Sixth Position Research Articles

Sickle Cell Disease Clinical Classification

Introduction:Sickle cell disease (SCD) is one of the most common genetic disorders. The abnormality is due to the substitution of a glutamic acid by a valine at the sixth position on the β-globin chain , resulting in pathologic hemoglobin called hemoglobin S, this results from an autosomal recessive mutation on chromosome 11 [1]. The classic physiopathology of the SCD is based on the polymerization of hemoglobin S, followed by sickling and dehydration of the red blood cells (RBCs). The slowing down of blood circulation and obstruction of the microcirculation by the deformed RBCs is the reason of the manifestations and complications of SCD. [2]. SCD may lead to various clinical acute and chronic complications, which have a high mortality rate . The laboratory genotyping and phenotyping classifications don't indicate the clinical severity of sickle cell disease , many SCD patients have underling serous complicaions , which make SCD clinicaly sever moderate or mild inspite the similiraty in in the HPLC result . Aim: This study is to grade SCD clinical severity based on the number and seriousness of the complications .Method:In his on going project 30 SCD patients from both age and gender . The clinical evalation performed along with th following tests complete blood count , kidney fuunction test , liver function test , serum ferritin , coagulation profile , antibody sceerning , high performance liquid chromatography (HPLC) , chest X-Ray , ECG , Echocardiography .The patients also assessed from psychology and social point of view . The grades of the disease are 15 according to the number of the complications the severity is mild , moderate and sever .Mild disease is 1-5 moderate 6-10 and severe 11-15 complications . The severity of the more than 1is sever less than 1 is moderate , less than 0.5 is mild . The factor calculated as any sever X 3 , any moderate multiply by 2 qnd any moderate is multiply by 1 and he normal is 0 table 1 & table 2 .Results :In the 30 patients they showed in the 1-kidneynormal (N ) 17 , mild (MI ) 2 , moderate (MO ) 4 , Severe (SV ) 7; 2-Liver N 4 , MI 6 , MO 16 , SV 4; 3-Spleen N 5, MI 2 , MO 11 , SV 12;4-Gall bladder (GB ) N 4, MI 1, MO 10 , SV 15; 5-Bone N 5, MI 5, MO 7 , SV 13; 6-Genitalia (Gent ) N 15, MI 11, MO 3 , SV 1; 7-Respiratory (Resp ) N 22, MI 1, MO 3 , SV 4; 8-Cardiovascular system (CVS ) N 15, MI 3, MO 2 , SV 10; 9-Cental Nervous System (CNS ) N 20, MI 5, MO 2 , SV 3; 10-TX N O, MI 15, MO 10, SV 5; 11-Antibodies (Ab ) N 22, MI 3, MO 2 , SV 3; 12-Ferritin N 10, MI 4, MO 5 , SV 11; 13-Psychiatry (Psy) N 5, MI 4, MO 6 , SV 15; 14-Social (SOC ) N 10, MI 6, MO 5 , SV 9; 15-Pain N 0, MI 5, MO 15 , SV 10;Conclusion:The clinical classification for sickle cell disease is mandatory in this systemic disorder. The disease graded clinically according to 15 systemic complicatins each clinical grades from 1-15 are are given SCD1-15. The clinical severity based on the number the severit of the complications .The clinical classification also determind by the severity score of the complications .

Recovery of Thymic Function after Allogeneic Hematopoietic Stem Cell Transplantation in with Sickle Cell Anemia Patients

Introduction: Sickle cell anemia (SCA) is a hereditary chronic disorder of hemoglobin (Hb) caused by a single mutation in the human β-globin gene leading to an amino acid substitution (Glu → Val) in the sixth position of the β-globin chain. The polymerization of the resulting abnormal hemoglobin (HbS) under hypoxic conditions is a key event in the complex pathophysiology of SCA (Hebbel, 2011). Vaso-occlusive crisis (VOC) is the main clinical manifestation and caused by a mechanical obstruction of small blood vessels by rigidly distorted red blood cells (RBCs) and local inflammation (Raphael; Vichinsky, 2005). SCA represents a serious public health problem in many countries. Currently, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for SCA. However, allo-HSCT can have severe drawbacks, such as the development of graft-versus-host disease (GvHD). Another main concern is the profound and long-lasting immunodeficiency consecutive to transplantation procedure. A potent immune reconstitution (IR) after HSCT is essential to limit the infection risk and disease relapse (Toubert et al., 2012). The reconstitution of a diverse peripheral T cell repertoire is a long and continuous process that depends on a functional thymus to produce naïve T cells. Therefore, thymus plays a crucial role in the quality of IR and clinical outcome after allo-HSCT. The aim of this study was to evaluate the thymic function in SCA patients treated with allo-HSCT and analyze the impact of acute GvHD on patient's thymic function.Methods and Patients: Twenty-nine patients SCA patients were treated with allo-HSCT and evaluated in this work. Peripheral blood mononuclear cells were collected before transplantation (day 0) and at 1, 3, 6, 12, 24 and >24 months post-transplantation periods. Fifteen healthy individuals (afrodescendants) matched by age/gender were enrolled as controls. Thymic function was evaluated by quantification of signal joint (sj)-T-cell receptor excision circles (sjTREC) and βTREC in the genomic DNA by real-time quantitative PCR. Intra-thymic T-cell division (n) was calculated by the formula: n= LOG(sjTREC/βTREC)/LOG2. Nonparametric Mann-Whitney test was used and the results were considered statistically significant when p < 0.05.Results: sjTREC and β-TREC levels were significantly reduced one month after transplantation. However, at 6 months post-transplantation their levels increased substantially. At 12 months post-HSCT, significantly higher sjTREC and β-TREC levels were found, compared to the first periods after transplantation. The intra-thymic cell division was significantly reduced at 1 month after transplantation, compared to the control group and pre-transplantation period. Patients who developed acute GvHD showed decreased sjTREC and β-TREC levels at 6 months post-transplantation, compared to control group and to patients without GvHD.Conclusions: Our findings demonstrated that SCA patients have, despite of the inflammatory environment, a preserved thymus and present rebound of its important function after undergoing allo-HSCT. In addition, we observed that patients undergoing acute GvHD have a decreased thymic function, compromising their immune status during early immune reconstitution phase. DisclosuresNo relevant conflicts of interest to declare.

Prevalence of Stroke in Asian Patients with Sickle Cell Anemia: A Systematic Review and Meta-Analysis

Sickle cell anemia (SCA) is an inherited autosomal recessive disease. It is caused due to point mutation that substitutes glutamate with valine at the sixth amino acid position of the beta chain of hemoglobin molecules leading to the sickling of the red blood cells and decreased structural deformability. Silent cerebral infarcts are the most common neurological complication of SCA, while overt stroke comprises substantial burden in patients with SCA. This meta-analysis aimed to find the pooled prevalence of overt stroke in SCA patients and discuss the importance of screening them. PubMed, Embase, and Google Scholar were the electronic databases used to search the studies. A total of 765 articles were retrieved upon detailed searching in the abovementioned databases. After a series of removing duplicate articles, title and abstract screening, and full-text review, 20 articles were found eligible and included in the study. The total number of participants from all the included studies was 3,956, and pooled prevalence of stroke in patients with sickle cell anemia in Asia was found to be 5% (95% CI: 4%, 6%) with a range from 1 to 41%. Stroke occurrence in sickle cell anemia patients is an emergency complication that needs immediate intervention and management. Because of the high prevalence of stroke in patients with sickle cell anemia, clinicians should focus on its prevention and treatment strategies.

The effect of Doxorubicin and Thioridazine on squamous The effect of Doxorubicin and Thioridazine on squamous carcinoma cell line

Background: Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers occupying the sixth position worldwide. PI3k/Akt signaling pathway plays a significant role in regulating diverse cellular functions. This includes cell growth, proliferation and survival via inhibition of apoptosis, transcription and protein synthesis. One of the most acknowledged and approved chemotherapeutic agents is Doxorubicin (DOX) which is a non- selective class I anthracycline. In spite of DOX being one of the most acknowledged chemotherapeutic agents, its use has been limited by its toxic side effects and the development of chemoresistance. Nowadays, Thioridazine (TZ) which is a newly repurposed drug that was originally used in the treatment of psychosis, schizophrenia and anxiety, has been tested in the treatment of breast, ovarian, gastric cancers and leukemias. Methods: MTT was employed to assess the effect of TZ and DOX on the separately and in combination, with different doses and durations on the HEp2 cell line. The efficacy of both drugs was evaluated separately and in combination with different doses and durations on inhibition of cell migration on the HEp2 cell line. Results: The results of this study revealed that the highest viability was with the control group followed by the TZ group I (low dose), compared to the other groups. While it showed that the lowest mean viability was with the combination group VI (high dose) compared to other groups. Regarding the mean values of cell migration, the lowest mean value was noted in the combination group III, and the highest mean values was noted in the control group, followed by the DOX group I. Conclusion: From the results of this study it can be concluded that combination group of DOX an d TZ is a promising treatment for HEp2 cell line.

SOCIAL PERMISSIVE REASONING AS INHERITED POVERTY (CRITICAL VIEW OF A POLITICAL DYNASTY PRONE TO CORRUPTION)

Political Dynasty and Corruption are like two inseparable things. In Indonesia, political dynasty has been growing since the era of reformation, right after the implementation of regional autonomy system which enables the continuation of local politics succession directly. At 2018 regional election, there were five provinces with candidates from political dynasties such as: Banten, South Sumatera, West Java, East Java, and West Kalimantan.As a causality relation, corruption is the outcome and permissive behavior is the cause. In the Province of Banten, corruption occurs due to the permissive behavior stemmed socially ad structurally in the society. One of the influence of the permissive behavior towards corruption is the level of education. The lower it is, the higher the level of poverty, thus more permissive they are towards corruption, as well as the society’s lack of knowledge about negative effects of political dynasty. The people in Banten seems don’t fully acknowledge that political dynasty is degrading the essence of democracy and prone to corruption practice. In 2016, Banten helds sixth position in Indonesia in their level of poverty, and the second lowest in Java. Based on statistical data, until 2017 the amount of people with poverty in the cities and rural areas has increased.This research used qualitative research method in explanative manner, where the target of this research was to explain the social permissive reasoning phenomenon in the society of Banten as an inherited poverty of a political dynasty which prone to corruption, with several facts that supported data and research analysis which can be used to understand issues derived from such phenomenon.

Design and synthesis of quinoline-pyrimidine inspired hybrids as potential plasmodial inhibitors.

Presently, artemisinin-based combination therapy (ACT) is the first-line therapy of Plasmodium falciparum malaria. With the emergence of malaria parasites that are resistant to ACT, alternative antimalarial therapies are urgently needed. In line with this, we designed and synthesised a series of novel N-(7-chloroquinolin-4-yl)-N'-(4,6-diphenylpyrimidin-2-yl)alkanediamine hybrids (6a-7c) and evaluated their inhibitory activity against the NF54 chloroquine-susceptible strain as a promising class of antimalarial compounds. The antiplasmodial screening revealed that seven analogues showed promising to good activity with half-maximal inhibitory concentration (IC50)=0.32μM-4.30μM. Compound 7a with 1,4-diamine butyl linker and 4-hydroxyl phenyl on fourth and sixth position of pyrimidine core showed the most prominent activity with an IC50 value of 0.32±0.06μM, with a favourable safety profile of 9.79 to human kidney epithelial (HEK293) cells. The remaining six analogues showed moderate activity with IC50 values ranging from 7.50μM to 83.01μM. We further investigated the binding affinities of the molecules to two essential cytosolic P.falciparum heat shock protein 70 homologues; PfHsp70-1 and PfHsp70-z. Compound 7a exhibited the highest binding affinity for both PfHsp70s with KD in a lower nanomolar range (4.4-11.4nM). Furthermore, molecular docking revealed that compounds 6, 6k, 7b and 7a exhibited better fitness in PfHsp70-1 with compound 7a showing the highest and lowest binding scores of-9.8kcal/mol. Therefore, we speculate that PfHsp70-1 is one of the targets of these inhibitors. The bioisoteric replacement of the groups at phenyl ring at the fourth and sixth position of the pyrimidine core had a constructive association with antiplasmodial activity. The promising antiplasmodial activity of the synthesised analogues illustrates how crucial molecular hybridisation is as a strategy in the development of quinoline-pyrimidine hybrids as prospective antiprotozoal agents.

Sickle cell disease: progress towards combination drug therapy.

Dr. John Herrick described the first clinical case of sickle cell anaemia (SCA) in the United States in 1910. Subsequently, four decades later, Ingram and colleagues characterized the A to T substitution in DNA producing the GAG to GTG codon and replacement of glutamic acid with valine in the sixth position of the βS -globin chain. The establishment of Comprehensive Sickle Cell Centers in the United States in the 1970s was an important milestone in the development of treatment strategies and describing the natural history of sickle cell disease (SCD) comprised of genotypes including homozygous haemoglobin SS (HbSS), HbSβ0 thalassaemia, HbSC and HbSβ+ thalassaemia, among others. Early drug studies demonstrating effective treatments of HbSS and HbSβ0 thalassaemia, stimulated clinical trials to develop disease-specific therapies to induce fetal haemoglobin due to its ability to block HbS polymerization. Subsequently, hydroxycarbamide proved efficacious in adults with SCA and was Food and Drug Administration (FDA)-approved in 1998. After two decades of hydroxycarbamide use for SCD, there continues to be limited clinical acceptance of this chemotherapy drug, providing the impetus for investigators and pharmaceutical companies to develop non-chemotherapy agents. Investigative efforts to determine the role of events downstream of deoxy-HbS polymerization, such as endothelial cell activation, cellular adhesion, chronic inflammation, intravascular haemolysis and nitric oxide scavenging, have expanded drug targets which reverse the pathophysiology of SCD. After two decades of slow progress in the field, since 2018 three new drugs were FDA-approved for SCA, but research efforts to develop treatments continue. Currently over 30 treatment intervention trials are in progress to investigate a wide range of agents acting by complementary mechanisms, providing the rationale for ushering in the age of effective and safe combination drug therapy for SCD. Parallel efforts to develop curative therapies using haematopoietic stem cell transplant and gene therapy provide individuals with SCD multiple treatment options. We will discuss progress made towards drug development and potential combination drug therapy for SCD with the standard of care hydroxycarbamide.

Coordination Chemistry of Bulky Aminopryridinates with Main Group and Transition Metals.

The coordination chemistry of bidentate aminopyridinato ligands (ApH), in particular 2-aminopyridines, is a highly popular area of research. Due to easy accessibility and versatility, 2-aminopyridines have played a prominent role as alternatives to cyclopentadienyl ligands in coordination chemistry. Easily modifiable steric bulks and the ability for fine-tuning of electronic effects have allowed researchers to control not only the metal-to-ligand stoichiometry but also the properties of their metal complexes. Previously, ligand redistribution was frequently observed for ligands of small steric demands. Bulky aminopyridinato ligands refer to ligands that incorporate alkyl-substituted phenyl groups at the amine/amido nitrogen and at the sixth position of the pyridine ring. The steric crowding allowed the stabilization of transition metals in unusually low oxidation conditions. One of the remarkable developments, for example, is the stabilization of metal-metal quintuple bonds by these ligands, thus providing a diamagnetic platform to study such systems chemically. Application of metal aminopyridinates in homogeneous catalysis has also broadened considerably in recent years. This review provides a comprehensive account of advances made with such ligands since their development for main group and transition elements.

Брачное поведение женщин-мигранток из стран Центральной Азии

The results of a study of the features of matrimonial behavior of migrant women from Central Asian countries are presented in this article. The conclusions are based on the analysis of statistical data on the number of marriages between citizens of different States in the Russian marriage market. Marriage in the migration process is a widespread phenomenon. In some countries, the proportion of marriages with foreigners reaches 30—40 % of the total number of marriages. In Russia, the share of marriages complicated by a foreign component is 6,5 %. Of these, the largest number of marriages were concluded by citizens of Ukraine. The countries of Central Asia — Tajikistan, Uzbekistan, Kazakhstan, and Kyrgyzstan — occupy the second, fourth, sixth, and ninth positions in the list, respectively. Citizens of Turkmenistan are much less active in getting married in Russia. In our country, number of marriages with foreign men is significantly higher than foreign women. However, this ratio is not met among citizens of Kazakhstan and Kyrgyzstan: more marriages are performed by women than men. The total marriage rates among migrants were calculated to determine the intensity of marriage by foreigners from Central Asian countries. The highest value of the total marriage rate of migrants is observed among citizens of Tajikistan, the lowest is among citizens of Turkmenistan. At the same time, the total marriage rate among women from Kyrgyzstan, Turkmenistan and Uzbekistan exceeds that of men. It is meaning that women from these countries are more likely to marry in Russia. The vast majority of marriages with a foreign component — 96 % — are between foreigners and Russians. The remaining 4 % of marriages are those in which both the bride and groom are foreign citizens. Citizens of Central Asian countries if they marry someone other than a Russian, choose their compatriot in the vast majority. It should be noted that the practice of marriage in the country of emigration is not limited only to marriage migration. It is not uncommon for people who come to the country for employment, education, or other aims to find life partners and register relationships. However, we should not exclude the widespread adoption of a pragmatic approach to marriage, in which migrants consider to marriage as an opportunity to be legalized in the country of immigration in a simplified manner, faster and easier to obtain citizenship. Therefore, the development and implementation of state regulation measures in this area is particularly relevant.

μ-Oxo-bridged diiron(iii) complexes of tripodal 4N ligands as catalysts for alkane hydroxylation reaction using m-CPBA as an oxidant: substrate vs. self hydroxylation.

A series of non-heme μ-oxo-bridged dinuclear iron(iii) complexes of the type [Fe2(μ-O)(L1–L6)2Cl2]Cl21–6 have been isolated and their catalytic activity towards oxidative transformation of alkanes into alcohols has been studied using m-choloroperbenzoic acid (m-CPBA) as an oxidant. All the complexes were characterized by CHN, electrochemical, and UV-visible spectroscopic techniques. The molecular structures of 2 and 5 have been determined successfully by single crystal X-ray diffraction analysis and both possesses octahedral coordination geometry and each iron atom is coordinated by four nitrogen atoms of the 4N ligand and a bridging oxygen. The sixth position of each octahedron is coordinated by a chloride ion. The (μ-oxo)diiron(iii) core is linear in 2 (Fe–O–Fe, 180.0°), whereas it is non-linear (Fe–O–Fe, 161°) in 5. All the diiron(iii) complexes show quasi-reversible one electron transfer in the cyclic voltammagram and catalyze the hydroxylation of alkanes like cyclohexane, adamantane with m-CPBA as an oxidant. In acetonitrile solution, adding excess m-CPBA to the diiron(iii) complex 2 without chloride ions leads to intramolecular hydroxylation reaction of the oxidant. Interestingly, 2 catalyzes alkane hydroxylation in the presence of chloride ions, but intramolecular hydroxylation in the absence of chloride ions. The observed selectivity for cyclohexane (A/K, 5–7) and adamantane (3°/2°, 9–18) suggests the involvement of high-valent iron–oxo species rather than freely diffusing radicals in the catalytic reaction. Moreover, 4 oxidizes (A/K, 7) cyclohexane very efficiently up to 513 TON while 5 oxidizes adamantane with good selectivity (3°/2°, 18) using m-CPBA as an oxidant. The electronic effects of ligand donors dictate the efficiency and selectivity of catalytic hydroxylation of alkanes.

Scholarly Impact of Law School Faculties in 2021: Updating the Leiter Score Ranking for the Top Third

This updated 2021 study explores the scholarly impact of law faculties, ranking the top third of ABA-accredited law schools. Refined by Brian Leiter, the “Scholarly Impact Score” for a law faculty is calculated from the mean and the median of total law journal citations over the past five years to the work of tenured faculty members. In addition to a school-by-school ranking, we report the mean, median, and weighted score, along with a list of the tenured law faculty members at each school with the ten highest individual citation counts. While the law faculty at Yale continues to hold the top ranked position in the 2021 Scholarly Impact Ranking, Chicago has now moved into the second spot, with Harvard at third. NYU and Columbia continue to rank in the fourth and fifth positions respectively. California-Berkeley has moved up into a tie for the sixth position with Stanford. The law faculties at two schools in the top ten have moved up one ranking position, with Pennsylvania now at eight and Vanderbilt at nine. In one of the most striking changes since the 2018 Scholarly Impact Ranking, Virginia has climbed from sixteen to a tie for the ninth position in 2021. The law schools with the highest rises in the 2021 Scholarly Impact Ranking are American by 18 ordinal levels (to #46), Georgia up 15 positions (to #43), and Brooklyn up 11 positions (to #33). Several law faculties achieve a Scholarly Impact Ranking in 2021 well above the law school rankings reported by U.S. News for 2022: Vanderbilt (at #9) shows a significant gap with U.S. News Ranking (at #16). Among schools close to the top ten for Scholarly Impact, the University of California-Irvine (at #14) has the greatest incongruity with the 2022 U.S. News ranking (at #35). In the Scholarly Impact top 25, George Washington University rises to #18 in Scholarly Impact, while lagging at #27 for U.S. News. Minnesota is also at #18 in Scholarly Impact, but at #22 in U.S. News. The University of California-Davis hits #22 in Scholarly Impact, while left well behind by U.S. News at #35. George Mason continues to be a Top 25 Scholarly Impact school at #23, while dropping in U.S. News to #41. Fordham also ranks at #23 for Scholarly Impact, but down at #35 for U.S. News. The most dramatically under-valued law faculty remains the University of St. Thomas (Minnesota), which continues to rank inside the top 25 (at #23) for Scholarly Impact for 2021, while being relegated by U.S. News below the top 100 (at #126)—a difference of 103 ordinal levels. In addition, we report the results of an experimental survey of U.S. News academic voters for a general academic impact ranking. Cass Sunstein, Kimberle Crenshaw, Erwin Chemerinsky, and Angela Onwuachi-Willig hold the top four positions, with Mark Lemley, Catharine MacKinnnon, and Orin Kerr tied for the fifth position. Notably, this subjective survey about individual law faculty reputation correlates tightly with scholarly impact. Even when freely invited to evaluate individual professor impact on any academic basis, the surveyed law professors voted for three of the top four cited professors in our Scholarly Impact Ranking. Six of the seven are in the top 3 percent of all studied faculty for scholarly citations (which is likely closer to the top 1 percent for all law faculties in ABA-accredited law schools). In sum, citation-based scholarly impact is a strong proxy for faculty excellence overall.

Hemoglobin Genotypes Modulate Inflammatory Response to Plasmodium Infection.

In 2018, 228 million cases and 405,000 malaria-associated deaths were reported worldwide with a majority being in Africa. A wide range of factors, including parasitemia, host immunity, inflammatory responses to infection, and host hemoglobin genotype, mediate the severity of malaria. Among the hemoglobinopathies, hemoglobin S (HbS) is caused by a single amino acid substitution of Glutamic Acid replaced by Valine at the sixth position of the beta-globin chain (E6V). Hemoglobin C (HbC) on the other hand, involves a single amino acid substitution of Glutamic Acid by a Lysine (E6K), which has received the most attention. These substitutions alter the stability of Hb leading to wide-ranging hematological disorders. The homozygous state of hemoglobin S (HbSS) results in sickle cell anemia (SCA) whereas the heterozygous state (HbAS) results in sickle cell trait (SCT). Both mutations are reported to mediate the reduction in the severity and fatality of Plasmodium falciparum malaria. The mechanism underlying this protection is poorly understood. Since both malaria and sickle cell disease (SCD) are associated with the destruction of erythrocytes and widespread systemic inflammation, identifying which inflammatory factor(s) mediate susceptibility of individuals with different hemoglobin genotypes to Plasmodium infection could result in the discovery of new predictive markers and interventions against malaria or SCD severity. We hypothesized that hemoglobin genotypes modulate the inflammatory response to Plasmodium infection. We conducted a cross-sectional study in Ghana, West Africa, between 2014 and 2019 to ascertain the relationships between blood inflammatory cytokines, Plasmodium infection, and hemoglobin genotype. A total of 923 volunteers were enrolled in the study. A total of 74, age and sex-matched subjects were identified with various genotypes including HbAS, HbAC, HbSS, HbSC, HbCC, or HbAA. Complete blood counts and serum inflammatory cytokine expression levels were assessed. The results indicate that differential expression of CXCL10, TNF-α, CCL2, IL-8, and IL-6 were tightly linked to hemoglobin genotype and severity of Plasmodium infection and that these cytokine levels may be predictive for susceptibility to severe malaria or SCD severity.

Design, Synthesis and Evaluation of 2,4,6-substituted Pyrimidine Derivatives as BACE-1 Inhibitor: Plausible Lead for Alzheimer's Disease.

Design and synthesis of 2,4,6-substituted pyrimidine derivatives has been reported. In vitro FRET-based screening of synthesized derivatives was performed to evaluate the BACE-1 inhibition profile. Based on the docking simulation studies, a library of derivatives was designed, synthesized and evaluated for BACE-1 inhibition in-vitro. The docking studies were performed on Glide (Schrodinger suite) and Molegro virtual docker. Theoretical toxicity was predicted using Osiris Property Explorer. The synthesized compounds were tested for BACE-1 inhibition using in vitro assay based on Fluorescence Resonance Energy Transfer technique. The percent inhibition was calculated as a measure of activity. The designed compounds revealed strong interactions with the desired amino acids of BACE-1 active sites. The aromatic rings placed at the fourth and sixth position of the pyrimidine ring occupied S1 and S3 substrate-binding clefts while the amino group formed hydrogen bonding interactions with Asp32 and Asp228. In silico data ensured that the compounds were orally bioavailable and brain permeable. The in vitro testing showed that the compounds inhibited BACE-1 at 10μM concentration. Compounds substituted with m-benzyloxy on one aromatic ring and o,p-di-chloro on another aromatic ring displayed maximum BACE-1 inhibition. Compound 2.13A displayed high docking score and was found to be most potent with IC50 of 6.92μM. The series displayed a good correlation between the docking score and BACE-1 inhibition profile.

Improving Recurrence Prediction Accuracy of Ovarian Cancer Using Multi-phase Feature Selection Methodology

ABSTRACT Ovarian cancer stands in the sixth position among the most commonly occurring cancers in the world. Because of the high rate of recurrence, this gynecological malignancy seems to be a vital reason behind cancer-related death among women as tumor recurrence stands as an obstacle in ovarian cancer treatment. It is crucial to find those recurrence causing factors in order to plan suitable therapies with high prognostic results. Hence, in this work, a multistage feature selection methodology is proposed to identify key MiRNAs and clinical features for improving the accuracy of ovarian cancer recurrence prediction. MiRNA expression profiles of ovarian cancer patients and their corresponding clinical data were downloaded from the TCGA cancer repository. From 588 MiRNAs, 6 key MiRNAs were selected using the Inheritable Bi-objective Combinatorial Genetic Algorithm (IBCGA) followed by factor analysis. The biological importance of the resultant MiRNAs in cancer and cellular pathways were studied using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Further, recurrence prediction was performed using the obtained MiRNA expression profiles and clinical factors, chosen using correlation analysis. The proposed approach using the selected features yielded a prediction accuracy of 91.86% using the XGBoost classifier while the same without feature selection was 76.59%. Compared to previous similar works, this model provides a better result in terms of accuracy and reveals influential MiRNAs in ovarian cancer.

Estimation of serum Adenosine Deaminase (ADA) level in sickle cell disease (SCD) and its association with reticulocyte count in a rural population of Chhattisgarh state

Prevalence of Sicklecell disease (SCD) is ranging from 1 to 40% and more in state like Chhattisgarh because of more share of Tribal population by this state in India. Genetic mutation at a sixth position of the β-globin chain (replacement of glutamic acid by valine) is the biochemical basis of this abnormality. Tissue specific increase of adenosine deaminase is related with lysis of RBC membrane in sickle cell disease. To know the pathology and biochemical basis of increase in serum adenosine deaminase in SCD is ardent. Prospective case-control study is conducted by taking thirty SCD cases [from Durg District of Chhattisgarh State] attending General Medicine OPD in our Medical College. Thirty age and sex matched healthy volunteers were selected as controls from same population. ADA estimation done by enzymatic-kinetic method. Complete hemogram done by Beckman Coulter and retiuculocyte count done by direct microscopic examination. Adenosine deaminase level in SCD was higher as compare to control group and difference is statistically highly significant i.e. p value 0.00 (

Straw management effects on sugarcane growth, nutrient cycling and water use in the Brazilian semiarid region

It was evaluated how straw management modifies the development, growth, nutrient cycling and crop water productivity of sugarcane in the semiarid region of Brazil. The experiment was carried out using two plots with 5 ha each, being one without straw on the soil surface and one with 26 Mg·ha-1 covering the soil. Sugarcane growth and development and straw decomposition coefficient were evaluated, whereas the industrial yield, juice quality, dry matter partitioning, and crop water productivity were determined at harvesting. The straw decomposition coefficient was 0.0049 Mg·ha-1·day-1, and the remaining dry mass was equal to 24%. The straw affected the sugarcane growth and development until the first 100 days. The individual internode volume can be adopted as an indicator of the effect of straw on sugarcane growth because the internode volumes up to the sixth position in the with-straw treatment crop were lower than in the no-straw treatment, which was not observed in other variables of the stalks. Keeping straw on the soil surface reduced the crop lodging. Yield and juice quality were not affected, but crop water productivity was increased by keeping sugarcane straw in the field.

A Noncytotoxic Temporin L Analogue with In Vivo Antibacterial and Antiendotoxin Activities and a Nonmembrane-Lytic Mode of Action.

Cytotoxic frog antimicrobial peptide Temporin L (TempL) is an attractive molecule for the design of lead antimicrobial agents due to its short size and versatile biological activities. However, noncytotoxic TempL variants with desirable biological activities have rarely been reported. TempL analogue Q3K,TempL is water-soluble and possesses a significant antiendotoxin property along with comparable cytotoxicity to TempL. A phenylalanine residue, located at the hydrophobic face of Q3K,TempL and the "d" position of its phenylalanine zipper sequence, was replaced with a cationic lysine residue. This analogue, Q3K,F8K,TempL, showed reduced hydrophobic moment and was noncytotoxic with lower antimicrobial activity. Interestingly, swapping between tryptophan at the fourth and serine at the sixth positions turned Q3K,F8K,TempL totally amphipathic as reflected by its helical wheel projection with clusters of hydrophobic and hydrophilic residues and the highest hydrophobic moment among these peptides. Surprisingly, this analogue, SW,Q3K,F8K,TempL, was as noncytotoxic as Q3K,F8K,TempL but showed augmented antimicrobial and antiendotoxin properties, comparable to that of TempL and Q3K,TempL. SW,Q3K,F8K,TempL exhibited appreciable survival of mice against P.aeruginosa infection and a lipopolysaccharide (LPS) challenge. Unlike TempL and Q3K,TempL, SW,Q3K,F8K,TempL adopted an unordered secondary structure in bacterial membrane mimetic lipid vesicles and did not permeabilize them or depolarize the bacterial membrane. Overall, the results demonstrate the design of a nontoxic TempL analogue that possesses clusters of hydrophobic and hydrophilic residues with impaired secondary structure and shows a nonmembrane-lytic mechanism and in vivo antiendotoxin and antimicrobial activities. This paradigm of design of antimicrobial peptide with clusters of hydrophobic and hydrophilic residues and high hydrophobic moment but low secondary structure could be attempted further.

Differences in Balance Ability and Motor Control between Dancers and Non-Dancers with Varying Foot Positions.

The purpose of this study was to investigate balance and motor control in dancers and non-dancers with different foot positions. Physically active female dancers (n = 11) and non-dancers (n = 9) randomly completed two balance tests in a single visit: 1) Y-balance test (YBT), and 2) motor control test (MCT). Each test was completed with two different foot positions: 1) first ballet position in which heels were touching and feet were externally rotated to 140 degrees, and 2) sixth ballet position in which heels were spaced 10 cm apart and forward parallel. For the YBT, participants completed three attempts at anterior, posteromedial, and posterolateral reaches, which were averaged and standardized to limb length for a composite score. For the MCT, participants completed a multi-directional target test on a Biosway balance system, and accuracy and time to completion were analyzed. Findings revealed no differences in YBT score (p = 0.255), MCT score (p = 0.383), or MCT time (p = 0.306) between groups in the sixth position. However, dancers displayed better YBT scores (p = 0.036), MCT scores (p = 0.020), and faster MCT times (p = 0.009) in the first position. Results suggest that superior balance and motor control in dancers may be limited to less innate dance-specific foot positions.

Glycosylase base editors enable C-to-A and C-to-G base changes.

Current base editors (BEs) catalyze only base transitions (C to T and A to G) and cannot produce base transversions. Here we present BEs that cause C-to-A transversions in Escherichia coli and C-to-G transversions in mammalian cells. These glycosylase base editors (GBEs) consist of a Cas9 nickase, a cytidine deaminase and a uracil-DNA glycosylase (Ung). Ung excises the U base created by the deaminase, forming an apurinic/apyrimidinic (AP) site that initiates the DNA repair process. In E. coli, we used activation-induced cytidine deaminase (AID) to construct AID-nCas9-Ung and found that it converts C to A with an average editing specificity of 93.8% ± 4.8% and editing efficiency of 87.2% ± 6.9%. For use in mammalian cells, we replaced AID with rat APOBEC1 (APOBEC-nCas9-Ung). We tested APOBEC-nCas9-Ung at 30 endogenous sites, and we observed C-to-G conversions with a high editing specificity at the sixth position of the protospacer between 29.7% and 92.2% and an editing efficiency between 5.3% and 53.0%. APOBEC-nCas9-Ung supplements the current adenine and cytidine BEs (ABE and CBE, respectively) and could be used to target G/C disease-causing mutations.

Basic indices of Russian steel industry operation in 2019

An extensive analysis of steel industry state in Russia in 2019 presented. Dynamics and structure of basic products of Russian and world steel industry has shown. Russia moved from the sixth position to the fifth one by results of 2019 among the biggest steel producers with the production volume of 72 million tons (99.3% comparing with 2018), accounting for 3.9% of the world production. Data on production dynamics of basic types of products of Russian steel industry within 2018-2019 presented. Steel plants of Russia in 2019 produced 51.2 million tons of cast iron, which is 1.2% lower comparing with 2018. Production of finished products accounts for 61.5 million tons, decrease by 0.1%; production of steel decreased by 0.7% down to 72 million tons. In 2019 the share of BOF and EAF steel in the total volume of steel production accounted for 97.9% comparing with 97.8% in 2018. In 2019 the total value export of steel ingots, billets and rolled products accounted for USD 20.88 billion and decreased by 18.6% comparing with the value volume of 2018 (USD 25.67 billion). The total value volume of raw materials import (ores, iron ore concentrates), ferroalloys, steel ingots, billets and rolled products in 2019 accounted for USD 5.7 billion and decreased by 1.3% comparing with the value volume of 2018 (USD 5.8 billion). Economic indices of steel-works operation presented, as well as information on consumption of material and energy resources and investment activity of basic metallurgical plant in 2019.