bluuebunny/crossref_metadata_2025 huggingface dataset:
EL DERECHO A LA LIBERTAD DE OPINIÓN Y EXPRESIÓN Y SU VULNERACIÓN COMO DERECHO FUNDAMENTAL
Authors:   Universidad Estatal de Bolívar, Bonilla Diego , Samaniego Delia ,   Universidad Estatal de Bolívar
Published: February 2021

El derecho a la libertad de opinión y expresión es uno de los derechos más amenazados, tanto por los gobiernos represores que quieren impedir cambios en el sistema, así como, por personas que pretenden imponer su ideología o valores personales callando a otros. Esta investigación tuvo como objetivo principal, determinar el alcance del derecho a la libertad de opinión y expresión en Venezuela, partiendo de un análisis jurídico dogmático de la normativa internacional. De igual forma esta investigación permite establecer que la libertad de opinión y expresión es un derecho fundamental, por tanto, el Estado debe garantizar este derecho para que las sociedad pueda acceder a la libre opinión y expresión, siendo una condición esencial y suficiente para la obtención de la verdad, la autorrealización y el consecuente alcance de una verdadera democracia, ya que sin la habilidad de opinar libremente, o de denunciar injusticias y luchar por los cambios en sistema de administración estatal, el hombre estaría condenado a la opresión y coerción. La libertad de expresión y opinión no es un derecho absoluto, pero si un derecho fundamental que permite medir la democracia de un Estado.
Increased Mesenchymal Stem Cell Functionalization in Three-Dimensional Manufacturing Settings for Enhanced Therapeutic Applications
Authors: Kouroupis Dimitrios , Correa Diego
Published: February 2021

Mesenchymal stem/stromal cell (MSC) exist within their in vivo niches as part of heterogeneous cell populations, exhibiting variable stemness potential and supportive functionalities. Conventional extensive 2D in vitro MSC expansion, aimed at obtaining clinically relevant therapeutic cell numbers, results in detrimental effects on both cellular characteristics (e.g., phenotypic changes and senescence) and functions (e.g., differentiation capacity and immunomodulatory effects). These deleterious effects, added to the inherent inter-donor variability, negatively affect the standardization and reproducibility of MSC therapeutic potential. The resulting manufacturing challenges that drive the qualitative variability of MSC-based products is evident in various clinical trials where MSC therapeutic efficacy is moderate or, in some cases, totally insufficient. To circumvent these limitations, various in vitro/ex vivo techniques have been applied to manufacturing protocols to induce specific features, attributes, and functions in expanding cells. Exposure to inflammatory cues (cell priming) is one of them, however, with untoward effects such as transient expression of HLA-DR preventing allogeneic therapeutic schemes. MSC functionalization can be also achieved by in vitro 3D culturing techniques, in an effort to more closely recapitulate the in vivo MSC niche. The resulting spheroid structures provide spatial cell organization with increased cell–cell interactions, stable, or even enhanced phenotypic profiles, and increased trophic and immunomodulatory functionalities. In that context, MSC 3D spheroids have shown enhanced “medicinal signaling” activities and increased homing and survival capacities upon transplantation in vivo. Importantly, MSC spheroids have been applied in various preclinical animal models including wound healing, bone and osteochondral defects, and cardiovascular diseases showing safety and efficacy in vivo. Therefore, the incorporation of 3D MSC culturing approach into cell-based therapy would significantly impact the field, as more reproducible clinical outcomes may be achieved without requiring ex vivo stimulatory regimes. In the present review, we discuss the MSC functionalization in 3D settings and how this strategy can contribute to an improved MSC-based product for safer and more effective therapeutic applications.
COVID-19: Molecular and Cellular Response
Authors: Alipoor Shamila D. , Mortaz Esmaeil , Jamaati Hamidreza , Tabarsi Payam , Bayram Hasan , Varahram Mohammad , Adcock Ian M.
Published: February 2021

In late December 2019, a vtiral pneumonia with an unknown agent was reported in Wuhan, China. A novel coronavirus was identified as the causative agent. Because of the human-to-human transmission and rapid spread; coronavirus disease 2019 (COVID-19) has rapidly increased to an epidemic scale and poses a severe threat to human health; it has been declared a public health emergency of international concern (PHEIC) by the World Health Organization (WHO). This review aims to summarize the recent research progress of COVID-19 molecular features and immunopathogenesis to provide a reference for further research in prevention and treatment of SARS coronavirus2 (SARS-CoV-2) infection based on the knowledge from researches on SARS-CoV and Middle East respiratory syndrome-related coronavirus (MERS-CoV).
Genetic Interactions Between Aspergillus fumigatus Basic Leucine Zipper (bZIP) Transcription Factors AtfA, AtfB, AtfC, and AtfD
Authors: Silva Lilian Pereira , Horta Maria Augusta Crivelente , Goldman Gustavo Henrique
Published: February 2021

Aspergillus fumigatus is an opportunistic fungus, capable of causing Invasive Aspergillosis in immunocompromised patients, recently transplanted or undergoing chemotherapy. In the present work, we continued the investigation on A. fumigatus AtfA-D transcription factors (TFs) characterizing possible genetic and physical interactions between them after normal growth and stressing conditions. We constructed double null mutants for all the possible combinations of ΔatfA-, -B, -C, and -D, and look into their susceptibility to different stressing conditions. Our results indicate complex genetic interactions among these TFs that could impact the response to different kinds of stressful conditions. AtfA-D interactions also affect the A. fumigatus virulence in Galleria mellonella. AtfA:GFP is ~97% located in the nucleus while about 20–30% of AtfB, -C, and -D:GFP locate into the nucleus in the absence of any stress. Under stressing conditions, AtfB, -C, and -D:GFP translocate to the nucleus about 60–80% upon the addition of sorbitol or H2O2. These four TFs are also interacting physically forming all the possible combinations of heterodimers. We also identified that AtfA-D physically interact with the MAPK SakA in the absence of any stress and upon osmotic and cell wall stresses. They are involved in the accumulation of trehalose, glycogen and metabolic assimilation of different carbon sources.
Genetic Background Shapes Phenotypic Response to Diet for Adiposity in the Collaborative Cross
Authors: Yam Phoebe , Albright Jody , VerHague Melissa , Gertz Erik R. , Pardo-Manuel de Villena Fernando , Bennett Brian J.
Published: February 2021

Defined as chronic excessive accumulation of adiposity, obesity results from long-term imbalance between energy intake and expenditure. The mechanisms behind how caloric imbalance occurs are complex and influenced by numerous biological and environmental factors, especially genetics, and diet. Population-based diet recommendations have had limited success partly due to the wide variation in physiological responses across individuals when they consume the same diet. Thus, it is necessary to broaden our understanding of how individual genetics and diet interact relative to the development of obesity for improving weight loss treatment. To determine how consumption of diets with different macronutrient composition alter adiposity and other obesity-related traits in a genetically diverse population, we analyzed body composition, metabolic rate, clinical blood chemistries, and circulating metabolites in 22 strains of mice from the Collaborative Cross (CC), a highly diverse recombinant inbred mouse population, before and after 8 weeks of feeding either a high protein or high fat high sucrose diet. At both baseline and post-diet, adiposity and other obesity-related traits exhibited a broad range of phenotypic variation based on CC strain; diet-induced changes in adiposity and other traits also depended largely on CC strain. In addition to estimating heritability at baseline, we also quantified the effect size of diet for each trait, which varied by trait and experimental diet. Our findings identified CC strains prone to developing obesity, demonstrate the genotypic and phenotypic diversity of the CC for studying complex traits, and highlight the importance of accounting for genetic differences when making dietary recommendations.
Gene Size Matters: An Analysis of Gene Length in the Human Genome
Authors: Lopes Inês , Altab Gulam , Raina Priyanka , de Magalhães João Pedro
Published: February 2021

While it is expected for gene length to be associated with factors such as intron number and evolutionary conservation, we are yet to understand the connections between gene length and function in the human genome. In this study, we show that, as expected, there is a strong positive correlation between gene length, transcript length, and protein size as well as a correlation with the number of genetic variants and introns. Among tissue-specific genes, we find that the longest transcripts tend to be expressed in the blood vessels, nerves, thyroid, cervix uteri, and the brain, while the smallest transcripts tend to be expressed in the pancreas, skin, stomach, vagina, and testis. We report, as shown previously, that natural selection suppresses changes for genes with longer transcripts and promotes changes for genes with smaller transcripts. We also observe that genes with longer transcripts tend to have a higher number of co-expressed genes and protein-protein interactions, as well as more associated publications. In the functional analysis, we show that bigger transcripts are often associated with neuronal development, while smaller transcripts tend to play roles in skin development and in the immune system. Furthermore, pathways related to cancer, neurons, and heart diseases tend to have genes with longer transcripts, with smaller transcripts being present in pathways related to immune responses and neurodegenerative diseases. Based on our results, we hypothesize that longer genes tend to be associated with functions that are important in the early development stages, while smaller genes tend to play a role in functions that are important throughout the whole life, like the immune system, which requires fast responses.
Delineation of Mitochondrial DNA Variants From Exome Sequencing Data and Association of Haplogroups With Obesity in Kuwait
Authors: Dashti Mohammed , Alsaleh Hussain , Eaaswarkhanth Muthukrishnan , John Sumi Elsa , Nizam Rasheeba , Melhem Motasem , Hebbar Prashantha , Sharma Prem , Al-Mulla Fahd , Thanaraj Thangavel Alphonse
Published: February 2021

Background/Objectives

Whole-exome sequencing is a valuable tool to determine genetic variations that are associated with rare and common health conditions. A limited number of studies demonstrated that mitochondrial DNA can be captured using whole-exome sequencing. Previous studies have suggested that mitochondrial DNA variants and haplogroup lineages are associated with obesity. Therefore, we investigated the role of mitochondrial variants and haplogroups contributing to the risk of obesity in Arabs in Kuwait using exome sequencing data.

Subjects/Methods

Indirect mitochondrial genomes were extracted from exome sequencing data from 288 unrelated native Arab individuals from Kuwait. The cohort was divided into obese [body mass index (BMI) ≥ 30 kg/m2] and non-obese (BMI < 30 kg/m2) groups. Mitochondrial variants were identified, and haplogroups were classified and compared with other sequencing technologies. Statistical analysis was performed to determine associations and identify mitochondrial variants and haplogroups affecting obesity.

Results

Haplogroup R showed a protective effect on obesity [odds ratio (OR) = 0.311; P = 0.006], whereas haplogroup L individuals were at high risk of obesity (OR = 2.285; P = 0.046). Significant differences in mitochondrial variants between the obese and non-obese groups were mainly haplogroup-defining mutations and were involved in processes in energy generation. The majority of mitochondrial variants and haplogroups extracted from exome were in agreement with technical replica from Sanger and whole-genome sequencing.

Conclusions

This is the first to utilize whole-exome data to extract entire mitochondrial haplogroups to study its association with obesity in an Arab population.
Identifying Client Targets for Improved Mobilization and Uptake of Integrated Family Planning and Reproductive Health in Environmental Programs in Kenya
Authors: Obat Edmon , Schaefer Krista , Opiyo Mumma , Otieno George , Windindi Henrietta , Omuodo Derick , Mehta Supriya D.
Published: February 2021

Background: We conducted a population health environment program in Lake Victoria Basin (LVB) and assessed incorporation and integration of family planning with environmental conservation.

Methods: Routine program data were collected from clients by community-based distributors from four environmental community-based organizations. Multivariable regressions identified factors associated with distribution of: (1) oral contraceptive pills to women, (2) male condoms, and (3) integrated family planning and environmental messaging.

Results: April 2015 through May 2016, 10,239 client encounters were completed, with 56% made by men. We distributed contraceptive pills at 28% of client encounters. Multivariable modeling showed this was more likely for women <40 years old (p < 0.001) and was less likely for women attending household (30%) and group sessions (46%) compared to individual sessions (p < 0.001). Male condoms were distributed at 73% of client encounters; (p < 0.01, all) women were half as likely to receive condoms than men, and single and widowed clients were more likely than married clients to receive condoms. Integrated messaging occurred at 89% of client encounters, and was 85% more likely for women, increased with client age, and was less likely for single and widowed persons. Exit interviews with 87 clients (42% male, 58% female) confirmed program data by report of commodities received: 27% contraceptive pills, 75% male condoms, 91% integrated messaging.

Conclusions: Partnership with environmental conservation organizations effectively expanded family planning and reproductive health to non-traditional audiences and men among rural communities surrounding LVB-Kenya. Specific client subgroups can be targeted for improved mobilization and uptake of services.
Memory B-Cell Responses Against Merozoite Antigens After Acute Plasmodium falciparum Malaria, Assessed Over One Year Using a Novel Multiplexed FluoroSpot Assay
Authors: Jahnmatz Peter , Sundling Christopher , Yman Victor , Widman Linnea , Asghar Muhammad , Sondén Klara , Stenström Christine , Smedman Christian , Ndungu Francis , Ahlborg Niklas , Färnert Anna
Published: February 2021

Memory B cells (MBCs) are believed to be important for the maintenance of immunity to malaria, and these cells need to be explored in the context of different parasite antigens and their breadth and kinetics after natural infections. However, frequencies of antigen-specific MBCs are low in peripheral blood, limiting the number of antigens that can be studied, especially when small blood volumes are available. Here, we developed a multiplexed reversed B-cell FluoroSpot assay capable of simultaneously detecting MBCs specific for the four Plasmodium falciparum blood-stage antigens, MSP-119, MSP-2, MSP-3 and AMA-1. We used the assay to study the kinetics of the MBC response after an acute episode of malaria and up to one year following treatment in travelers returning to Sweden from sub-Saharan Africa. We show that the FluoroSpot assay can detect MBCs to all four merozoite antigens in the same well, and that the breadth and kinetics varied between individuals. We further found that individuals experiencing a primary infection could mount and maintain parasite-specific MBCs to a similar extent as previously exposed adults, already after a single infection. We conclude that the multiplexed B-cell FluoroSpot is a powerful tool for assessing antigen-specific MBC responses to several antigens simultaneously, and that the kinetics of MBC responses against merozoite surface antigens differ over the course of one year. These findings contribute to the understanding of acquisition and maintenance of immune responses to malaria.
A Matter of Life or Death: Productively Infected and Bystander CD4 T Cells in Early HIV Infection
Authors: Cao Dechao , Khanal Sushant , Wang Ling , Li Zhengke , Zhao Juan , Nguyen Lam Nhat , Nguyen Lam Ngoc Thao , Dang Xindi , Schank Madison , Thakuri Bal Krishna Chand , Zhang Jinyu , Lu Zeyuan , Wu Xiao Y. , Morrison Zheng D. , El Gazzar Mohamed , Ning Shunbin , Moorman Jonathan P. , Yao Zhi Q.
Published: February 2021

CD4 T cell death or survival following initial HIV infection is crucial for the development of viral reservoirs and latent infection, making its evaluation critical in devising strategies for HIV cure. Here we infected primary CD4 T cells with a wild-type HIV-1 and investigated the death and survival mechanisms in productively infected and bystander cells during early HIV infection. We found that HIV-infected cells exhibited increased programmed cell death, such as apoptosis, pyroptosis, and ferroptosis, than uninfected cells. However, productively infected (p24+) cells and bystander (p24-) cells displayed different patterns of cell death due to differential expression of pro-/anti-apoptotic proteins and signaling molecules. Cell death was triggered by an aberrant DNA damage response (DDR), as evidenced by increases in γH2AX levels, which inversely correlated with telomere length and telomerase levels during HIV infection. Mechanistically, HIV-infected cells exhibited a gradual shortening of telomeres following infection. Notably, p24+ cells had longer telomeres compared to p24- cells, and telomere length positively correlated with the telomerase, pAKT, and pATM expressions in HIV-infected CD4 T cells. Importantly, blockade of viral entry attenuated the HIV-induced inhibition of telomerase, pAKT, and pATM as well as the associated telomere erosion and cell death. Moreover, ATM inhibition promoted survival of HIV-infected CD4 T cells, especially p24+ cells, and rescued telomerase and AKT activities by inhibiting cell activation, HIV infection, and DDR. These results indicate that productively infected and bystander CD4 T cells employ different mechanisms for their survival and death, suggesting a possible pro-survival, pro-reservoir mechanism during early HIV infection.
Immunomodulatory Effects of Azithromycin Revisited: Potential Applications to COVID-19
Authors: Venditto Vincent J. , Haydar Dalia , Abdel-Latif Ahmed , Gensel John C. , Anstead Michael I. , Pitts Michelle G. , Creameans Jarrod , Kopper Timothy J. , Peng Chi , Feola David J.
Published: February 2021

The rapid advancement of the COVID-19 pandemic has prompted an accelerated pursuit to identify effective therapeutics. Stages of the disease course have been defined by viral burden, lung pathology, and progression through phases of the immune response. Immunological factors including inflammatory cell infiltration and cytokine storm have been associated with severe disease and death. Many immunomodulatory therapies for COVID-19 are currently being investigated, and preliminary results support the premise of targeting the immune response. However, because suppressing immune mechanisms could also impact the clearance of the virus in the early stages of infection, therapeutic success is likely to depend on timing with respect to the disease course. Azithromycin is an immunomodulatory drug that has been shown to have antiviral effects and potential benefit in patients with COVID-19. Multiple immunomodulatory effects have been defined for azithromycin which could provide efficacy during the late stages of the disease, including inhibition of pro-inflammatory cytokine production, inhibition of neutrophil influx, induction of regulatory functions of macrophages, and alterations in autophagy. Here we review the published evidence of these mechanisms along with the current clinical use of azithromycin as an immunomodulatory therapeutic. We then discuss the potential impact of azithromycin on the immune response to COVID-19, as well as caution against immunosuppressive and off-target effects including cardiotoxicity in these patients. While azithromycin has the potential to contribute efficacy, its impact on the COVID-19 immune response requires additional characterization so as to better define its role in individualized therapy.
Berberine Promotes Induction of Immunological Tolerance to an Allograft via Downregulating Memory CD8+ T-Cells Through Altering the Gut Microbiota
Authors: Qiu Feifei , Lu Weihui , Ye Shulin , Liu Huazhen , Zeng Qiaohuang , Huang Haiding , Liang Chun-Ling , Chen Yuchao , Zheng Fang , Zhang Qunfang , Lu Chuan-Jian , Dai Zhenhua
Published: February 2021

Emerging evidence has linked the gut microbiota dysbiosis to transplant rejection while memory T-cells pose a threat to long-term transplant survival. However, it's unclear if the gut microbiome alters the formation and function of alloreactive memory T-cells. Here we studied the effects of berberine, a narrow-spectrum antibiotic that is barely absorbed when orally administered, on the gut microbiota, memory T-cells, and allograft survival. In this study, C57BL/6 mice transplanted with islets or a heart from BALB/c mice were treated orally with berberine. Allograft survival was observed, while spleen, and lymph node T-cells from recipient mice were analyzed using a flow cytometer. High-throughput sequencing and qPCR were performed to analyze the gut microbiota. CD8+T-cells from recipients were cultured with the bacteria to determine potential T-cell memory cross-reactivity to a specific pathogen. We found that berberine suppressed islet allograft rejection, reduced effector CD8+CD44highCD62Llowand central memory CD8+CD44highCD62LhighT-cells (TCM), altered the gut microbiota composition and specifically loweredBacillus cereusabundance. Further, berberine promoted long-term islet allograft survival induced by conventional costimulatory blockade and induced cardiac allograft tolerance as well. Re-colonization ofB. cereusupregulated CD8+TCMcells and reversed long-term islet allograft survival induced by berberine plus the conventional costimulatory blockade. Finally, alloantigen-experienced memory CD8+T-cells from transplanted recipients rapidly responded toB. cereus in vitro. Thus, berberine prolonged allograft survival by repressing CD8+TCMthrough regulating the gut microbiota. We have provided the first evidence that donor-specific memory T-cell generation is linked to a specific microbe and uncovered a novel mechanism underlying the therapeutic effects of berberine. This study may be implicated for suppressing human transplant rejection since berberine is already used in clinic to treat intestinal infections.
Exploiting Joint-Resident Stem Cells by Exogenous SOX9 for Cartilage Regeneration for Therapy of Osteoarthritis
Authors: Zhang Xiaowei , Wu Shili , Zhu Yong , Chu Cong-Qiu
Published: February 2021

The lack of effective treatment options for osteoarthritis (OA) is mostly due to the very limited regenerative capacity of articular cartilage. Mesenchymal stem cells (MSCs) have been most extensively explored for cell-based therapy to induce cartilage regeneration for OA. However, current in vitro expanded MSC-based approaches have significant drawbacks. On the other hand, osteoarthritic joints contain chondrocyte progenitors and MSCs in several niches which have the potential yet fail to differentiate into chondrocytes for cartilage regeneration. One of the underlying mechanisms of the failure is that these chondrocyte progenitors and MSCs in OA joints are deficient in the activity of chondrogenic transcription factor SOX9 (SRY-type high-mobility group box-9). Thereby, replenishing with exogenous SOX9 would reactivate the potential of these stem cells to differentiate into chondrocytes. Cell-permeable, super-positively charged SOX9 (scSOX9) protein is able to promote hyaline-like cartilage regeneration by inducing chondrogenic differentiation of bone marrow derived MSCs in vivo. This scSOX9 protein can be administered into osteoarthritic joints by intra-articular injection. This one-step, cell-free supplement of exogenous SOX9 may harness the regenerative potential of the intrinsic MSCs within the joint cavity to stimulate cartilage regeneration in OA.
Alteration of Gut Microbiota After Antibiotic Exposure in Finishing Swine
Authors: Jo Hee Eun , Kwon Min-Sung , Whon Tae Woong , Kim Doo Wan , Yun Misun , Lee Jieun , Shin Mi-Young , Kim Sung-Hak , Choi Hak-Jong
Published: February 2021

Subclinical doses of antimicrobials are commonly used in the swine industry to control infectious diseases and growth performance. Accumulating evidence suggests that swine administered with antibiotics are susceptible to disease development due to disruption of the beneficial gut microbial community, which is associated with host immune regulation, nutrient digestion, and colonization resistance against pathogens. In this study, we found that finishing swine administered with lincomycin showed gut dysbiosis and increased diarrhea incidence compared with control swine. 16S rRNA amplicon sequencing was used to analyze the gut microbiota in finishing swine administered with lincomycin. The relative abundance of detrimental microbes, such as species of Clostridium, Aerococcus, Escherichia-Shigella, and Corynebacterium was increased in the feces of lincomycin-administered finishing swine, but that of bacteria associated with fiber degradation, such as species of Treponema, Succinivibrio, Fibrobacter, and Cellulosilyticum was decreased. Moreover, administration of lincomycin significantly increased the enrichment of metabolic pathways related to pathogenicity and deficiency of polysaccharide degradation. These results suggest that lincomycin treatment could cause severe disruption of the commensal microbiota in finishing swine.
The Impact of Disease Comorbidities in Alzheimer's Disease
Authors: Santiago Jose A. , Potashkin Judith A.
Published: February 2021

A wide range of comorbid diseases is associated with Alzheimer's disease (AD), the most common neurodegenerative disease worldwide. Evidence from clinical and molecular studies suggest that chronic diseases, including diabetes, cardiovascular disease, depression, and inflammatory bowel disease, may be associated with an increased risk of AD in different populations. Disruption in several shared biological pathways has been proposed as the underlying mechanism for the association between AD and these comorbidities. Notably, inflammation is a common dysregulated pathway shared by most of the comorbidities associated with AD. Some drugs commonly prescribed to patients with diabetes and cardiovascular disease have shown promising results in AD patients. Systems-based biology studies have identified common genetic factors and dysregulated pathways that may explain the relationship of comorbid disorders in AD. Nonetheless, the precise mechanisms for the occurrence of disease comorbidities in AD are not entirely understood. Here, we discuss the impact of the most common comorbidities in the clinical management of AD patients.
What Triggers the Interictal Epileptic Spike? A Multimodal Multiscale Analysis of the Dynamic of Synaptic and Non-synaptic Neuronal and Vascular Compartments Using Electrical and Optical Measurements
Authors: Arnal-Real Cristian , Mahmoudzadeh Mahdi , Manoochehri Mana , Nourhashemi Mina , Wallois Fabrice
Published: February 2021

Interictal spikes (IISs) may result from a disturbance of the intimate functional balance between various neuronal (synaptic and non-synaptic), vascular, and metabolic compartments. To better characterize the complex interactions within these compartments at different scales we developed a simultaneous multimodal-multiscale approach and measure their activity around the time of the IIS. We performed such measurements in an epileptic rat model (n= 43). We thus evaluated (1) synaptic dynamics by combining electrocorticography and multiunit activity recording in the time and time-frequency domain, (2) non-synaptic dynamics by recording modifications in light scattering induced by changes in the membrane configuration related to cell activity using the fast optical signal, and (3) vascular dynamics using functional near-infrared spectroscopy and, independently but simultaneously to the electrocorticography, the changes in cerebral blood flow using diffuse correlation spectroscopy. The first observed alterations in the measured signals occurred in the hemodynamic compartments a few seconds before the peak of the IIS. These hemodynamic changes were followed by changes in coherence and then synchronization between the deep and superficial neural networks in the 1 s preceding the IIS peaks. Finally, changes in light scattering before the epileptic spikes suggest a change in membrane configuration before the IIS. Our multimodal, multiscale approach highlights the complexity of (1) interactions between the various neuronal, vascular, and extracellular compartments, (2) neural interactions between various layers, (3) the synaptic mechanisms (coherence and synchronization), and (4) non-synaptic mechanisms that take place in the neuronal network around the time of the IISs in a very specific cerebral hemodynamic environment.
Impact of National Lockdown on the Hyperacute Stroke Care and Rapid Transient Ischaemic Attack Outpatient Service in a Comprehensive Tertiary Stroke Centre During the COVID-19 Pandemic
Authors: D'Anna Lucio , Brown Maddison , Oishi Sikdar , Ellis Natalya , Brown Zoe , Bentley Paul , Drumm Brian , Halse Omid , Jamil Sohaa , Jenkins Harri , Malik Abid , Kalladka Dheeraj , Venter Marius , Kwan Joseph , Banerjee Soma
Published: February 2021

Background: The COVID-19 pandemic is having major implications for stroke services worldwide. We aimed to study the impact of the national lockdown period during the COVID-19 outbreak on stroke and transient ischemic attack (TIA) care in London, UK.

Methods: We retrospectively analyzed data from a quality improvement registry of consecutive patients presenting with acute ischemic stroke and TIA to the Stroke Department, Imperial College Health Care Trust London during the national lockdown period (between March 23rd and 30th June 2020). As controls, we evaluated the clinical reports and stroke quality metrics of patients presenting with stroke or TIA in the same period of 2019.

Results: Between March 23rd and 30th June 2020, we documented a fall in the number of stroke admissions by 31.33% and of TIA outpatient referrals by 24.44% compared to the same period in 2019. During the lockdown, we observed a significant increase in symptom onset-to-door time in patients presenting with stroke (median = 240 vs. 160 min, p = 0.020) and TIA (median = 3 vs. 0 days, p = 0.002) and a significant reduction in the total number of patients thrombolysed [27 (11.49%) vs. 46 (16.25%, p = 0.030)]. Patients in the 2020 cohort presented with a lower median pre-stroke mRS (p = 0.015), but an increased NIHSS (p = 0.002). We registered a marked decrease in mimic diagnoses compared to the same period of 2019. Statistically significant differences were found between the COVID and pre-COVID cohorts in the time from onset to door (median 99 vs. 88 min, p = 0.026) and from onset to needle (median 148 vs. 126 min, p = 0.036) for thrombolysis whilst we did not observe any significant delay to reperfusion therapies (door-to-needle and door-to-groin puncture time).

Conclusions: National lockdown in the UK due to the COVID-19 pandemic was associated with a significant decrease in acute stroke admission and TIA evaluations at our stroke center. Moreover, a lower proportion of acute stroke patients in the pandemic cohort benefited from reperfusion therapy. Further research is needed to evaluate the long-term effects of the pandemic on stroke care.
Circadian Responses to Light-Flash Exposure: Conceptualization and New Data Guiding Future Directions
Authors: Wong Kwoon Y. , Fernandez Fabian-Xosé
Published: February 2021

A growing number of studies document circadian phase-shifting after exposure to millisecond light flashes. When strung together by intervening periods of darkness, these stimuli evoke pacemaker responses rivaling or outmatching those created by steady luminance, suggesting that the circadian system's relationship to light can be contextualized outside the principle of simple dose-dependence. In the current review, we present a brief chronology of this work. We then develop a conceptual model around it that attempts to relate the circadian effects of flashes to a natural integrative process the pacemaker uses to intermittently sample the photic information available at dawn and dusk. Presumably, these snapshots are employed as building blocks in the construction of a coherent representation of twilight the pacemaker consults to orient the next day's physiology (in that way, flash-resetting of pacemaker rhythms might be less an example of a circadian visual illusion and more an example of the kinds of gestalt inferences that the image-forming system routinely makes when identifying objects within the visual field; i.e., closure). We conclude our review with a discussion on the role of cones in the pacemaker's twilight predictions, providing new electrophysiological data suggesting that classical photoreceptors—but not melanopsin—are necessary for millisecond, intermediate-intensity flash responses in ipRGCs (intrinsically photosensitive retinal ganglion cells). Future investigations are necessary to confirm this “Cone Sentinel Model” of circadian flash-integration and twilight-prediction, and to further define the contribution of cones vs. rods in transducing pacemaker flash signals.
Safety and Efficacy of Tirofiban for Acute Ischemic Stroke Patients With Large Artery Atherosclerosis Stroke Etiology Undergoing Endovascular Therapy
Authors: Huo Xiaochuan , Raynald  , Wang Anxin , Mo Dapeng , Gao Feng , Ma Ning , Wang Yilong , Wang Yongjun , Miao Zhongrong
Published: February 2021

Objective: To investigate the safety and efficacy of tirofiban in acute ischemic stroke (AIS) patients with large artery atherosclerosis (LAA) stroke etiology receiving endovascular therapy (EVT).

Methods: In this multi-center prospective study, patients who were considered to have an indication received a low dose intra-arterial bolus (0.25–1 mg) of tirofiban. The safety and efficacy outcomes at 90-day follow-ups included symptomatic intracranial hemorrhage (sICH), recanalization rate, functional outcome, and mortality.

Results: Among the 649 AIS patients with LAA, those in the tirofiban group (n = 244) showed higher systolic blood pressure (BP) and NIHSS score on admission, puncture-to-recanalization time, lower frequency of intravenous thrombolysis and intra-arterial thrombolysis, higher frequency of antiplatelet, heparinization, mechanical stent retrieval, aspiration, balloon angioplasty, and more retrieval times compared with those in the non-tirofiban group (n = 405) (all P < 0.05). Tirofiban was found to be associated with superior clinical outcomes in anterior circulation stroke and major stroke patients [adjusted odds ratio (OR) = 2.163, 95% confidence interval (CI) = 1.130–4.140, P = 0.02 and adjusted OR = 2.361, 95% CI = 1.326–4.202, P = 0.004, respectively] and a lower risk of mortality at 90-day follow-ups (adjusted OR = 0.159, 95% CI = 0.042–0.599, P = 0.007 and adjusted OR = 0.252, 95% CI = 0.103–0.621, P = 0.003, respectively). There was no significant difference in sICH between the two groups.

Conclusions: Tirofiban in AIS patients with LAA undergoing EVT is safe and may benefit the functional outcomes in anterior circulation and major stroke patients and showed a trend for reduced mortality.
Therapeutic Hypothermia Inhibits the Classical Complement Pathway in a Rat Model of Neonatal Hypoxic-Ischemic Encephalopathy
Authors: Shah Tushar A. , Pallera Haree K. , Kaszowski Cortney L. , Bass William Thomas , Lattanzio Frank A.
Published: February 2021

Objective

Complement activation is instrumental in the pathogenesis of Hypoxic-ischemic encephalopathy (HIE), a significant cause of neonatal mortality and disability worldwide. Therapeutic hypothermia (HT), the only available treatment for HIE, only modestly improves outcomes. Complement modulation as a therapeutic adjunct to HT has been considered, but is challenging due to the wide-ranging role of the complement system in neuroinflammation, homeostasis and neurogenesis in the developing brain. We sought to identify potential therapeutic targets by measuring the impact of treatment with HT on complement effector expression in neurons and glia in neonatal HIE, with particular emphasis on the interactions between microglia and C1q.

Methods

The Vannucci model was used to induce HIE in term-equivalent rat pups. At P10-12, pups were randomly assigned to three different treatment groups: Sham (control), normothermia (NT), and hypothermia (HT) treatment. Local and systemic complement expression and neuronal apoptosis were measured by ELISA, TUNEL and immunofluorescence labeling, and differences compared between groups.

Results

Treatment with HT is associated with decreased systemic and microglial expression of C1q, decreased systemic C5a levels, and decreased microglial and neuronal deposition of C3 and C9. The effect of HT on cytokines was variable with decreased expression of pro and anti-inflammatory effectors. HT treatment was associated with decreased C1q binding on cells undergoing apoptosis.

Conclusion

Our data demonstrate the extreme complexity of the immune response in neonatal HIE. We propose modulation of downstream effectors C3a and C5a as a therapeutic adjunct to HT to enhance neuroprotection in the developing brain.
Development of a Physiologically Based Pharmacokinetic Model for Hydroxychloroquine and Its Application in Dose Optimization in Specific COVID-19 Patients
Authors: Zhang Miao , Yao Xueting , Hou Zhe , Guo Xuan , Tu Siqi , Lei Zihan , Yu Zhiheng , Liu Xuanlin , Cui Cheng , Chen Xijing , Shen Ning , Song Chunli , Qiao Jie , Xiang Xiaoqiang , Li Haiyan , Liu Dongyang
Published: February 2021

In Feb 2020, we developed a physiologically-based pharmacokinetic (PBPK) model of hydroxychloroquine (HCQ) and integrated in vitro anti-viral effect to support dosing design of HCQ in the treatment of COVID-19 patients in China. This, along with emerging research and clinical findings, supported broader uptake of HCQ as a potential treatment for COVID-19 globally at the beginning of the pandemics. Therefore, many COVID-19 patients have been or will be exposed to HCQ, including specific populations with underlying intrinsic and/or extrinsic characteristics that may affect the disposition and drug actions of HCQ. It is critical to update our PBPK model of HCQ with adequate drug absorption and disposition mechanisms to support optimal dosing of HCQ in these specific populations. We conducted relevant in vitro and in vivo experiments to support HCQ PBPK model update. Different aspects of this model are validated using PK study from 11 published references. With parameterization informed by results from monkeys, a permeability-limited lung model is employed to describe HCQ distribution in the lung tissues. The updated model is applied to optimize HCQ dosing regimens for specific populations, including those taking concomitant medications. In order to meet predefined HCQ exposure target, HCQ dose may need to be reduced in young children, elderly subjects with organ impairment and/or coadministration with a strong CYP2C8/CYP2D6/CYP3A4 inhibitor, and be increased in pregnant women. The updated HCQ PBPK model informed by new metabolism and distribution data can be used to effectively support dosing recommendations for clinical trials in specific COVID-19 patients and treatment of patients with malaria or autoimmune diseases.
Plant microRNAs from Moringa oleifera Regulate Immune Response and HIV Infection
Authors: Minutolo Antonella , Potestà Marina , Roglia Valentina , Cirilli Marco , Iacovelli Federico , Cerva Carlotta , Fokam Joseph , Desideri Alessandro , Andreoni Massimo , Grelli Sandro , Colizzi Vittorio , Muleo Rosario , Montesano Carla
Published: February 2021

Traditional medicine is often chosen due to its affordability, its familiarity with patient’s cultural practices, and its wider access to the local community. Plants play an important role in providing indispensable nutrients, while specific small RNAs can regulate human gene expression in a cross-kingdom manner. The aim of the study was to evaluate the effects of plant-enriched purified extract microRNAs from Moringa oleifera seeds (MO) on the immune response and on HIV infection. Bioinformatic analysis shows that plant microRNAs (p-miRs) from MO belonging to 18 conserved families, including p-miR160h, p-miR166, p-miR482b, p-miR159c, p-miR395d, p-miR2118a, p-miR393a, p-miR167f-3p, and p-miR858b are predicted to target with high affinity BCL2, IL2RA, TNF, and VAV1, all these being involved in the cell cycle, apoptosis, immune response and also in the regulation of HIV pathogenesis. The effects of MO p-miRs transfected into HIV+ PBMCs were analyzed and revealed a decrease in viability associated with an increase of apoptosis; an increase of T helper cells expressing Fas and a decrease of intracellular Bcl2 protein expression. Meanwhile no effects were detected in PBMCs from healthy donors. In CD4+ T cells, transfection significantly reduced cell activation and modified the T cell differentiation, thereby decreasing both central and effector memory cells while increasing terminal effector memory cells. Interestingly, the p-miRs transfection induces a reduction of intracellular HIV p24 protein and a reduction of viral DNA integration. Finally, we evaluated the effect of synthetic (mimic) p-miR858b whose sequence is present in the MO p-miR pool and predicted to target VAV1, a protein involved in HIV-Nef binding. This protein plays a pivotal role in T cell antigen receptor (TCR) signaling, so triggering the activation of various pathways. The transfection of HIV+ PBMCs with the synthetic p-miR858b showed a reduced expression of VAV1 and HIV p24 proteins. Overall, our evidence defines putative mechanisms underlying a supplementary benefit of traditional medicine, alongside current antiretroviral therapy, in managing HIV infection in resource-limited settings where MO remains widely available.
Biologics During Pregnancy and Breastfeeding Among Women With Rheumatic Diseases: Safety Clinical Evidence on the Road
Authors: Beltagy Asmaa , Aghamajidi Azin , Trespidi Laura , Ossola Wally , Meroni Pier Luigi
Published: February 2021

Females are generally more affected by autoimmune diseases, a fact that underlines the relationship with pregnancy and the safety of anti-rheumatic drugs in pregnancy and lactation. Biologic therapies are increasingly prescribed to treat and maintain remission in a significant number of systemic autoimmune rheumatic diseases. The experience with the use of biologics during gestation is extremely lacking because of the observational nature of the available studies and the difficulty in designing proper clinical trials in pregnancy. Among the studied biologics, more information was published on TNFα inhibitors and, in particular, on their potential passage through the placenta and impact on the fetus. Currently, a fragment of anti-TNFα monoclonal IgG, certolizumab pegol, is considered safe with almost no placental transfer. Subsequent observations are suggesting a comparable safety for the soluble TNFα receptor etanercept. Another biologic, eculizumab, the anti-C5a antibody used to treat complement-mediated microangiopathies, is also considered safe due to the unique engineered IgG2/4κ formulation that limits its passage through the placental barrier. Still, long-term data about children born to women treated with biologics in pregnancy are not attainable. Data on breastfeeding are currently available for several biologics. This article reviews the literature available about which drugs are considered safe during pregnancy and lactation, which are not, and on future prospects.
Protecting Intestinal Microenvironment Alleviates Acute Graft-Versus-Host Disease
Authors: Zhou Zhengcan , Shang Ting , Li Xiurong , Zhu Hongyan , Qi Yu-Bo , Zhao Xin , Chen Xi , Shi Zhe-Xin , Pan Guixiang , Wang Yue-Fei , Fan Guanwei , Gao Xiumei , Zhu Yan , Feng Yuxin
Published: February 2021

Acute gut graft-versus-host disease (aGVHD) is a leading threat to the survival of allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Abnormal gut microbiota is correlated with poor prognosis in allo-HSCT recipients. A disrupted intestinal microenvironment exacerbates dysbiosis in GVHD patients. We hypothesized that maintaining the integrity of the intestinal barrier may protect gut microbiota and attenuate aGVHD. This hypothesis was tested in a murine aGVHD model and anin vitrointestinal epithelial culture. Millipore cytokine array was utilized to determine the expression of proinflammatory cytokines in the serum. The 16S rRNA sequencing was used to determine the abundance and diversity of gut microbiota. Combining Xuebijing injection (XBJ) with a reduced dose of cyclosporine A (CsA) is superior to CsA alone in improving the survival of aGVHD mice and delayed aGVHD progression. This regimen also reduced interleukin 6 (IL-6) and IL-12 levels in the peripheral blood. 16S rRNA analysis revealed the combination treatment protected gut microbiota in aGVHD mice by reversing the dysbiosis at the phylum, genus, and species level. It inhibited enterococcal expansion, a hallmark of GVHD progression. It inhibited enterococcal expansion, a hallmark of GVHD progression. Furthermore,Escherichia coliexpansion was inhibited by this regimen. Pathology analysis revealed that the combination treatment improved the integrity of the intestinal tissue of aGVHD mice. It also reduced the intestinal permeability in aGVHD mice. Besides, XBJ ameliorated doxorubicin-induced intestinal epithelial death in CCK-8 assay. Overall, combining XBJ with CsA protected the intestinal microenvironment to prevent aGVHD. Our findings suggested that protecting the intestinal microenvironment could be a novel strategy to manage aGVHD. Combining XBJ with CsA may reduce the side effects of current aGVHD prevention regimens and improve the quality of life of allo-HSCT recipients.