovascular complications in a Peruvian population of oncology patients]. / Complicaciones cardiovasculares agudas en una población peruana de pacientes oncológicos.

Objective: To know the most frequent acute cardiovascular complications in a Peruvian population of oncologic patients. Materials and methods: Retrospective, descriptive study of oncologic patients treated at Clinica Delgado between January 2014 and December 2019, from which the subgroup with the seven most prevalent cancers at the national level was selected according to information from Globocan 2018. Additionally, we evaluated the epidemiology of patients with cardiovascular complications that conditioned their hospitalization or were detected during this, calculating their cardiovascular risk according to Hermann and SCORE risk scales. Results: Forty-four patients had complications; 27 (61.4%) were hospitalized due to acute cardiovascular causes. The mean age of this subgroup was 69.88 years (SD 12.77), and 22 (81.5%) were older than 60 years. Fourteen (51.9%) were male. According to the Hermann scale, 33.3% had intermediate-risk and 14.9% had a high or very high risk. According to the SCORE scale, 62.97% had an intermediate-risk and 7.40% high risk. The most common acute cardiovascular complications were deep vein thrombosis and ischemic stroke (66.65%). One patient (3.7%) reported previous cardiovascular disease. Four patients (14.8%) had a fatal outcome during hospitalization. The median length of hospitalization was five days. Conclusions: We present the cases of acute cardiovascular complications in a population of oncologic patients and their vascular risk according to Hermann and SCORE scales. The most common complications were deep vein thrombosis (48.14%), stroke (18.51%), and myocardial infarction (14.81%).

Individual human cortical progenitors can produce excitatory and inhibitory neurons.

The cerebral cortex is a cellularly complex structure comprising a rich diversity of neuronal and glial cell types. Cortical neurons can be broadly categorized into two classes-excitatory neurons that use the neurotransmitter glutamate, and inhibitory interneurons that use γ-aminobutyric acid (GABA). Previous developmental studies in rodents have led to a prevailing model in which excitatory neurons are born from progenitors located in the cortex, whereas cortical interneurons are born from a separate population of progenitors located outside the developing cortex in the ganglionic eminences1-5. However, the developmental potential of human cortical progenitors has not been thoroughly explored. Here we show that, in addition to excitatory neurons and glia, human cortical progenitors are also capable of producing GABAergic neurons with the transcriptional characteristics and morphologies of cortical interneurons. By developing a cellular barcoding tool called 'single-cell-RNA-sequencing-compatible tracer for identifying clonal relationships' (STICR), we were able to carry out clonal lineage tracing of 1,912 primary human cortical progenitors from six specimens, and to capture both the transcriptional identities and the clonal relationships of their progeny. A subpopulation of cortically born GABAergic neurons was transcriptionally similar to cortical interneurons born from the caudal ganglionic eminence, and these cells were frequently related to excitatory neurons and glia. Our results show that individual human cortical progenitors can generate both excitatory neurons and cortical interneurons, providing a new framework for understanding the origins of neuronal diversity in the human cortex.

Kick-Fukui: A Fukui Function-Guided Method for Molecular Structure Prediction.

Here, we introduce a hybrid method, named Kick-Fukui, to explore the potential energy surface (PES) of clusters and molecules using the Coulombic integral between the Fukui functions in the first screening of the best individuals. In the process, small stable molecules or clusters whose combination has the stoichiometry of the explored species are used as assembly units. First, a small set of candidates has been selected from a large and stochastically generated (Kick) population according to the maximum value of the Coulombic integral between the Fukui functions of both fragments. Subsequently, these few candidates are optimized using a gradient method and density functional theory (DFT) calculations. The performance of the program has been evaluated to explore the PES of various systems, including atomic and molecular clusters. In most cases studied, the global minimum (GM) has been identified with a low computational cost. The strategy does not allow to identify the GM of some silicon clusters; however, it predicts local minima very close in energy to the GM that could be used as the initial population of evolutionary algorithms.

[Epidemiological characteristics of heart transplant recipients in Peru 2010-2020]. / Características epidemiológicas de receptores de trasplante cardiaco en el Perú, 2010-2020.

Objective: To evaluate the epidemiological, clinical, surgical, pathological characteristics and outcomes in the follow-up of heart transplant recipients at the National Cardiovascular Institute during 2010-2020. Material and Methods: A retrospective descriptive study was performed by reviewing the medical records of patients undergoing heart transplantation at a national referral center, describing the clinical, surgical, laboratory, pathology characteristics and survival of patients up to 10 years of follow-up. Results: Eighty-six patients were transplanted in 10 years, the median age was 41 years (RIQ 28-56), being predominantly male (66.3%). The three leading causes of indication for heart transplantation were: dilated cardiomyopathy (48.9%), ischemic heart disease (17.4%), and myocarditis (6.9%). Total ischemia time was 160 minutes (RIQ 129.7-233.5). Survival at one, five, and ten years was 84.8%, 73.6%, and 65.7% respectively. The main cause of death was non-cardiac: infectious (39.1%) and of unknown origin (26%). Conclusions: The main etiology of heart failure in heart transplant recipients in Peru in recent years was nonischemic dilated cardiomyopathy. We observed that the survival rate was similar to that of international registries; however, the rate of mortality due to infectious causes and death of unknown origin is high, which poses a challenge in the management of post-transplant patients.

[Incessant focal atrial tachycardia as a cause of cardiomyopathy. About a case]. / Taquicardia atrial focal incesante como causa de cardiomiopatía. A propósito de un caso.

Focal atrial tachycardia is a rare type of supraventricular tachyarrhythmia, generally present in young people, and is a rare cause of tachycardiomyopathy (10%). We present a clinical case of tachycardiomyopathy in a 30-year-old man, without comorbidities, who was diagnosed with incessant focal atrial tachycardia, refractory to medical therapy, and electrical cardioversion. Successful endocardial ablation was performed, and in outpatient follow-up at 6 months, he showed a recovery of the left ventricular ejection fraction and reduction of the left chambers to normal ranges, with progressive decrease of dyspnea.

Publisher Correction: A protein assembly mediates Xist localization and gene silencing.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A protein assembly mediates Xist localization and gene silencing.

Nuclear compartments have diverse roles in regulating gene expression, yet the molecular forces and components that drive compartment formation remain largely unclear1. The long non-coding RNA Xist establishes an intra-chromosomal compartment by localizing at a high concentration in a territory spatially close to its transcription locus2 and binding diverse proteins3-5 to achieve X-chromosome inactivation (XCI)6,7. The XCI process therefore serves as a paradigm for understanding how RNA-mediated recruitment of various proteins induces a functional compartment. The properties of the inactive X (Xi)-compartment are known to change over time, because after initial Xist spreading and transcriptional shutoff a state is reached in which gene silencing remains stable even if Xist is turned off8. Here we show that the Xist RNA-binding proteins PTBP19, MATR310, TDP-4311 and CELF112 assemble on the multivalent E-repeat element of Xist7 and, via self-aggregation and heterotypic protein-protein interactions, form a condensate1 in the Xi. This condensate is required for gene silencing and for the anchoring of Xist to the Xi territory, and can be sustained in the absence of Xist. Notably, these E-repeat-binding proteins become essential coincident with transition to the Xist-independent XCI phase8, indicating that the condensate seeded by the E-repeat underlies the developmental switch from Xist-dependence to Xist-independence. Taken together, our data show that Xist forms the Xi compartment by seeding a heteromeric condensate that consists of ubiquitous RNA-binding proteins, revealing an unanticipated mechanism for heritable gene silencing.

Clustered gamma-protocadherins regulate cortical interneuron programmed cell death.

Cortical function critically depends on inhibitory/excitatory balance. Cortical inhibitory interneurons (cINs) are born in the ventral forebrain and migrate into cortex, where their numbers are adjusted by programmed cell death. Here, we show that loss of clustered gamma protocadherins (Pcdhg), but not of genes in the alpha or beta clusters, increased dramatically cIN BAX-dependent cell death in mice. Surprisingly, electrophysiological and morphological properties of Pcdhg-deficient and wild-type cINs during the period of cIN cell death were indistinguishable. Co-transplantation of wild-type with Pcdhg-deficient interneuron precursors further reduced mutant cIN survival, but the proportion of mutant and wild-type cells undergoing cell death was not affected by their density. Transplantation also allowed us to test for the contribution of Pcdhg isoforms to the regulation of cIN cell death. We conclude that Pcdhg, specifically Pcdhgc3, Pcdhgc4, and Pcdhgc5, play a critical role in regulating cIN survival during the endogenous period of programmed cIN death.

Cell stress in cortical organoids impairs molecular subtype specification.

Cortical organoids are self-organizing three-dimensional cultures that model features of the developing human cerebral cortex1,2. However, the fidelity of organoid models remains unclear3-5. Here we analyse the transcriptomes of individual primary human cortical cells from different developmental periods and cortical areas. We find that cortical development is characterized by progenitor maturation trajectories, the emergence of diverse cell subtypes and areal specification of newborn neurons. By contrast, organoids contain broad cell classes, but do not recapitulate distinct cellular subtype identities and appropriate progenitor maturation. Although the molecular signatures of cortical areas emerge in organoid neurons, they are not spatially segregated. Organoids also ectopically activate cellular stress pathways, which impairs cell-type specification. However, organoid stress and subtype defects are alleviated by transplantation into the mouse cortex. Together, these datasets and analytical tools provide a framework for evaluating and improving the accuracy of cortical organoids as models of human brain development.

[Cardiac Amyloidosis: Experience in a National Reference Cardiovascular Institute]. / Amiloidosis Cardíaca: Experiencia en un Instituto Cardiovascular de Referencia Nacional.

Objectives: To determine the clinical, imaging and laboratory characteristics and one year after diagnosis survival of patients with cardiac amyloidosis in a national reference hospital. Materials and methods: Case series study. We evaluated the clinical characteristics, complementary examinations and survival of patients with cardiac amyloidosis diagnosed, treated and followed up in the Clinical Cardiology service of the National Cardiovascular Institute - INCOR EsSalud in Lima, Peru. Results: We found eight patients with diagnosis of cardiac amyloidosis. The median age was 64.5 years and 75% were male. The etiology of cases was unspecified cardiac amyloidosis (25%), transthyretin cardiac amyloidosis (37.5%), and light chain cardiac amyloidosis (37.5%). Symptomatic heart failure (NYHA II-III) was the most common initial presentation symptom (87.5%). The most frequent extracardiac manifestations were: sensory-motor neuropathy (62.5%), musculoskeletal (37.5%), nephropathy (25%), bilateral carpal tunnel syndrome (25%), monoclonal gammopathies (25%) and refractory pleural effusion (25 %). Survival at one year was 75% and the cause of the 2 deaths was sudden death. Conclusions: In this study of cardiac amyloidosis at a specialized center, the most frequent clinical manifestations were heart failure and sensory-motor neuropathy. Mortality was 25% per year, and in all cases as sudden death.

Exploring the Potential Energy Surface of Trimetallic Deltahedral Zintl Ions: Lowest-Energy [Sn6Ge2Bi]3- and [(Sn6Ge2Bi)2]4- Structures.

The synthesis and structural characterization of the dimer [(Sn6Ge2Bi)2]4- raise the possibility of obtaining a broad variety of analogous compounds with different Sn/Ge/Bi proportions. Several combinations of nine atoms have been detected by electrospray mass spectrometry as potential assembly units. However, [(Sn6Ge2Bi)2]4- remains as the unique experimentally characterized species in this series. This fact has motivated us to explore its potential energy surface, as well as its monomers' [Sn6Ge2Bi]3-/2-, in an effort to gain insight into the factors that might be privileging the experimental viability of this species. Our results show that the lowest-energy [Sn6Ge2Bi]3- structure remains in its oxidized product [Sn6Ge2Bi]2-, which corresponds to that identified in the dimer [(Sn6Ge2Bi)2]4-. Additionally, local minima, very close in energy to the lowest-energy monomer, are chiral mixtures that dimerize into diverse structures with a probable energetic cost, making them noncompetitive isomers. Finally, the global minimum of the dimer [(Sn6Ge2Bi)2]4- presents the most stable monomers as assembly units. These results show the importance of considering the simultaneity of all of these conditions for the viability of these types of compounds.

AUTOMATON: A Program That Combines a Probabilistic Cellular Automata and a Genetic Algorithm for Global Minimum Search of Clusters and Molecules.

A novel program for the search of global minimum structures of atomic clusters and molecules in the gas phase, AUTOMATON, is introduced in this work. This program involves the following: first, the generation of an initial population, using a simplified probabilistic cellular automaton method, which allows easy control of the adequate distribution of atoms in space; second, the fittest individuals are selected to evolve, through genetic operations (mating and mutations), until the best candidate for a global minimum surfaces. In addition, we propose a simple way to build the descendant structures by establishing a ranking of genes to be inherited. Thus, by means of a chemical formula checker procedure, genes are transferred to the offspring, ensuring that they always have the appropriate type and number of atoms. It is worth noting that a fraction of the fittest group is subject to mutation operations. This program also includes algorithms to identify duplicate structures: one based on geometric similarity and another on the similar distribution of atomic charges. The effectiveness of the program was evaluated in a group of 45 molecules, considering organic and organometallic compounds (benzene, cyclopentadienyl anion, and ferrocene), Zintl ion clusters [Sn9- m- nGe mBi n](4- n)- ( n = 1-4 and m = 0-(9- n)), star-shaped clusters (Li7E5+, E = BH, C, Si, Ge) and a variety of boron-based clusters. The global minimum and the lowest-energy isomers reported in the literature were found for all the cases considered in this article. These results successfully prove AUTOMATON's effectiveness on the identification of energetically preferred structures of a wide variety of chemical species.

Heart failure complicating myocardial infarction. A report of the Peruvian Registry of ST-elevation myocardial infarction (PERSTEMI).

OBJECTIVES: The aim of this study is to determine the incidence, associated factors, and 30-day mortality of patients with heart failure (HF) after ST elevation myocardial infarction (STEMI) in Peru. METHODS: Observational, cohort, multicentre study was conducted at the national level on patients enrolled in the Peruvian registry of STEMI, excluding patients with a history of HF. A comparison was made with the epidemiological characteristics, treatment, and 30 day-outcome of patients with (Group 1) and without (Group 2) heart failure after infarction. RESULTS: Of the 388 patients studied, 48.7% had symptoms of HF, or a left ventricular ejection fraction <40% after infarction (Group 1). Age>75 years, anterior wall infarction, and the absence of electrocardiographic signs of reperfusion were the factors related to a higher incidence of HF. The hospital mortality in Group 1 was 20.6%, and the independent factors related to higher mortality were age>75 years, and the absence of electrocardiographic signs of reperfusion. CONCLUSIONS: Heart failure complicates almost 50% of patients with STEMI, and is associated with higher hospital and 30-day mortality. Age greater than 75 years and the absence of negative T waves in the post-reperfusion ECG are independent factors for a higher incidence of HF and 30-day mortality.

Heart failure complicating myocardial infarction. A report of the Peruvian Registry of ST-elevation myocardial infarction (PERSTEMI) / Insuficiencia cardiaca complicando el infarto de miocardio. Un reporte de Peruvian Registry of ST-elevation Myocardial Infarction (PERSTEMI)

Abstract Objectives: The aim of this study is to determine the incidence, associated factors, and 30-day mortality of patients with heart failure (HF) after ST elevation myocardial infarction (STEMI) in Peru. Methods: Observational, cohort, multicentre study was conducted at the national level on patients enrolled in the Peruvian registry of STEMI, excluding patients with a history of HF. A comparison was made with the epidemiological characteristics, treatment, and 30 day-outcome of patients with (Group 1) and without (Group 2) heart failure after infarction. Results: Of the 388 patients studied, 48.7% had symptoms of HF, or a left ventricular ejection fraction <40% after infarction (Group 1). Age > 75 years, anterior wall infarction, and the absence of electrocardiographic signs of reperfusion were the factors related to a higher incidence of HF. The hospital mortality in Group 1 was 20.6%, and the independent factors related to higher mortality were age > 75 years, and the absence of electrocardiographic signs of reperfusion. Conclusions: Heart failure complicates almost 50% of patients with STEMI, and is associated with higher hospital and 30-day mortality. Age greater than 75 years and the absence of negative T waves in the post-reperfusion ECG are independent factors for a higher incidence of HF and 30-day mortality.

Resumen Objetivos: Se desea saber la incidencia, los factores asociados y la mortalidad a 30 días de los pacientes con insuficiencia cardiaca (IC) postinfarto de miocardio con elevación del segmento ST (IMCEST) en Perú. Métodos: Estudio observacional, de cohortes, multicéntrico a nivel nacional, de pacientes enrolados en el registro peruano de IMCEST, excluyendo los pacientes con antecedente de IC. Se compararon las características epidemiológicas, tratamiento y evolución a 30 días de los pacientes con (grupo 1) y sin (grupo 2) IC postinfarto. Resultados: De 388 pacientes se encontró un 48.7% con síntomas de IC o fracción de eyección de ventrículo izquierdo < 40% postinfarto (grupo 1). La edad > 75 años, el infarto de pared anterior y la ausencia de signos electrocardiográficos de reperfusión fueron los factores relacionados a mayor incidencia de IC. La mortalidad intrahospitalaria en el grupo 1 fue del 20.6% y los factores independientes relacionados a mayor mortalidad fueron la edad > 75 años y la ausencia de signos electrocardiográficos de reperfusión. Conclusiones: La IC complica casi al 50% de pacientes con IMCEST y está asociada a mayor mortalidad intrahospitalaria y a 30 días. La edad > 75 años y la ausencia de ondas T negativas en el electrocardiograma posreperfusión son factores independientes de mayor incidencia de IC y de mortalidad a 30 días.

Transplantation of GABAergic interneurons for cell-based therapy.

Many neurological disorders stem from defects in or the loss of specific neurons. Neuron transplantation has tremendous clinical potential for central nervous system therapy as it may allow for the targeted replacement of those cells that are lost in diseases. Normally, most neurons are added during restricted periods of embryonic and fetal development. The permissive milieu of the developing brain promotes neuronal migration, neuronal differentiation, and synaptogenesis. Once this active period of neurogenesis ends, the chemical and physical environment of the brain changes dramatically. The brain parenchyma becomes highly packed with neuronal and glial processes, extracellular matrix, myelin, and synapses. The migration of grafted cells to allow them to home into target regions and become functionally integrated is a key challenge to neuronal transplantation. Interestingly, transplanted young telencephalic inhibitory interneurons are able to migrate, differentiate, and integrate widely throughout the postnatal brain. These grafted interneurons can also functionally modify local circuit activity. These features have facilitated the use of interneuron transplantation to study fundamental neurodevelopmental processes including cell migration, cell specification, and programmed neuronal cell death. Additionally, these cells provide a unique opportunity to develop interneuron-based strategies for the treatment of diseases linked to interneuron dysfunction and neurological disorders associated to circuit hyperexcitability.