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Piotr H Pawłowski Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warszawa, PolandCorrespondence: Piotr H Pawłowski Tel +48-22-659-70-72Email piotrp@ibb.waw.plAbstract: The change in the formal charge of 34 SARS-CoV-2 lineages from September 2020 to June 2021 was analyzed according to the monthly evidence of the European agency. The reported point mutations and small insertions are electrically neutral (17), positive (12), or negative (3). They had been found in the spike glycoprotein S, in the RBD and S1/S2 regions, crucial for initiation of viral infection. The most often observed were positive mutations, especially D614G and E484K, located in the region of S1/S2 junction, and in the receptor-binding domain (RBD), respectively. They are related to G and A switching. Positive mutations are stretching equally in both areas, but in the RBD region, they are more dispersed. In the set of analyzed virus variants, the increasing tendency in the number of positively charged residues in spike protein was observed. Furthermore, the well-documented WHO classes show an increase in the COVID-19 percentage case fatality with the positive increase in the spike crucial region’s total charge. The data mining, applying classifier algorithm based on the artificial neuronal network, confirms that the value and the distribution of additional positive charge in S may be important factors enabling virus impact to immunity. This may be promoted by the stronger long-range electrostatic attraction of the virus particle to the host cell, preceding the infection. The estimation of the potential energy for the RBD approaching the angiotensin-converting enzyme (ACE2) was presented.Keywords: coronavirus, COVID-19, SARS-CoV-2, spike protein S, amino acids, charge, potential energy, electrostatic interactions

In experiments in non-inbred rats, it has been established that chronic intoxication of ethanol (30 days, total dose – 6.0 LD50) essentially reduces concentration of cytokines IFNγ, IL-2, IL-4, IL-10 in blood, increases concentration of IL-6, reduces an interrelation IFNγ/IL-4 in comparison with the control, suppresses of immune responses, which displays the greater lesion of Th1-cells in comparison with Th2-lymphosytes.

SARS-COV-2, the etiologic agent of COVID-19 is able to infect cells through its Spike protein (SPp) which must first bind to its receptor ACE2. Most currently developed vaccines target the SARS-COV-2 encoded Spike protein. Many SARS-COV-2 variants have been identified that exhibit several mutations in their Spike protein. SARS-COV-2 variant, B.1.526 was identified in New York, U.S.A. [Annavajhala, M.K. (2021) medRxiv, DOI: 10.1101/2020.02.23.21) and shown to contain the mutations, L5F, T95I, D253G, E484K, S477N, D614G and A701V. T95 and S477 of SPp are phosphorylation sites for a number of Protein kinases, including Cdk1 and GSK-3. Here, through Computerized Structure Model Analysis and Thermodynamic Calculations, it is shown that phosphorylations of T95 and S477 increases the stabilities of SARS-COV-2 encoded SPp-ACE2 and SPp-DC-SIGN complexes with very marginal effects on the binding efficiencies between the components of the complexes, and mutations T95I and S477N antagonize the effects of the phosphorylations of T95 and S477. Thus, it appears that SARS-COV-2 variant, B.1.526 has adapted to exploit the protein phosphorylation apparatus of its host cells to its advantage, and the effects of phosphorylation of of T95 and S477 are blunted through random mutation. Whether Neutralizing Antibodies that target SPp can recognize the phosphorylated forms of SPp is currently unknown.

OBJETIVO: Ainda que as características clássicas da síndrome fetal alcoólica tenham sido descritas desde 1968, a pesquisa sobre a teratogênese do álcool apenas recentemente demonstrou que o cérebro é o órgão do corpo mais vulnerável aos efeitos da exposição pré-natal ao álcool. No presente artigo, fazemos uma revisão da literatura focalizando principalmente os distúrbios comportamentais relacionados à exposição pré-natal ao álcool. FONTES DOS DADOS: Foi realizada uma pesquisa com base no PubMed sobre a literatura publicada entre 1968 e 2006, com as palavras-chave etanol, gestação e comportamento. Foram estabelecidos limites a estudos em humanos. SÍNTESE DOS DADOS: Os dados apresentados nesta revisão sugerem que jovens com efeitos do espectro do álcool fetal estão sob risco maior de terem comportamento social disruptivo, entre outros problemas neurocomportamentais. CONCLUSÕES: Ainda que seja impossível separar completamente a teratogênese sobre o cérebro decorrente da exposição ao álcool de influências ambientais pós-natais como a causa definitiva desses resultados, o pediatra deve ser estimulado ao diagnóstico precoce de crianças afetadas pela síndrome fetal alcoólica e efeitos do espectro do álcool fetal. Isso permite iniciar o manejo e cuidados apropriados para evitar as conseqüências em longo prazo no comportamento e assegurar uma adaptação social e escolar melhor e mais produtiva.OBJECTIVE: Although the classic features of fetal alcohol syndrome have been recognized since 1968, research on alcohol teratogenesis has only recently demonstrated that the brain is the organ in the body most vulnerable to the effects of prenatal alcohol exposure. In this present article, we reviewed the literature focusing mainly on behavioral disturbances related to prenatal ethanol exposure. SOURCES: We performed a PubMed search on the literature published between 1968 and 2006 using the terms ethanol, pregnancy and behavior. We limited our search to studies on humans. SUMMARY OF THE FINDINGS: The data presented in this review suggested that youths with fetal alcohol spectrum disorder are at risk of disruptive social behavior, among other neurobehavioral abnormalities. CONCLUSIONS: Although it is still impossible to completely separate brain teratogenesis secondary to alcohol exposure from environmental postnatal influences as the definite cause for these outcomes, the pediatrician should be encouraged to early diagnose children affected by fetal alcohol syndrome and fetal alcohol spectrum disorder. This provides proper management and care and avoids long-term consequences on their behavior, besides ensuring better and productive school and social adaptation.

Objetivos: La inducción de hipotermia moderada en pacientes con infarto de la arteria cerebral media (ACM) puede ocasionar alteraciones metabólicas y nutricionales. En la actualidad se desconoce cuál es el mejor método para realizar la valoración nutricional en este grupo de población. El objetivo del presente estudio fue valorar la utilidad del balance nitrogenado en el seguimiento de pacientes con infarto de la ACM y sometidos a hipotermia moderada (32-33 ºC) mediante enfriamiento intravascular, en la Unidad de Cuidados Neurocríticos de un hospital de tercer nivel. Material y métodos: Se diseñó un estudio retrospectivo en el que se incluyeron pacientes con infarto de la ACM de los que se recogieron variables biodemográficas, clínicas, de hipotermia y nutricionales. Del mismo modo se realizó el seguimiento prospectivo de un paciente con infarto de la ACM e hipotermia inducida, recogiendo las mismas variables en distintos tiempos de su evolución clínica. Resultados: En la serie retrospectiva se incluyeron 6 pacientes con infarto de ACM sometidos a hipotermia moderada durante un periodo promedio de 12 días (intervalo 9-15). Se constataron pérdidas de nitrógeno (media 9,9 g) inferiores a las que cabría esperar en pacientes críticos durante la fase aguda. En el seguimiento prospectivo del paciente con infarto maligno de la ACM desde día 1 hasta día 22 tras la aplicación de la hipotermia se observaron, al igual que en la serie de pacientes anteriormente descrita, valores bajos de nitrógeno eliminado durante la fase de hipotermia inducida que se elevaron posteriormente cuando el paciente recuperó la normotermia. El nitrógeno eliminado promedio durante el periodo de hipotermia fue de 10,7 g y presentó una elevación hasta 27,3 g durante el periodo normotérmico (día 17). Conclusiones: Estos resultados sugieren que la supresión metabólica inducida por la hipotermia moderada es clínicamente relevante y que, por lo tanto, la determinación del balance nitrogenado no parece ser una herramienta útil en el seguimiento nutricional de este tipo de pacientes.Objectives: Induction of moderate hypothermia in patients with median cerebral artery (MCA) infarction may produce metabolic and nutritional impairments. Currently, we do not know which is the best method to carry out nutritional assessment in this population group. The aim of the present study was to assess the usefulness of nitrogen balance in the follow-up of patients with MCA submitted to moderate hypothermia (32-33 ºC) by means of intravascular cooling at the Neurocritical Patients Unit at a tertiary hospital. Material and methods: We designed a retrospective study including patients with MCA infarction of whom we gathered bio-demographical, clinical, hypothermia, and nutritional variables. Similarly, we carried out a prospective follow-up of a patient with MCA infarction and induced hypothermia, gathering the same variables at different time points of his clinical course. Results: Six patients with MCA infarction submitted to moderate hypothermia for a mean duration of 12 days (interval 9-15) were included in the retrospective series. We observed that nitrogen losses (mean 9.9 g) were lower than those previously thought for critical patients during the acute phase. During the prospective follow-up of the patient with malignant infarction of the MCA from day 1 to day 22 after the application of hypothermia, low levels of nitrogen losses were similarly observed during the phase of induced hypothermia, which increased later on when the patient recovered normothermia. The mean nitrogen expenditure during the period of hypothermia was 10.7 g and increased up to 27.3 g during the normothermia period (day 17). Conclusions: These results suggest that moderate hypothermia-induced metabolic suppression is clinically relevant and thus the determination of nitrogen balance does not seem to be a useful tool in the nutritional followup of this type of patients.

Harrison and Simmonds (1984) provided the first clear evidence that neuroactive steroids act at specific neurotransmitter receptors, investigating the potentiation of muscimol-induced GABAA responses by alphaxalone (3α-hydroxy 5α -pregnane l l,20-dione) in cortical slices. Within 2 years, a progesterone metabolite (3α-hydroxy-5α-pregnan-20-one, 3α,5α-THP, allopregnanolone) and a deoxycorticosterone metabolite (3α,21-dihydroxy-5α-pregnan-20-one, 3α,5α-THDOC, tetrahydrodeoxycorticosterone, THDOC) were shown to be positive modulators of GABAA receptors (Majewska et al., 1986). That same year, publications showed that ethanol has direct action at GABAA receptors (Allan and Harris, 1986, Suzdak et al., 1986). Thus, the GABAA receptor complex was identified as a membrane-bound target providing a pharmacological basis for shared sensitivity between neurosteroids and ethanol. The common behavioral effects of ethanol and neuroactive steroids were compared directly using drug discrimination procedures (Ator et al., 1993). The N-methyl-D-aspartate (NMDA) receptor complex, a membrane-bound ionophore important for excitatory glutamate neurotransmission, was shown to be antagonized by low concentrations of ethanol (Lovinger et al., 1989). Since data were emerging for neurosteroid activity at NMDA receptors (Wu et al., 1991), the stage was set for the suggestion that neurosteroids, and physiological states that alter circulating neuroactive steroids, could affect sensitivity to alcohol (Grant et al., 1997). The unique interface of ethanol and neurosteroids encompasses molecular, cellular, physiological and behavioral processes. This review will highlight a variety of mechanisms by which neurosteroids affect sensitivity to ethanol, including metabolic pathways, physiological states associated with activity of the hypothalamic-pituitary adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes, and the effects of chronic exposure to ethanol, in addition to behavioral implications.

Naomi Hauser,1,2 Kathryn C Conlon,2– 4 Angel Desai,1 Leda N Kobziar5 1Department of Medicine, Division of Infectious Disease, University of California Davis Health, Sacramento, CA, USA; 2Climate Adaptation Research Center, University of California, Davis, CA, USA; 3Department of Public Health Sciences, School of Medicine, University of California Davis, Davis, CA, USA; 4Department of Veterinary Medicine & Epidemiology, School of Veterinary Medicine, University of California Davis, Davis, CA, USA; 5Department of Natural Resources and Society, University of Idaho, Coeur d’Alene, ID, USACorrespondence: Naomi HauserDepartment of Medicine, Division of Infectious Disease, University of California Davis Health, 4150 V St, PSSB G500, Sacramento, CA, 95817, USATel +1 916-734-8516Fax +1 916-734-7766Email nehauser@ucdavis.eduAbstract: Climate change is increasingly recognized for its impacts on human health, including how biotic and abiotic factors are driving shifts in infectious disease. Changes in ecological conditions and processes due to temperature and precipitation fluctuations and intensified disturbance regimes are affecting infectious pathogen transmission, habitat, hosts, and the characteristics of pathogens themselves. Understanding the relationships between climate change and infectious diseases can help clinicians broaden the scope of differential diagnoses when interviewing, diagnosing, and treating patients presenting with infections lacking obvious agents or transmission pathways. Here, we highlight key examples of how the mechanisms of climate change affect infectious diseases associated with water, fire, land, insects, and human transmission pathways in the hope of expanding the analytical framework for infectious disease diagnoses. Increased awareness of these relationships can help prepare both clinical physicians and epidemiologists for continued impacts of climate change on infectious disease in the future.Keywords: climate change, global warming, infectious disease, environment, antimicrobial resistance

Lina T Al Kury,1 Alam Zeb,2 Zain Ul Abidin,2 Nadeem Irshad,3 Imran Malik,2 Arooj Mohsin Alvi,2 Atif Ali Khan Khalil,4 Sareer Ahmad,4 Muhammad Faheem,2 Arif-Ullah Khan,2 Fawad Ali Shah,2 Shupeng Li51College of Natural and Health Sciences, Zayed University, Abu Dhabi, United Arab Emirates; 2Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan; 3Department of Pharmacy, Quaid-I-Azam University, Islamabad, Pakistan; 4Rehman Medical Institute, Peshawar, Pakistan; 5State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, People’s Republic of ChinaPurpose: Melatonin and celecoxib are antioxidants and anti-inflammatory agents that exert protective effects in different experimental models. In this study, the neuroprotective effects of melatonin and celecoxib were demonstrated against ethanol-induced neuronal injury by in silico, morphological, and biochemical approaches.Methods: For the in silico study, 3-D structures were constructed and docking analysis performed. For in vivo studies, rats were treated with ethanol, melatonin, and celecoxib. Brain samples were collected for biochemical and morphological analysis.Results: Homology modeling was performed to build 3-D structures for IL1β), TNFα, TLR4, and inducible nitric oxide synthase. Structural refinement was achieved via molecular dynamic simulation and processed for docking and postdocking analysis. Further in vivo experiments showed that ethanol induced marked neuronal injury characterized by downregulated glutathione, glutathione S-transferase, and upregulated inducible nitric oxide synthase. Additionally, ethanol increased the expression of TNFα and IL1β. Finally, neuronal apoptosis was demonstrated in ethanol-intoxicated animals using caspase 3 and activated JNK staining. On the other hand, melatonin and celecoxib treatment ameliorated the biochemical and immunohistochemical alterations induced by ethanol.Conclusion: These results demonstrated that ethanol induced neurodegeneration by activating inflammatory and apoptotic proteins in rat brain, while melatonin and celecoxib may protect rat brain by downregulating inflammatory and apoptotic markers.Keywords: simulation, docking, cortex, hippocampus, ethanol, neurodegeneration

Ethnobotanical claims regarding Kigelia africana reported antiulcer properties as part of its medicinal application. In this work, aqueous leaf extract from K. africana was investigated for its phytochemical constituents and antiulcer potential against ethanol-induced ulcer in rats. The participation of oxidative stress on ethanol-induced ulcer and the potential protective antioxidant activity of K. africana extracts were investigated by determining vitamin C and thiobarbituric acid reactive species (TBARS) contents in the gastric mucosa of rats. The HPLC analysis showed the presence of gallic acid, chlorogenic acid, caffeic acid and also the flavonoids rutin, quercetin and kaempferol in the aqueous plant extract. Oral treatment with K. africana extract (1.75; 3.5; 7 and 14mg/kg) one hour after ulcer induction with ethanol decreased in a dose dependent manner the ulcer index. Ethanol increased significantly stomachal TBARS levels and decreased vitamin C content when compared to the control animals. K. africana blunted the ethanol-induced oxidative stress and restored vitamin C content to the control levels. The present results indicate that the aqueous leaf extract from K. africana possesses antiulcer potential. The presence of flavonoids in plant extract suggests that its antiulcerogenic potential is associated with antioxidant activity. Of particular therapeutic potential, K. africana was effective against ethanol even after the induction of ulcer, indicating that it can have protective and curative effects against gastric lesion. EXCLI Journal ; Vol. 13, 2014