bluuebunny/crossref_metadata_2025 huggingface dataset:
Proceso contable y emprendimientos familiares creados durante el COVID 19, en la parroquia La Dolorosa del cantón Azogues, año 2021
Authors: Castro-Lema Johanna Janneth , Pico-Gutiérrez Eduardo Vinicio
Published: August 2022

El presente trabajo de investigación se enfoca en analizar el proceso de contabilidad para buen funcionamiento a las empresas familiares, creadas en la pandemia de Covid-19, en el cantón Azogues, Provincia de Cañar. Cabe destacar que la contabilidad empresarial, para todo modelo de negocio es necesario, ya que les va a permitir ejercer el control y tomar las decisiones necesarias para lograr los resultados propuestos. Para la recolección de datos, se aplicó como técnica; la encuesta a 200 habitantes de los emprendedores familiares, mediante un cuestionario creado en la aplicación web de Google Forms. Luego de la información recaba, se realizó la respectiva tabulación y análisis de las encuestas. Para conocer el conocimiento que tienen los emprendedores sobre la contabilidad, se utilizó como método de trabajo de investigación el inductivo para el desarrollo de los conceptos descomponiéndolos en sus partes, que permitieron identificar el deficiente conocimiento de los emprendedores sobre las Normas generales y manejo del registro contable de su negocio, ya que esto va a permitir conocer los posibles escenarios y la viabilidad de que los emprendimientos familiares funcionen y mejoren sus ingresos económicos; teniendo sentido financiero y operativo. La estructura contable básica, incluido el registro de las transacciones diarias, es la contribución más importante de este estudio ya que ayude al empresario a tener una comprensión más amplia de los controles del negocio.
Análisis del marketing digital en las pymes de la ciudad de Machala. Estudio en tiempos de COVID
Authors: Zambrano-Luna Rocio Anamileth , Figueroa-Celi María De Los Ángeles , Mora-Sanchez Norman Vinicio , Pacheco-Molina Andrés Marcelo
Published: August 2022

La investigación expone la evaluación del Marketing digital sobre el impacto que tiene en el desempeño estratégico y financiero a través de un análisis estadístico en el software SPSS, el objetivo de la investigación se baso en estudiar a través de un modelo investigativo la significancia relacional de los constructos objeto de estudio, la investigación uso una estructura metodológica cuantitativa con alcance correlacional, en una muestra de 230 PYMES de la ciudad de Machala. Como resultado del estudio se obtuvo respuestas que difieren de las hipótesis, entendiendo así el comportamiento del Marketing digital en los negocios, los efectos verifican la valoración que obtuvieron los constructos entre sí, se obtuvo valoraciones no esperadas, concluyendo que la gestión del Marketing digital esta subdesarrollada por parte de las pequeñas y medianas empresas en la ciudad de Machala.
Diseño de un modelo de cadena de valor para los agronegocios en la provincia de El Oro
Authors: Poma-Hidalgo Edinson Jayro , Carvajal-Romero Héctor , Quezada-Campoverde Jessica Maribel , Vega-Granda Andrea del Cisne
Published: August 2022

La provincia de El Oro es netamente agrícola, dado al contexto actual de las dificultades asociadas a la crisis económica y financiera, producto de la pandemia Covid-19, el desarrollo de las pequeñas y medianas empresas se visto afectado. El alcance de la presente investigación es de tipo no experimental, se determinó como principal objetivo realizar el diseño de un modelo de cadena de valor para los agronegocios en la provincia de El Oro, para los tres principales productos agrícolas de mayor producción, banano, café y cacao. La cadena de valor en la producción agroalimentaria es fundamental para dinamizar la economía local, sin embargo, los beneficios para los productores agrícolas que decidan utilizar la cadena de valor en el eslabón en el que participa, logran introducir incrementos de productividad e innovaciones en el producto, servicio. El presente estudio recopiló la información de algunos agentes que participan en la cadena de valor de la producción- comercialización. Se evidencia que los pequeños productores son los que menos utilizan la cadena de valor, mientras que los grandes productores si lo utilizan obteniendo mayores ingresos y una apropiación más equilibrada del valor agregado, permite a los agronegocios tener una dinámica en cuanto a la búsqueda de estrategias de mercado, innovación y mejora continua y se adapte fácilmente a las condiciones macroeconómicas del país.
realidad de la multiculturalidad en los sistemas de salud ecuatorianos
Authors: Flores-Bosmediano Edison Marcos , Núñez-Silva Gualberto Bolívar , Flores-Benitez Fernando Rene
Published: August 2022

Durante varias décadas, el estado y las instituciones ecuatorianas han visibilizado y se han preocupados por las comunidades etnias de país, construyendo leyes, normativas, planes, entre otros. En ese sentido, esta investigación tiene como objetivo analizar la interacción de los sistemas de salud ecuatorianos con las comunidades etnias y como se puede insertar sus procesos ancestrales dentro de sus políticas. La metodología utilizada tiene un abordaje cualitativo, de tipo documental con un enfoque bibliográfico, donde se consultaron diferentes artículos científicos, tesis, libros, documentos de organizaciones internacionales y nacionales, constituciones, leyes, entre otros, existen mucha información relevante lo cual es muy significativo, pero se tuvo que tomar la información que sustentaran en forma precisa en tema. Se obtuvo como resultados las conceptualizaciones y caracterizaciones de etnia, multiculturalidad, las bases legales fundamentales que apoyan a dichas comunidades y como se ha tratado el factor salud en esas comunidades, permitiendo el análisis de cómo han interactuado a la fecha los sistemas de salud ecuatoriano con las diferentes etnias de Ecuador. Se obtuvo como conclusión principal que, pese a todas las leyes, normativas e iniciativas por parte del estado, aún en los centros de salud no se observa la incorporación de medicinas tradicionales y complementarias, ni se observa mucho interés por partes de miembros del sector salud adquirir las competencias para su aplicación.
Ventas en línea de los productos de consumo masivo como estrategia de crecimiento de las mypymes en la ciudad de Portoviejo
Authors: Cedeño-Fernández Héctor Lenín , Zaldumbide-Peralvo David Alejandro
Published: August 2022

Desde la llegada de la internet, las ventas en línea comenzaron a crecer significativamente, pasando de ser un mecanismo empleado por unas cuentas grandes empresas, a ser una herramienta fundamental para múltiples negocios. En el presente trabajo se analizó el papel de las ventas en línea de productos de consumo masivo en el crecimiento de mypymes de la Calle Chile de la ciudad de Portoviejo, Ecuador. La importancia de este tipo de análisis estriba en conocer si a raíz de la pandemia se iniciaron cambios en este tipo de negocios, los cuales, a diferencia de las dinámicas comerciales en otros sectores como la gastronomía o el comercio de tecnologías, no habían tenido el mismo proceso de digitalización comercial. Por lo cual, empleando cuestionarios, se buscó determinar si algunos aspectos como la infraestructura digital, ventas en línea, fomento público, entre otras, influyeron en el crecimiento de estas a través de la relación con las ventas totales. Se halló que, a diferencia de otros estudios, las ventas en línea no representan un factor influyente en el crecimiento de las mypymes analizadas.
Calidad del servicio de consulta externa, en establecimientos de salud pública nivel II de la ciudad de Portoviejo, Ecuador
Authors: Mera-Risco Ximena Lourdes
Published: August 2022

En los servicios de salud es prioritaria la atención interpersonal, a través de este aspecto se identifica el cumplimiento de las expectativas del usuario y su nivel de satisfacción respecto a la calidad del servicio recibido. El objetivo de este estudio es evaluar la calidad del servicio de consulta externa, en Establecimientos de Salud Pública (ESP), nivel II de la ciudad de Portoviejo. La investigación se realizó con un enfoque cuantitativo, tipo descriptivo, con un diseño no experimental - transversal. Se consideró una muestra estratificada y se aplicó una encuesta a 315 usuarios por medio del instrumento SerQual que consta de cinco dimensiones de la calidad como: elementos tangibles, fiabilidad, capacidad de respuesta, seguridad y empatía. Los resultados obtenidos exponen que el grupo con mayor prevalencia fue el sexo femenino (60%), estado civil soltero (41.6%) y grupo de edad 21 a 30 años (28.3%). En general los usuarios respondieron de forma neutral respecto a los servicios de salud. En las dimensiones de tangibilidad, capacidad de respuesta y empatía exhibieron neutralidad total; mientras que, fiabilidad reveló neutralidad e inconformidad, así como, seguridad neutralidad y satisfacción. Existe un bajo índice de pacientes satisfechos con la calidad del servicio recibido; esto se debe a las deficiencias halladas, como la falta de disponibilidad de citas de acuerdo a los requerimientos del usuario, trámites engorrosos y falta de rapidez en la atención interna. La mayor satisfacción en la atención recibida se encontró en la dimensión de seguridad.
Evolución del uso de plataformas digitales para la adquisición de bienes y servicios Postcovid19
Authors: Castillo-Tapuy Andrea Yomaira , Montenegro-Ramírez Arturo Fernando
Published: August 2022

El mundo actual, aún se encuentra en emergencia sanitaria, social, y por supuesto económica, con un alto nivel de incertidumbre, muchas economías se cierran y paralizan, aún existen cuarentenas y restricciones. El Covid-19, ha desafiado al sistema socioeconómico mundial y de igual manera a las empresas ecuatorianas, las cuales, a consecuencia de la pandemia han debido repensar su modelo de negocio, principalmente aplicando estrategias digitales, y el uso de plataformas digitales para sus transacciones comerciales y la adquisición de bienes y servicios con mecanismos seguros y herramientas eficientes, lo que ocasiona una búsqueda de nuevas estrategias para balancear sus actividades. Por medio de una revisión bibliográfica, este artículo pretende disponer de una visión global y nacional sobre la evolución de las plataformas digitales y su impacto en la comercialización de bienes y servicios post pandemia. Ahora por la facilidad en costo y accesibilidad la tendencia es aprovechar de las transacciones electrónicas y la tecnología digital para garantizar producción, sostener la demanda de bienes y servicios, y evitar la paralización de cadenas de suministro, y sus operaciones. Se concluye que el uso y aprovechamiento de los recursos virtuales como sitios web y aplicaciones móviles garantizan la seguridad en las transacciones, la interacción comercial y la gestión en el manejo de objetos digitales multimediales, fijando un impacto positivo en la forma de efectuar los negocios y la comercialización de bienes y servicios.
Aplicación de la responsabilidad social empresarial en la cantera MEGAROK S.A. como una estrategia de competitividad
Authors: Saldarriaga-Mero Polivio Andrés , Oviedo Daniela
Published: August 2022

La presente investigación tiene como objetivo conocer el grado de aplicabilidad de responsabilidad social empresarial (RSE) en empresas que desarrollan sus actividades con recursos no renovables (minería de agregados para la construcción). Esta investigación contribuirá al análisis de esta temática en el ámbito local ya que existen muy poca información en referencia a las empresas bajo este modelo de negocios. Para esto, se usará el instrumento de autodiagnóstico desarrollado por la fundación del empresariado Chihuahuense FECHAC. Además, busca conocer la percepción de la alta gerencia acerca de las ventajas competitivas que la RSE brinda a estas empresas que se desarrollan en la minería de agregados para la construcción. Para cumplir con estos objetivos, se realizó un estudio de caso de la empresa MEGAROK S.A ubicada en la provincia de Manabí. Se desarrolló un análisis cuantitativo-cualitativo para encontrar así una correlación de las variables estudiadas en esta investigación. Cabe destacar que es necesario desarrollar un instrumento de medición de RSE que sea aplicable a las empresas locales y bajo este modelo de negocios.
Consumo orgánico y sostenible: análisis del consumidor ecuatoriano
Authors: Macas-Quito María , Erreyes-Barrezueta Karen , Bonisoli Lorenzo
Published: August 2022

El consumo de productos orgánicos promueve importantes avances en las prácticas de sostenibilidad agrícola. El presente estudio se enfoca en el análisis de los factores que influyen en el comportamiento de consumo sostenible del consumidor ecuatoriano. Para el análisis se ha desarrollado una encuesta dirigida a 172 consumidores de productos orgánicos y las respuestas han sido elaboradas con la técnica de SEM-PLS. Los resultados muestran que la acción del gobierno y la presión social no influyen en el comportamiento de compra mientras que la influencia ambiental, la educación y la condición del mercado explican más del 50% de la varianza del comportamiento de compra sostenible (R2=0.517). Este resultado puede guiar a las empresas productoras de productos orgánicos para expandir la filosofía de consumo sostenible.
Through the Lenses of Morality and Responsibility: BRICS, Climate Change and Sustainable Development
Authors: KIPRIZLI Göktuğ
Published: August 2022

The aim of this article is to shed a broader light on the social identity of the BRICS group of countries (Brazil, Russia, India, China, and South Africa) whose growing economic power is the defining motive of their social construct in international relations. In line with this purpose, the article examines the BRICS nations’ positions concerning the moral aspect and the notion of responsibility for the nexus between climate change and sustainable development. This article argues that their statements and discourse on climate change and sustainable development forge the process of constructing a separate group identity for the BRICS partners. The articulation of moral appraisals and the notion of responsibility in the areas of climate change and sustainable development help the BRICS countries build their self-conception and self-categorization corresponding to their identity as emerging powers, so their actions are accomplished accordingly.
Inflammatory Bowel Disease – An Update for Primary Care Physicians
Authors: Lim Chong Teik , Salazar Ennaliza , Tan Malcolm Teck Kiang , Chan Webber
Published: August 2022

Inflammatory bowel disease (IBD) is a chronic, idiopathic, inflammatory disorder of the gastrointestinal tract that is typically categorised into Crohn’s disease and ulcerative colitis. Traditionally, IBD was regarded as a disease of the western world. Newer epidemiological studies suggest that, with the turn of the 21st century, IBD has become a global disease with rising incidence in newly industrialised countries in Asia, Africa, and South America. There are also advances in the diagnostics and therapeutic armamentarium of IBD. In this review, we provide an update on the epidemiology, clinical features, investigations, and management of IBD. We also highlight the importance of vaccination in IBD and provide practical points for family physicians.
The GLP-1RAs: From Evolution to Revolution
Authors: Mishra Nitish
Published: August 2022

Research on incretin hormones has advanced considerably over the past few decades. Although the initial molecule – glucose-dependent insulinotropic polypeptide – failed to stimulate insulin secretion in patients with type 2 diabetes, it led to the discovery of glucagon-like peptide 1 (GLP-1). As GLP-1 impacts on various tissues and cells throughout the body, it allows patients with type 2 diabetes to benefit in many ways, in addition to lowering blood glucose levels. In a bid to harness these benefits pharmacologically, analogues were evolved from GLP-1 to produce a class of peptides known as GLP-1 receptor agonists (GLP-1RAs). The mechanism of action by which GLP-1RAs achieve their effects on lowering glucose levels, body weight, systolic blood pressure as well as lipid profiles, and improving cardiovascular and renal outcomes will be further discussed. With the advancement in research and development, the advent of scientific research and development has greatly accelerated the global implementation and local approved use of the first oral GLP-1RA, allowing the abovementioned benefits to be easily accessed. Oral GLP-1RA is set to bring about a revolution in the management of type 2 diabetes in Singapore.
Capturing And Evaluting Complications in Type 2 Diabetes
Authors: Tan Eng Kiat Kevin
Published: August 2022

The goal of Type 2 diabetes management is to prevent and delay diabetes-related micro- and macro-vascular complications. Unfortunately, Type 2 diabetes may remain undiagnosed for years before presentation, allowing the onset of diabetes-related complications to occur even before diabetes diagnosis. Then there is the heterogeneity of Type 2 diabetes – there are thought to be subtypes within Type 2 diabetes which have different disease progression rates and risk of complications. Additionally, there is the present-day concept that the concept of Type 2 diabetes as a coronary heart risk equivalent is overly simplistic as not all patients with diabetes are at the same cardiovascular risk. Instead, individual patients will need to be risk-stratified for appropriate interventions. Despite these conundrums, protocols should be in place for early and regular complication screening, together with proactive and holistic management of diabetes mellitus. This article seeks to remind readers of what is necessary.
The Ecosystem of Community Mental Health in Singapore
Authors: Teo David Choon Liang , Ng Jared , Soo Shuenn Chiang , Kwan Shuyi Charmaine , Tan Weng Mooi , Ho Chih Wei Sally , Peh Lai Huat Andrew
Published: August 2022

Community psychiatry focuses on the delivery of a coordinated programme of mental healthcare to a specified population. Mental illness is prevalent and a significant cause of morbidity in Singapore. In line with Singapore’s drive toward right siting of care, community psychiatry will play a pivotal role in providing timely access to effective and affordable mental healthcare in the community. This paper provides an overview of the community mental health ecosystem and range of services that seek to integrate mental and physical healthcare with social and community support in Singapore. We discuss systemic challenges such as financing issues and patient confidentiality in relation to the important role primary care physicians play in enhancing community mental health. Finally, we propose solutions and future directions to develop an effective and sustainable ecosystem for community mental health in Singapore.
Current Management and Treatment for Patients with Chronic Kidney Disease
Authors: Choo Chon Jun Jason
Published: August 2022

The incidence of chronic kidney disease (CKD) is rising in many parts of the world and primary care providers are poised to be the first point of contact for these patients. The optimal management of patients with CKD include early detection, cause identification, CKD progression retardation (including dietary support, blood pressure control, drug therapeutics), management of comorbid conditions, acute kidney injury prevention, and knowing when to refer for specialist care. In general, the concept of CKD progression retardation involves patient education on topics such as lifestyle modification measures, e.g., diet, to reduce burden on the kidneys and use of medications that can confer renoprotection while causing little if any side effects. The advent of SGLT2 inhibitors, nonsteroidal mineralocorticoid receptor antagonists, and new potassium binders provides our patients with new hope to further lengthen the time to end-stage kidney failure. It is therefore necessary that stakeholders involved in the care of patients with CKD understand the latest evidence to optimise care and patient wellbeing.
Complications of Chronic Kidney Disease: Therapeutic Approaches and What Can Be Done to Halt Disease Progression?
Authors: Khan Behram Ali
Published: August 2022

Singapore is one of the most rapidly ageing societies in the world. Currently, Singapore ranks first in the world for the incidence of diabetes-induced end-stage renal disease (ESRD) and seventh for the incidence of kidney failures per million population. It is estimated that nearly one-quarter of Singapore’s population will have chronic kidney disease (CKD) by 2035. Disease management of CKD has been identified as a critical issue due to the rapid increase in cases among the elderly in recent years. Chronic kidney disease is associated with adverse clinical outcomes, and metabolic complications such as anaemia, cardiovascular events, and CKD-associated metabolic bone diseases present treatment management complexities to healthcare professionals. Early detection and management of CKD can avert complications before symptoms occur and prevent the progressive loss of kidney function over time. Angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARBs) are recommended for hypertension and proteinuria management in CKD patients with and without diabetes. However, neither of these agents alone reduces the risk of all-cause mortality; furthermore, combinational therapy of ACEI plus ARB is associated with renal dysfunction, stroke, and/or hyperkalaemia. Recently, the use of sodium–glucose cotransporter 2 inhibitors (SGLT2i) has been shown to provide favourable effects on the kidney and cardiovascular outcomes in patients with or without type 2 diabetes mellitus. Studies have shown that early initiation of SGLT2i may slow or halt the progression of CKD in patients with the risk of CKD and ESRD. This review discusses the mechanisms underlying the progression of CKD, its associated risk factors and summarises the management strategies as per Kidney Disease Outcomes Quality Initiative clinical practice guideline recommendations. This article also summarises the evidence regarding the use of SGLT2i in slowing the progression of CKD and improvement of health-related quality of life.
Common drug-drug interactions in kidney transplant recipients – A practical guide for the family physician
Authors: Liew Ian Tatt , Kee Yi Shern Terence , Ho Quan Yao , Thangaraju Sobhana D/O , Lee Puay Hoon
Published: August 2022

Kidney transplantation offers improved mortality and morbidity compared to dialysis in patients with end-stage kidney disease (ESKD) and is the preferred renal replacement therapy of choice. With their improved health status, kidney transplant recipients (KTRs) may seek care in the community as the first line of medical attention. With the increasing prevalence of ESKD in Singapore, family physicians will play an expanded role in the care of the KTR. To avoid allograft rejection, KTRs are on lifelong immunosuppressive therapy which has potential for adverse drug-drug interactions and drug toxicity. It would be prudent to be aware of potential interactions between immunosuppressive agents and commonly prescribed medications in the primary care setting.
Common Physical Health Issues in Persons with Intellectual Disability
Authors: Sriram Bhavani
Published: August 2022

Persons with Intellectual Disabilities (ID) have a higher prevalence of physical health impairments leading to morbidities and premature deaths. The common conditions implicated are epilepsy, gastrointestinal concerns such as constipation and dyspepsia, sensory impairments, musculoskeletal issues, and thyroid disorders. Chronic diseases including hypertension, type 2 diabetes, obesity, and metabolic syndromes occur at an earlier age and nearly half of these conditions are detected only by screening. Annual health checks by primary care teams in the community are being implemented in many countries. Comprehensive health checks using standard questionnaires and preventative health check guidelines specially designed for persons with intellectual disabilities are of great help to primary care physicians in busy clinical settings. Addressing the concerns raised by healthcare professionals on the lack of knowledge and understanding of health needs of persons with ID can be easily addressed by appropriate training programmes. Eliminating communication barriers can be achieved by appropriate training programmes and implementing the use of easy-read materials. Reasonable adjustments must be implemented in practices to facilitate better health experiences for persons with ID and their caregivers.
SG Enable and the Services Available for Persons with Intellectual disability in Singapore
Authors: (MSF) SG Enable
Published: August 2022

There are an estimated more than 100,000 Persons with Disabilities (PwDs) in Singapore, and these disabilities can include physical, sensory, intellectual disability, and developmental disabilities. The presence of a disability does not only affect the individual themselves but also impacts their caregivers and families significantly. Moreover, the care needs of a PwD often persist throughout their life, and change over the different life stages, leading to various challenges for the PwDs and their families. The Ministry of Social and Family Development (MSF) led the development of the Enabling Masterplans (EMP), which are 5-year road maps that serve to guide the development and support of disability-related services in Singapore. In 2013, MSF also established SG Enable as the focal agency that is the first stop for all disability matters in Singapore. SG Enable currently works closely with social service agencies (SSA) and community partners to provide effective and holistic support to PwDs and their caregivers. This article will outline briefly the different types of disabilities, the needs over the life course, and the role of SG Enable in addressing these needs.
Characterization of the active response of a guinea pig carotid artery
Authors: Navarrete Álvaro , Varela Pablo , López Miguel , García-Herrera Claudio M. , Celentano Diego J. , Krause Bernardo
Published: August 2022

This work presents a characterization of the active response of the carotid artery of guinea pig fetuses through a methodology that encompasses experiments, modeling and numerical simulation. To this end, the isometric contraction test is carried out in ring samples subjected to different levels of KCl concentrations and pre-stretching. Then, a coupled mechanochemical model, aimed at describing the smooth cell behavior and its influence on the passive and active mechanical response of the vascular tissue, is calibrated from the experimental measurements. Due to the complex stress and strain fields developed in the artery, a finite element numerical simulation of the test is performed to fit the model parameters, where those related to the phosphorylation and dephosphorylation activity along with the load-bearing capacity of the myosin cross-bridges are found to be the most predominant when sensitizing the active response. The main strengths of the model are associated with the prediction of the stationary state of the active mechanical response of the tissue through a realistic description of the mechanochemical process carried out at its cellular level.
A platform for automated and label-free monitoring of morphological features and kinetics of spheroid fusion
Authors: Deckers Thomas , Hall Gabriella Nilsson , Papantoniou Ioannis , Aerts Jean-Marie , Bloemen Veerle
Published: August 2022

Spheroids are widely applied as building blocks for biofabrication of living tissues, where they exhibit spontaneous fusion toward an integrated structure upon contact. Tissue fusion is a fundamental biological process, but due to a lack of automated monitoring systems, the in-depth characterization of this process is still limited. Therefore, a quantitative high-throughput platform was developed to semi-automatically select doublet candidates and automatically monitor their fusion kinetics. Spheroids with varying degrees of chondrogenic maturation (days 1, 7, 14, and 21) were produced from two different cell pools, and their fusion kinetics were analyzed via the following steps: (1) by applying a novel spheroid seeding approach, the background noise was decreased due to the removal of cell debris while a sufficient number of doublets were still generated. (2) The doublet candidates were semi-automatically selected, thereby reducing the time and effort spent on manual selection. This was achieved by automatic detection of the microwells and building a random forest classifier, obtaining average accuracies, sensitivities, and precisions ranging from 95.0% to 97.4%, from 51.5% to 92.0%, and from 66.7% to 83.9%, respectively. (3) A software tool was developed to automatically extract morphological features such as the doublet area, roundness, contact length, and intersphere angle. For all data sets, the segmentation procedure obtained average sensitivities and precisions ranging from 96.8% to 98.1% and from 97.7% to 98.8%, respectively. Moreover, the average relative errors for the doublet area and contact length ranged from 1.23% to 2.26% and from 2.30% to 4.66%, respectively, while the average absolute errors for the doublet roundness and intersphere angle ranged from 0.0083 to 0.0135 and from 10.70 to 13.44°, respectively. (4) The data of both cell pools were analyzed, and an exponential model was used to extract kinetic parameters from the time-series data of the doublet roundness. For both cell pools, the technology was able to characterize the fusion rate and quality in an automated manner and allowed us to demonstrate that an increased chondrogenic maturity was linked with a decreased fusion rate. The platform is also applicable to other spheroid types, enabling an increased understanding of tissue fusion. Finally, our approach to study spheroid fusion over time will aid in the design of controlled fabrication of “assembloids” and bottom-up biofabrication of living tissues using spheroids.
Olaparib, a PARP-1 inhibitor, protects retinal cells from ocular hypertension-associated oxidative damage
Authors: Yang Yuting , Wu Jihong , Lu Wei , Dai Yiqin , Zhang Youjia , Sun Xinghuai
Published: August 2022

Glaucoma is the most common cause of irreversible blindness worldwide. Elevated intraocular pressure (IOP) and relative hypoxia in the retina stimulate the production of reactive oxygen species (ROS), which, in turn, puts the retina and optic nerve under chronic oxidative stress. Emerging evidence has shown that oxidative stress can trigger PARP-1 overactivation, mitochondrial-associated endoplasmic reticulum membrane (MAM) dysregulation, and NLRP3 activation. Oxidative damage can trigger inflammasome activation, and NLRP3 is the only inflammasome associated with MAM dysregulation. In addition, multiple transcription factors are located on the MAM. This study aimed to investigate the protective effects and underlying mechanisms of a PARP-1 inhibitor (olaparib) against chronic ocular hypertension-associated retinal cell damage. We also mimicked hypoxic stimulation of a retinal precursor cell line by exposing the cells to 0.2% O2in vitro. We discovered that chronic ocular hypertension (COH) induces oxidative damage and MAM dysregulation in the retinal ganglion cells (RGCs). The protein levels of cleaved-PARP and NLRP3 were upregulated in the retinas of the COH rats. Olaparib, a PARP-1 inhibitor, alleviated COH-induced RGC loss, retinal morphological alterations, and photopic negative response amplitude reduction. Olaparib also relieved hypoxic stimulation-induced loss of cell viability and MAM dysregulation. Additionally, some indicators of mitochondrial performance, such as reactive oxygen species accumulation, mitochondrial Ca2+ influx, and mitochondrial membrane potential collapse, decreased after olaparib treatment. Olaparib attenuated the hypoxia-induced upregulation of NLRP3 protein levels as well as the phosphorylation of ERK1/2 and histone H2A.X. These results suggest that olaparib protects RGCs from chronic intraocular pressure elevation in vivo and alleviates the abnormal MAM dysregulation and mitochondrial dysfunction caused by hypoxia in vitro. This protection may be achieved by inhibiting PARP-1 overactivation, NLRP3 upregulation, and phosphorylation of ERK1/2.
Crosstalk between acetylation and the tyrosination/detyrosination cycle of α-tubulin in Alzheimer’s disease
Authors: Martínez-Hernández José , Parato Julie , Sharma Aditi , Soleilhac Jean-Marc , Qu Xiaoyi , Tein Ellen , Sproul Andrew , Andrieux Annie , Goldberg Yves , Moutin Marie-Jo , Bartolini Francesca , Peris Leticia
Published: August 2022

Microtubules (MTs) support a variety of neuronal functions, such as maintenance of cell structure, transport, and synaptic plasticity. Neuronal MTs are highly heterogeneous due to several tubulin isotypes and the presence of multiple post-translational modifications, such as detyrosination and acetylation. The tubulin tyrosination/detyrosination cycle is a key player in the maintenance of MT dynamics, as tyrosinated tubulin is associated with more dynamic MTs, while detyrosinated tubulin is linked to longer lived, more stable MTs. Dysfunction of tubulin re-tyrosination was recently correlated to Alzheimer’s disease progression. The implication of tubulin acetylation in Alzheimer’s disease has, however, remained controversial. Here, we demonstrate that tubulin acetylation accumulates in post-mortem brain tissues from Alzheimer’s disease patients and human neurons harboring the Alzheimer’s familial APP-V717I mutation. We further show that tubulin re-tyrosination, which is defective in Alzheimer’s disease, can control acetylated tubulin in primary neurons irrespective of the levels of the enzymes regulating tubulin acetylation, suggesting that reduced MT dynamics associated with impaired tubulin re-tyrosination might contribute to the accumulation of tubulin acetylation that we detected in Alzheimer’s disease.
Current status and perspective of tumor immunotherapy for head and neck squamous cell carcinoma
Authors: Yu Chenhang , Li Qiang , Zhang Yu , Wen Zhi-Fa , Dong Heng , Mou Yongbin
Published: August 2022

Head and neck squamous cell carcinoma (HNSCC) have a high incidence and mortality rate, and investigating the pathogenesis and potential therapeutic strategies of HNSCC is required for further progress. Immunotherapy is a considerable therapeutic strategy for HNSCC due to its potential to produce a broad and long-lasting antitumor response. However, immune escape, which involves mechanisms including dyregulation of cytokines, perturbation of immune checkpoints, and recruitment of inhibitory cell populations, limit the efficacy of immunotherapy. Currently, multiple immunotherapy strategies for HNSCC have been exploited, including immune checkpoint inhibitors, costimulatory agonists, antigenic vaccines, oncolytic virus therapy, adoptive T cell transfer (ACT), and epidermal growth factor receptor (EGFR)-targeted therapy. Each of these strategies has unique advantages, and the appropriate application of these immunotherapies in HNSCC treatment has significant value for patients. Therefore, this review comprehensively summarizes the mechanisms of immune escape and the characteristics of different immunotherapy strategies in HNSCC to provide a foundation and consideration for the clinical treatment of HNSCC.
Tenascin-C fibronectin D domain is involved in the fine-tuning of glial response to CNS injury in vitro
Authors: Bijelić Dunja , Adžić Marija , Perić Mina , Reiss Gebhard , Milošević Milena , Andjus Pavle R. , Jakovčevski Igor
Published: August 2022

Understanding processes that occur after injuries to the central nervous system is essential in order to gain insight into how the restoration of function can be improved. Extracellular glycoprotein tenascin-C (TnC) has numerous functions in wound healing process depending on the expression time, location, isoform and binding partners which makes it interesting to study in this context. We used an in vitro injury model, the mixed culture of cortical astrocytes and microglia, and observed that without TnC microglial cells tend to populate gap area in greater numbers and proliferate more, whereas astrocytes build up in the border region to promote faster gap closure. Alternatively spliced domain of TnC, fibronectin type III-like repeat D (FnD) strongly affected physiological properties and morphology of both astrocytes and microglia in this injury model. The rate of microglial proliferation in the injury region decreased significantly with the addition of FnD. Additionally, density of microglia also decreased, in part due to reduced proliferation, and possibly due to reduced migration and increased contact inhibition between enlarged FnD-treated cells. Overall morphology of FnD-treated microglia resembled the activated pro-inflammatory cells, and elevated expression of iNOS was in accordance with this phenotype. The effect of FnD on astrocytes was different, as it did not affect their proliferation, but stimulated migration of reactivated astrocytes into the scratched area 48 h after the lesion. Elevated expression and secretion of TNF-α and IL-1β upon FnD treatment indicated the onset of inflammation. Furthermore, on Western blots we observed increased intensity of precursor bands of β1 integrin and appearance of monomeric bands of P2Y12R after FnD treatment which substantiates and clarifies its role in cellular shape and motility changes. Our results show versatile functions of TnC and in particular FnD after injury, mostly contributing to ongoing inflammation in the injury region. Based on our findings, FnD might be instrumental in limiting immune cell infiltration, and promoting astrocyte migration within the injury region, thus influencing spaciotemporal organization of the wound and surrounding area.
Presence of chondroitin sulphate and requirement for heparan sulphate biosynthesis in the developing zebrafish inner ear
Authors: Jones Ana A. , Diamantopoulou Elvira , Baxendale Sarah , Whitfield Tanya T.
Published: August 2022

Epithelial morphogenesis to form the semicircular canal ducts of the zebrafish inner ear depends on the production of the large glycosaminoglycan hyaluronan, which is thought to contribute to the driving force that pushes projections of epithelium into the lumen of the otic vesicle. Proteoglycans are also implicated in otic morphogenesis: several of the genes coding for proteoglycan core proteins, together with enzymes that synthesise and modify their polysaccharide chains, are expressed in the developing zebrafish inner ear. In this study, we demonstrate the highly specific localisation of chondroitin sulphate to the sites of epithelial projection outgrowth in the ear, present before any morphological deformation of the epithelium. Staining for chondroitin sulphate is also present in the otolithic membrane, whereas the otoliths are strongly positive for keratan sulphate. We show that heparan sulphate biosynthesis is critical for normal epithelial projection outgrowth, otolith growth and tethering. In the ext2 mutant ear, which has reduced heparan sulphate levels, but continues to produce hyaluronan, epithelial projections are rudimentary, and do not grow sufficiently to meet and fuse to form the pillars of tissue that normally span the otic lumen. Staining for chondroitin sulphate and expression of versican b, a chondroitin sulphate proteoglycan core protein gene, persist abnormally at high levels in the unfused projections of the ext2 mutant ear. We propose a model for wild-type epithelial projection outgrowth in which hyaluronan and proteoglycans are linked to form a hydrated gel that fills the projection core, with both classes of molecule playing essential roles in zebrafish semicircular canal morphogenesis.
Deficiency of the bZIP transcription factors Mafg and Mafk causes misexpression of genes in distinct pathways and results in lens embryonic developmental defects
Authors: Patel Shaili D. , Anand Deepti , Motohashi Hozumi , Katsuoka Fumiki , Yamamoto Masayuki , Lachke Salil A.
Published: August 2022

Deficiency of the small Maf proteins Mafg and Mafk cause multiple defects, namely, progressive neuronal degeneration, cataract, thrombocytopenia and mid-gestational/perinatal lethality. Previous data showsMafg−/−:Mafk+/-compound knockout (KO) mice exhibit cataracts age 4-months onward. Strikingly,Mafg−/−:Mafk−/−double KO mice develop lens defects significantly early in life, during embryogenesis, but the pathobiology of these defects is unknown, and is addressed here. At embryonic day (E)16.5, the epithelium of lens inMafg−/−:Mafk−/−animals appears abnormally multilayered as demonstrated by E-cadherin and nuclear staining. Additionally,Mafg−/−:Mafk−/−lenses exhibit abnormal distribution of F-actin near the “fulcrum” region where epithelial cells undergo apical constriction prior to elongation and reorientation as early differentiating fiber cells. To identify the underlying molecular changes, we performed high-throughput RNA-sequencing of E16.5Mafg−/−:Mafk−/−lenses and identified a cohort of differentially expressed genes that were further prioritized using stringent filtering criteria and validated by RT-qPCR. Several key factors associated with the cytoskeleton, cell cycle or extracellular matrix (e.g.,Cdk1,Cdkn1c,Camsap1,Col3a1,Map3k12,Sipa1l1) were mis-expressed inMafg−/−:Mafk−/−lenses. Further, the congenital cataract-linked extracellular matrix peroxidasePxdnwas significantly overexpressed inMafg−/−:Mafk−/−lenses, which may cause abnormal cell morphology. These data also identified the ephrin signaling receptorEpha5to be reduced inMafg−/−:Mafk−/−lenses. This likely contributes to theMafg−/−:Mafk−/−multilayered lens epithelium pathology, as loss of an ephrin ligand, Efna5 (ephrin-A5), causes similar lens defects. Together, these findings uncover a novel early function of Mafg and Mafk in lens development and identify their new downstream regulatory relationships with key cellular factors.
Computation-accelerated discovery of the K2NiF4-type oxyhydrides combing density functional theory and machine learning approach
Authors: Bai Qiang , Duan Yunrui , Lian Jie , Wang Xiaomin
Published: August 2022

The emerging K2NiF4-type oxyhydrides with unique hydride ions (H−) and O2- coexisting in the anion sublattice offer superior functionalities for numerous applications. However, the exploration and innovations of the oxyhydrides are challenged by their rarity as a limited number of compounds reported in experiments, owing to the stringent laboratory conditions. Herein, we employed a suite of computations involving ab initio methods, informatics and machine learning to investigate the stability relationship of the K2NiF4-type oxyhydrides. The comprehensive stability map of the oxyhydrides chemical space was constructed to identify 76 new compounds with good thermodynamic stabilities using the high-throughput computations. Based on the established database, we reveal geometric constraints and electronegativities of cationic elements as significant factors governing the oxyhydrides stabilities via informatics tools. Besides fixed stoichiometry compounds, mixed-cation oxyhydrides can provide promising properties due to the enhancement of compositional tunability. However, the exploration of the mixed compounds is hindered by their huge quantity and the rarity of stable oxyhydrides. Therefore, we propose a two-step machine learning workflow consisting of a simple transfer learning to discover 114 formable oxyhydrides from thousands of unknown mixed compositions. The predicted high H− conductivities of the representative oxyhydrides indicate their suitability as energy conversion materials. Our study provides an insight into the oxyhydrides chemistry which is applicable to other mixed-anion systems, and demonstrates an efficient computational paradigm for other materials design applications, which are challenged by the unavailable and highly unbalanced materials database.
Overcoming the rise in local deposit resistance during electrophoretic deposition via suspension replenishing
Authors: Tiwari Prabal , Ferson Noah D. , Arnold David P. , Andrew Jennifer S.
Published: August 2022

Nanomaterials have unique properties, functionalities, and excellent performance, and as a result have gained significant interest across disciplines and industries. However, currently, there is a lack of techniques that can assemble as-synthesized nanomaterials in a scalable manner. Electrophoretic deposition (EPD) is a promising method for the scalable assembly of colloidally stable nanomaterials into thick films and arrays. In EPD, an electric field is used to assemble charged colloidal particles onto an oppositely charged substrate. However, in constant voltage EPD the deposition rate decreases with increasing deposition time, which has been attributed in part to the fact that the electric field in the suspension decreases with time. This decreasing electric field has been attributed to two probable causes, (i) increased resistance of the particle film and/or (ii) the growth of an ion-depletion region at the substrate. Here, to increase EPD yield and scalability we sought to distinguish between these two effects and found that the growth of the ion-depletion region plays the most significant role in the increase of the deposit resistance. Here, we also demonstrate a method to maintain constant deposit resistance in EPD by periodic replenishing of suspension, thereby improving EPD’s scalability.
Design, synthesis and biological evaluation of novel biphenylsulfonamide derivatives as selective AT2 receptor antagonists
Authors: Wang Danhui , Zhao Wenjie , Zhang Zuzhi , Zhang Yanchun , Li Jiaming , Huang Weijun
Published: August 2022

A novel series of benzenesulfonamide derivatives that selectively act on the AT2 receptor have been designed and synthesized. The binding affinity and functional activity were evaluated by radio-ligand binding analysis and cell neurite outgrowth assay, respectively. The compounds 8d, 8h, 8i, 8j, 8l, and 9h exhibited moderate selectivity and affinity for the AT2 receptor. Among them, 8j exhibited agonist activity and 8l displayed similar selectivity to the AT2 receptor with PD123,319. Molecular docking was carried out to analyze the binding mode and binding site between the compound and the AT2 receptor to provide a reference for further development.
Integrated microbiome and metabolome analysis reveals the potential therapeutic mechanism of Qing-Fei-Pai-Du decoction in mice with coronavirus-induced pneumonia
Authors: Wu Gaosong , Zhang Wendan , Zheng Ningning , Zu Xianpeng , Tian Saisai , Zhong Jing , Zhang Yuhao , Liao Jingyu , Sheng Lili , Ge Guanbo , Li Houkai , Zhang Weidong
Published: August 2022

Current studies have shown that gut microbiota may be closely related to the severity of coronavirus disease 2019 (COVID-19) by regulating the host immune response. Qing-Fei-Pai-Du decoction (QFPDD) is the recommended drug for clinical treatment of patients with COVID-19 in China, but whether it exerts a therapeutic effect by modulating the immune response through gut microbiota remains unclear. In this study, we evaluated the therapeutic effects of QFPDD in pneumonia model mice and performed 16S rRNA sequencing and serum and lung tissue metabolomic analysis to explore the underlying mechanisms during the treatment. Then, Spearman correlation analysis was performed on gut microbiome, serum metabolome, and immune-inflammation-related indicators. Our results suggest that QFPDD can restore the richness and diversity of gut microbiota, and multiple gut microbiota (including Alistipes, Odoribacter, Staphylococcus, Lachnospiraceae_NK4A136_group Enterorhabdus, and unclassified_f_Lachnospiraceae) are significantly associated with immune-inflammation-related indicators. In addition, various types of lipid metabolism changes were observed in serum and lung tissue metabolome, especially glycerophospholipids and fatty acids. A total of 27 differential metabolites (DMs) were significantly correlated with immune-inflammation-related indicators, including 9 glycerophospholipids, 7 fatty acids, 3 linoleic acid, 2 eicosanoids, 2 amino acids, 2 bile acids, and 2 others. Interestingly, these DMs showed a good correlation with the gut microbiota affected by QFPDD. The above results suggest that QFPDD can improve the immune function and reduce inflammation in pneumonia model mice by remodeling gut microbiota and host metabolism.