Probing Quantum Efficiency: Exploring System Hardness in Electronic Ground State Energy Estimation.

We consider the question of how correlated the system hardness is between classical algorithms of electronic structure theory in ground state estimation and quantum algorithms. To define the system hardness for classical algorithms, we employ empirical criterion based on the deviation of electronic energies produced by coupled cluster and configuration interaction methods from the exact ones along multiple bonds dissociation in a set of molecular systems. For quantum algorithms, we have selected the Variational Quantum Eigensolver (VQE) and Quantum Phase Estimation (QPE) methods. As characteristics of the system hardness for quantum methods, we analyzed circuit depths for the state preparation, the number of quantum measurements needed for the energy expectation value, and various cost characteristics for the Hamiltonian encodings via Trotter approximation and linear combination of unitaries (LCU). Our results show that the quantum resource requirements are mostly unaffected by classical hardness, with the only exception being the state preparation part, which contributes to both VQE and QPE algorithm costs. However, there are clear indications that constructing the initial state with a significant overlap with the true ground state is easier than obtaining the state with an energy expectation value within chemical precision. These results support optimism regarding the identification of a molecular system where a quantum algorithm excels over its classical counterpart, as quantum methods can maintain efficiency in classically challenging systems.

Serine Depletion Promotes Anti-Tumor Immunity by Activating Mitochondrial DNA-mediated cGAS-STING Signaling.

Serine is critical for supporting cancer metabolism, and depriving malignant cells of this non-essential amino acid exerts anti-neoplastic effects, in large part, through disrupting metabolic pathways. Given the intricate relationship between cancer metabolism and the immune system, the metabolic defects imposed by serine deprivation might impact tumor-targeting immunity. Here, we demonstrated that restricting endogenous and exogenous sources of serine in colorectal cancer (CRC) cells results in mitochondrial dysfunction, leading to mitochondrial DNA (mtDNA) accumulation in the cytosol and consequent cGAS-STING1-driven type I interferon (IFN) secretion. Depleting mtDNA or blocking its release attenuated cGAS-STING1 activation during serine deprivation. In vivo studies revealed that serine deprivation limits tumor growth, accompanied by enhanced type I IFN signaling and intratumoral infiltration of immune effector cells. Notably, the tumor-suppressive and immune-enhancing effects of serine restriction were impaired by T cell depletion and IFN receptor blockade. Moreover, disrupting cGAS-STING1 signaling in CRC cells limited the immunostimulatory and tumor-suppressive effects of serine deprivation. Lastly, serine depletion increased the sensitivity of tumors to an immune checkpoint inhibitor targeting PD-1. Taken together, these findings reveal a role for serine as a suppressor of anti-tumor immunity, suggesting that serine deprivation may be employed to enhance tumor immunogenicity and improve responsiveness to immune checkpoint inhibitors.

Un acercamiento a las variables y su escala de clasificación, a través de la "edad" como variable de estudio

La operacionalización de las variables constituye una acción investigativa de gran importancia metodológica. En este artículo se repasan, someramente, aspectos teóricos acerca de las variables de estudio, con el propósito de fundamentar la mayor utilidad y conveniencia de declarar, en el proyecto de investigación, el tipo de escala que será empleada para la agrupación de los datos provenientes de las unidades de análisis, en lugar del tipo de variable, como suele hacerse. Esta idea adquiere un evidente sentido práctico cuando se trabaja con variables cuantitativas.

The variables' operationalization constitutes a research action of great methodological importance. This article briefly reviews theoretical aspects about the study variables, to substantiate the greatest usefulness and convenience of declaring, in the research project, the type of scale that will be used to group the data coming from of the units of analysis, instead of the type of variable, as is usually done. This idea takes on an obvious practical meaning when working with quantitative variables.

Contribución de la Facultad de Ciencias Médicas de Cienfuegos a la utilización de la tecnología computacional en la docencia médica superior. Reseña del empleo de simulaciones clínicas en el periodo 1990-2007

El artículo ha tenido como objetivo reseñar, de forma cronológica, los acontecimientos más relevantes relacionados con la utilización de simulaciones computarizadas en el proceso docente, en el contexto particular de la Facultad de Ciencias Médicas de Cienfuegos durante el periodo 1990-2007. Entre los acontecimientos identificados se encuentran los siguientes: la elaboración e introducción de simulaciones en la asignatura Medicina Interna correspondiente al tercer año de la carrera (curso 1990-1991); la introducción de la simulación, con fines evaluativos, en el internado de Medicina Interna (1997-2000); el desarrollo de un nuevo software para la elaboración de simulaciones (2002); y la extensión del uso de simulaciones a los seminarios de actualización terapéutica correspondientes al internado de Pediatría (2007). Se evidenció que la contribución realizada por la institución docente al tema abordado, no solo consistió en la elaboración de ejercicios de simulación y su introducción en la práctica formativa, sino también en la ejecución de acciones dirigidas a la capacitación de profesores, el perfeccionamiento de las herramientas utilizadas (programas, metodologías) y la socialización de las experiencias; todo lo cual se acompañó de una amplia actividad investigativa que mereció reconocimientos a diferentes niveles.

The objective of this article is to review chronologically, the most relevant events related to the use of computerized simulations in the teaching process, in the particular context of the Cienfuegos Medical Sciences Faculty from 1990 to 2007. Among the identified events are: the development and introduction of simulations in the Internal Medicine subject corresponding to the third year of the degree (course 1990-1991); the introduction of simulation, for evaluation purposes, in the Internal Medicine internship (1997-2000); the development of a new software for the elaboration of simulations (2002); and the extension of the use of simulations to therapeutic update seminars corresponding to the Pediatrics internship (2007). It was evidenced that the contribution made by the educational institution to the topic addressed, not only consisted in the preparation of simulation exercises and their introduction in the training practice, but also in the teacher training, the improvement of the tools used (programs, methodologies) and the sharing of experiences; all of which was accompanied by extensive research activity that deserved recognition at different levels.

Cost Evaluation of Professional Services in a Rural Community Pharmacy: A Monocentric Exploratory Approach.

The increasing pressure on healthcare systems (HCSs) is a cause for concern worldwide. Rising costs, uncertainty about sustainability, and aging populations are the main issues that make it challenging to allocate scarce resources to the needs of HCSs. Clinical professional pharmacy services (PSs) have been shown to help alleviate system stress and to reach the entire population, although a cost of provision is borne. The objective of this study was to evaluate the provision costs of three PSs, a medicine-dispensing service (MDS), a multicompartmental compliance aid system service (MCAS), and a cognitive impairment screening service (CISS), in a rural community pharmacy. A cost analysis was performed using a time-driven activity-based costing model. The time dedicated to PS provision was appropriately recorded, and the corresponding expenses were extracted from the accounting records. A provision time of 4.80 min and a cost of EUR 2.24 were estimated for the MDS, while 18.33 min and EUR 8.73 were calculated for the MCAS, and 122.20 min and EUR 56.72 were calculated for the CISS. The total provision time represented 85% of the pharmacist's effective working time. Tailored cost analysis is a useful tool for making decisions on the implementation of a PS. Larger studies including a variety of pharmacies and locations are necessary to accurately assess costs and engage in discussions on funding and remuneration.

Uso y abuso de los criterios de inclusión y exclusión en el proyecto de investigación

Uno de los aspectos metodológicos esenciales de una investigación es la delimitación de los sujetos a estudiar. Este artìculo aborda la tendencia actual a una excesiva e injustificada declaración de los criterios de inclusión y de exclusión en todo tipo de investigación. Se defiende la idea de que una adecuada utilización de las categorías universo y muestra hace innecesaria la declaración de criterios de inclusión y de exclusión en el diseño metodológico de la mayoría de los proyectos de trabajo de terminación de la especialidad que presentan nuestros residentes.

One of the essential methodological aspects of an investigation is the delimitation of the subjects to be studied. This article addresses the current trend towards an excessive and unjustified statement of inclusion and exclusion criteria in all types of research. The idea is defended that an adequate use of the universe and sample categories makes it unnecessary to declare inclusion and exclusion criteria in the methodological design of most of the specialty completion work projects presented by our residents.

Cellular shortening and calcium dynamics are improved by noisy stimulus in a model of cardiomyopathy.

Noise is present in cell biology. The capability of cells to respond to noisy environment have become essential. This study aimed to investigate whether noise can enhance the contractile response and Ca2+ handling in cardiomyocytes from a cardiomyopathy model. Experiments were conducted in an experimental setup with Gaussian white noise, frequency, and amplitude control to stimulate myocytes. Cell shortening, maximal shortening velocity, time to peak shortening, and time to half relaxation variables were recorded to cell shortening. Ca2+ transient amplitude and raise rate variables were registered to measure Ca2+ transients. Our results for cell shortening, Ca2+ transient amplitude, and raise rate suggest that cell response improve when myocytes are noise stimulated. Also, cell shortening, maximal shortening velocity, Ca2+ transient amplitude, and raise improves in control cells. Altogether, these findings suggest novel characteristics in how cells improve their response in a noisy environment.

Correction: How much (ATP) does it cost to build a trypanosome? A theoretical study on the quantity of ATP needed to maintain and duplicate a bloodstream-form Trypanosoma brucei cell.

[This corrects the article DOI: 10.1371/journal.ppat.1011522.].

¿Mi estudio es transversal o longitudinal?

La clasificación de los estudios en transversales o longitudinales constituye uno de los aspectos metodológicos que se declaran en los proyectos de investigación correspondientes a los trabajos de terminación de la especialidad. En este artículo se ofrecen elementos esclarecedores para la distinción entre ambos tipos de estudios; en este sentido, se considera que la esencia definitoria del estudio longitudinal radica en el interés del investigador por los cambios en el tiempo del fenómeno investigado.

The studies' classification as cross-sectional or longitudinal constitutes one of the methodological aspects that are declared in the research projects corresponding to the specialty's completion works. This article offers clarifying elements for the distinction between both types of studies; In this sense, it is considered that the longitudinal study's defining essence lies in the researcher's interest in the changes over time of the investigated phenomenon.

How much (ATP) does it cost to build a trypanosome? A theoretical study on the quantity of ATP needed to maintain and duplicate a bloodstream-form Trypanosoma brucei cell.

ATP hydrolysis is required for the synthesis, transport and polymerization of monomers for macromolecules as well as for the assembly of the latter into cellular structures. Other cellular processes not directly related to synthesis of biomass, such as maintenance of membrane potential and cellular shape, also require ATP. The unicellular flagellated parasite Trypanosoma brucei has a complex digenetic life cycle. The primary energy source for this parasite in its bloodstream form (BSF) is glucose, which is abundant in the host's bloodstream. Here, we made a detailed estimation of the energy budget during the BSF cell cycle. As glycolysis is the source of most produced ATP, we calculated that a single parasite produces 6.0 x 1011 molecules of ATP/cell cycle. Total biomass production (which involves biomass maintenance and duplication) accounts for ~63% of the total energy budget, while the total biomass duplication accounts for the remaining ~37% of the ATP consumption, with in both cases translation being the most expensive process. These values allowed us to estimate a theoretical YATP of 10.1 (g biomass)/mole ATP and a theoretical [Formula: see text] of 28.6 (g biomass)/mole ATP. Flagellar motility, variant surface glycoprotein recycling, transport and maintenance of transmembrane potential account for less than 30% of the consumed ATP. Finally, there is still ~5.5% available in the budget that is being used for other cellular processes of as yet unknown cost. These data put a new perspective on the assumptions about the relative energetic weight of the processes a BSF trypanosome undergoes during its cell cycle.

Long-term potentiation and its neurotrophin-dependent modulation in the superior cervical ganglion of the rat are influenced by KCNQ channel function.

Ganglionic long-term potentiation (gLTP) in the rat superior cervical ganglion (SCG) is differentially modulated by neurotrophic factors (Nts): brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). KCNQ/M channels, key regulators of neuronal excitability, and firing pattern are modulated by Nts; therefore, they might contribute to gLTP expression and to the Nts-dependent modulation of gLTP. In the SCG of rats, we characterized the presence of the KCNQ2 isoform and the effects of opposite KCNQ/M channel modulators on gLTP in control condition and under Nts modulation. Immunohistochemical and reverse transcriptase polymerase chain reaction analyses showed the expression of the KCNQ2 isoform. We found that 1 µmol/L XE991, a channel inhibitor, significantly reduced gLTP (∼50%), whereas 5 µmol/L flupirtine, a channel activator, significantly increased gLTP (1.3- to 1.7-fold). Both modulators counterbalanced the effects of the Nts on gLTP. Data suggest that KCNQ/M channels are likely involved in gLTP expression and in the modulation exerted by BDNF and NGF.

Una mirada a las series de casos y sus unidades de análisis

Las series de casos constituyen un tipo particular de estudio de uso muy frecuente en la investigación clínica. En este artículo se pretende resaltar la utilidad y plena vigencia de estos estudios como propuestas de proyectos de terminación de la especialidad, así como abordar sus particularidades más importantes en la delimitación de sus unidades de análisis. Cuando son bien realizadas, estas investigaciones constituyen una excelente fuente de actualización del conocimiento médico y una magnífica oportunidad para que los investigadores jóvenes se entrenen en el campo de la investigación científica.

Case series are a particular type of study that is very frequently used in clinical research. This article intends to highlight the usefulness and full validity of these studies as proposals for completion projects of the specialty, as well as to address their most important particularities in the delimitation of their analysis units. When they are well carried out, these researches constitute an excellent source of updating medical knowledge and a magnificent opportunity for young researchers to train in the scientific research field.

The impact of COVID-19 infection on labor outcomes of Mexican formal workers.

The outbreak of the COVID-19 pandemic had an immediate and severe impact on the economy. However, we do not know whether the disease may have a longer-term effect on people's employment opportunities. In this study, we focus on the effects of COVID-19 infection on labor market outcomes 12 months after diagnosis. We use a unique dataset that includes all formal private sector workers in the Mexican social security system and that links health outcomes with administrative records. We implement two alternative identification strategies to estimate the impact: matching estimators and individual fixed effects models. Our study finds that COVID-19 infection does not harm employment probabilities or wages. On the contrary, we find that workers who had tested positive for COVID had a higher likelihood of keeping their formal sector jobs and higher wages than those who did not. Moreover, our results describe mostly low-income workers.

Las hipótesis en el proyecto de investigación: ¿cuándo si, cuándo no?

La utilización de hipótesis en los proyectos de trabajo de terminación de la especialidad constituye uno de los aspectos metodológicos que amerita un análisis. El artículo pretende esclarecer a los investigadores jóvenes cuándo en una investigación debe ser declarada esta categoría. Se sugiere utilizar el alcance de la investigación (exploratorio, descriptivo, correlacional o explicativo) para la decisión de empleo o no de hipótesis en un proyecto investigativo. Se detallan condiciones que determinan el uso de hipótesis específicamente en los estudios descriptivos, los más frecuentemente realizados por los residentes.

The use of hypotheses in the specialty finishing projects constitutes one of the methodological aspects that deserves an analysis. The article aims to clarify for young researchers when this category should be declared in a research. It is suggested to use the scope of the research (exploratory, descriptive, correlational or explanatory) for the decision of whether or not to use hypotheses in a research project. Conditions that determine the use of hypotheses specifically in descriptive studies, the most frequently carried out by residents are detailed.

p53 engages the cGAS/STING cytosolic DNA sensing pathway for tumor suppression.

Tumor suppression by TP53 involves cell-autonomous and non-cell-autonomous mechanisms. TP53 can suppress tumor growth by modulating immune system functions; however, the mechanistic basis for this activity is not well understood. We report that p53 promotes the degradation of the DNA exonuclease TREX1, resulting in cytosolic dsDNA accumulation. We demonstrate that p53 requires the ubiquitin ligase TRIM24 to induce TREX1 degradation. The cytosolic DNA accumulation resulting from TREX1 degradation activates the cytosolic DNA-sensing cGAS/STING pathway, resulting in induction of type I interferons. TREX1 overexpression sufficed to block p53 activation of the cGAS/STING pathway. p53-mediated induction of type I interferon (IFNB1) is suppressed by cGAS/STING knockout, and p53's tumor suppressor activities are compromised by the loss of signaling through the cGAS/STING pathway. Thus, our study reveals that p53 utilizes the cGAS/STING innate immune system pathway for both cell-intrinsic and cell-extrinsic tumor suppressor activities.

Quantitative EEG Analysis in Angelman Syndrome: Candidate Method for Assessing Therapeutics.

The goal of these studies was to use quantitative (q)EEG techniques on data from children with Angelman syndrome (AS) using spectral power analysis, and to evaluate this as a potential biomarker and quantitative method to evaluate therapeutics. Although characteristic patterns are evident in visual inspection, using qEEG techniques has the potential to provide quantitative evidence of treatment efficacy. We first assessed spectral power from baseline EEG recordings collected from children with AS compared to age-matched neurotypical controls, which corroborated the previously reported finding of increased total power driven by elevated delta power in children with AS. We then retrospectively analyzed data collected during a clinical trial evaluating the safety and tolerability of minocycline (3 mg/kg/d) to compare pretreatment recordings from children with AS (4-12 years of age) to EEG activity at the end of treatment and following washout for EEG spectral power and epileptiform events. At baseline and during minocycline treatment, the AS subjects demonstrated increased delta power; however, following washout from minocycline treatment the AS subjects had significantly reduced EEG spectral power and epileptiform activity. Our findings support the use of qEEG analysis in evaluating AS and suggest that this technique may be useful to evaluate therapeutic efficacy in AS. Normalizing EEG power in AS therefore may become an important metric in screening therapeutics to gauge overall efficacy. As therapeutics transition from preclinical to clinical studies, it is vital to establish outcome measures that can quantitatively evaluate putative treatments for AS and neurological disorders with distinctive EEG patterns.

Addressing Psychosocial Factors in Cognitive Impairment Screening from a Holistic Perspective: The DeCo-Booklet Methodology Design and Pilot Study.

Cognitive impairment (CI), an intermediate phase between the decline in physiological cognition and dementia, is known to be mediated by a variety of risk and protective factors, with age being the most influential of these. The multifactorial nature of CI and the worldwide phenomenon of an aging population makes decoupling old age from disease through the concept of healthy aging (HA) a matter of major interest. Focusing on psychosocial variables and psychological constructs, here we designed and piloted a data collection booklet (DeCo-B) to assess CI and HA from a holistic perspective. The DeCo-B comprises six sections: sociodemographic factors, CI, meaning in life, psychosocial factors, health problems, and lifestyle. The estimated prevalence of CI and HA in our cohort were 24.4% and 6.6%, respectively. Spearman correlations mainly identified pairwise associations between the meaning in life domains and psychosocial variables. Moreover, age, marital status, purpose in life, resilience, chronic pain, cognitive reserve, and obstructive sleep apnea were significantly associated with an increased risk of CI. Our results showed that DeCo-B is a suitable tool for researching how modifiable risk and protective factors influence cognitive status. The complex interrelationships between variables should be further investigated and, for practical reasons, the questionnaire should be optimized in future work.

La relación problema-objetivo-diseño metodológico en el proyecto de investigación: una mirada a través de una situación ejemplo / The problem-objective-methodological design relationship in the research project: a look through an example situation

RESUMEN Las investigaciones relacionadas con factores de riesgo para las enfermedades, así como sobre factores pronósticos de diversos problemas de salud, constituyen propuestas frecuentes de proyectos de trabajos de terminación de la especialidad. En este artículo se ejemplifica, a través de diferentes variantes para la realización de estas investigaciones, la consecución de la imprescindible relación entre el problema de investigación, el objetivo y el diseño metodológico del estudio.

ABSTRACT Research related to risk factors for diseases, as well as prognostic factors for various health problems, are frequent proposals for completion projects in the specialty. This article exemplifies, through different variants for carrying out these investigations, the achievement of the essential relationship between the research problem, the objective and the methodological design of the study.

Impact of the withdrawal of renin-angiotensin-aldosterone inhibitors on mortality in COVID-19 patients.

Background: Chronic use of Angiotensin-converting enzyme (ACE) inhibitors (ACEi) and aldosterone-receptor blockers (ARB) is not associated with worse outcomes in patients with COVID-19. However, evidence on the impact of their discontinuation during hospital admission is scarce. Our aim was to determine whether withdrawal of ACEi, ARB and mineralocorticoid receptor antagonists (MRA) is associated with all-cause mortality in a real-life large cohort of patients with SARS-CoV-2 infection. Methods: Observational cohort study from a large referral center from 1 March 2020 to 20 April 2020. Withdrawal of renin-angiotensin-aldosterone system inhibitors was defined as the absence of any received dose during hospital admission in patients receiving chronic treatment. Prescriptions during admission were confirmed by data from the central pharmacy computerized system. Results: A total of 2042 patients (mean age 68.4±17.6, 57.1% male) with confirmed COVID-19 were included. During a median follow-up of 57 (21-55) days, 583 (28.6%) died. Prior to hospital admission 468 (22.9%), 343 (16.8%) and 83 (4.1%) patients were receiving ACEi, ARB and MRA respectively. During the study period, 216 (46.2%), 193 (56.3%) and 41 (49.4%) were withdrawn from the corresponding drug. After adjusting for age, cardiovascular risk factors, baseline comorbidities and in-hospital COVID-19 dedicated treatment, withdrawal of ACE inhibitors (hazard ration [HR] 1.48 [95% confidence interval -CI- 1.16-1.89]) and MRA (HR 2.01 [95% CI 1.30-3.10]) were shown to be independent predictors of all-cause mortality. No independent relationship between ARB withdrawal and mortality was observed. Conclusion: ACEi and MRA withdrawal were associated with higher mortality. Strong consideration should be given to not discontinuing these medications during hospital admission.

Introdução: O uso crónico de inibidores da ECA (IECA) e de antagonistas dos recetores de aldosterona (ARA) não está associado a resultados piores em doentes com Covid-19. No entanto, a evidência relativa ao impacto da sua retirada durante a admissão hospitalar é escassa. O nosso objetivo foi determinar se a retirada do IECA, ARA e antagonistas dos recetores dos mineralocorticóides (ARM) está associada à mortalidade por todas as causas numa grande coorte real de doentes com infeção por SRA-CoV-2. Métodos: Estudo coorte observacional a partir de um grande centro de referência de 1 de março de 2020 a 20 de abril de 2020. A retirada dos inibidores do sistema RAAS foi definida como a ausência de qualquer dose recebida durante a admissão hospitalar em doentes que recebem tratamento prolongado. As prescrições durante a admissão foram confirmadas por dados do sistema informático da farmácia central. Resultados: Um total de 2042 doentes (idade média de 68,4 ±17,6, 57,1% do sexo masculino) com COVID-19 confirmado foram incluídos. Durante um acompanhamento médio de 57 (21-55) dias, 583 (28,6%) morreram. Conclusão: A retirada do IECA e do ARM foi associada a uma mortalidade mais elevada. Deve ser dada grande atenção para não interromper estes medicamentos durante a admissão hospitalar.

Leishmania (Leishmania) mexicana Infection in Wild Rodents from an Emergent Focus of Cutaneous Leishmaniasis in Yucatan, Mexico.

In 2015, emergent cases of localized cutaneous leishmaniasis (LCL) were reported in Tinum, Yucatan, Mexico. As part of an eco-epidemiological study to characterize the elements that trigger Leishmania infection in that area, we conducted a field study to investigate the occurrence of Leishmania infection in wild rodents. From November 2019 to February 2020, rodents were caught from three sites located in the municipality of Tinum, Yucatan. For each specimen, clinical signs suggestive of Leishmania infection were recorded. Samples from the tail, liver, and spleen were taken for the identification of Leishmania DNA by PCR. Twenty rodents belonging to two species were caught including Heteromys gaumeri (55%, 11/20) and Ototylomys phyllotis (45%, 9/20). Fifty-five percent of the animals presented white spots on the tail, 15% had splenomegaly, and 5% had hepatomegaly. Fifty-five percent (11/20) of the animals were found infected by Leishmania. Heteromys gaumeri was caught in all trapping sites and was the most infected species (63.6%, 7/11). The percentage of infection for O. phyllotis was 44.4% (4/9). Leishmania (Leishmania) mexicana was identified as the infecting species in two H. gaumeri. This study provides, for the first time, evidence of Leishmania infection in wild rodents from the Yucatan state. Heteromys gaumeri and O. phyllotis may be involved in the transmission cycle of L. mexicana in this emergent focus; however, further longitudinal studies are needed to confirm their role as primary reservoirs.