Singlet Oxygen Generation by Porphyrins and Metalloporphyrins Revisited: a Quantitative Structure-property Relationship (QSPR) Study

state followed by formation of singlet oxygen (1O2), which is a highly reactive species and mediates various oxidative processes. The design of advanced sensitizers based on porphyrin compounds have attracted significant attention in recent years. However, it is still difficult to predict the efficiency of singlet oxygen generation for a given structure. Our goal was to develop a quantitative structure-property relationship (QSPR) model for the fast virtual screening and prediction of singlet oxygen quantum yields for pophyrins and metalloporphyrins. We performed QSPR analysis of a dataset containing 32 compounds, including various porphyrins and their analogues (chlorins and bacteriochlorins). Quantum-chemical descriptors were calculated using Density Functional Theory (DFT), namely B3LYP and M062X functionals. Three different machine learning methods were used to develop QSPR models: random forest regression (RFR), support vector regression (SVR), and multiple linear regression (MLR). The optimal QSPR model «structure – singlet oxygen generation quantum yield» obtained using RFR method demonstrated high determination coefficient for the training set (R2 = 0.949) and the highest predicting ability for the test set (pred_R2 = 0.875). This proves that the developed QSPR method is realiable and can be directly applied in the studies of singlet oxygen generation both for free base porphyrins and their metal complexes. We believe that QSPR approach developed in this study can be useful for the search of new poprhyrin photosensitizers with enhanced singlet oxygen generation ability

Diagnosis of tuberculosis through breath test:A systematic review

Background: Breath tests may diagnose tuberculosis (TB) through detecting specific volatile organic compounds produced by Mycobacterium tuberculosis or the infected host. Methods: To estimate the diagnostic accuracy of breath test with electronic-nose and other devices against culture or other tests for TB, we screened multiple databases until January 6, 2019. Findings: We included fourteen studies, with 1715 subjects in the analysis. The pooled sensitivity and specificity of electronic-nose were 0.93 (95% to 0.82-0.97) and 0.93 (95% to 0.82-0.97), respectively, and no heterogeneity was found. The sensitivity and specificity of other breath test devices ranged from 0.62 to 1.00, and 0.11 to 0.84, respectively. Interpretation: The low to moderate evidence of these studies shows that breath tests can diagnose TB accurately, however, to give a real-time test result, additional development is needed. Research should also focus on sputum smear negative TB, children, and the positioning of breath testing in the diagnostic work flow. (C) 2019 The Authors. Published by Elsevier B.V

Pengaruh Keadilan Organisasi, Kepuasan Kerja dan Penggunaan Media Sosial terhadap Kinerja Karyawan pada BPS (Badan Pusat Statistik) Sukoharjo

This study aims to determine the effect of organizational justice, job satisfaction and use of social media on employee performance. The sample in this study used a saturated sample, where all populations were sampled. Data analysis in this study used SMART-PLS. The object of this research was conducted at the Office of the Badan Pusat Statistik (BPS) Sukoharjo with a population of 102 respondents. The type of data used is primary data whose data is obtained directly from the respondents. The research method used is a questionnaire or interview method. The data analysis used in this research is the outer model testing stage, the inner model testing stage and the hypothesis testing stage. The results of the analysis test in this study show that organizational justice has a positive and significant effect on employee performance, with a t-statistic value of 2.309 greater than the t-table value of 1.96 and a probability value of 0.021 less than α (0.05). Then, job satisfaction has a positive and significant effect on employee performance, with a t-statistic value of 2,539 greater than the t-table value of 1.96 and a probability value of 0.011 less than α (0.05). Finally, the use of social media has a positive and significant effect on employee performance, with a t-statistic value of 4.154 greater than the t-table value of 1.96 and a probability value of 0.000 less than α (0.05)

Peran Metallothionein Terhadap Kemampuan Resistensi Logam Berat Pada Bakteri

Saat ini pencemaran lingkungan yang terjadi mencapai tahap yang mengkhawatirkan. Industri merupakan salah satu faktor yang menyumbang polusi dan mengakibatkan pencemaran di dunia. Salah satu polusi berbahaya yang mencemari lingkungan adalah logam berat. Pencemaran logam berat dapat diatasi dengan bioremediasi. Bioremediasi sangat bergantung terhadap bioremediator yang resisten terhadap zat pencemar. Salah satu agen bioremediasi yang memiliki kemampuan khusus terhadap resistensi logam berat adalah bakteri. Bakteri mampu hidup di hampir seluruh jenis lingkungan termasuk di lingkungan yang tercemar. Bakteri yang dapat hidup dan berkembang di lingkungan tercemar memiliki kemampuan khusus yang membuatnya tahan terhadap paparan logam, kemampuan tersebut didukung oleh protein-protein khusus yang dimiliki oleh bakteri.Salah satu protein khusus yang dimiliki bakteri untuk mempertahankan resistensinya terhadap logam berat adalah metallothinein. Metallothionein mampu mengikat logam sehingga tidak logam jadi tidak membahayakan bagi bakteri. Literatur review ini mengkaji mengenai struktur, fungsi, mekanisme metallothionein dalam resistensi terhadap logam berat, mekanisme ekspresi metallothionein oleh bakteri, dan faktor-faktor yang memengaruhi produksi metallothionein oleh bakteri. Literatur review yang dilakukan dengan mencari dan mengolah berbagai jurnal serta penelitian yang ada untuk mendapatkan gambaran mengenai suatu topik. Hasil literatur review ini adalah terdapat bakteri yang resisten logam berat, terutama bakteri gram positif. Bakteri-bakteri tersebut memiliki tingkat resistensi yang berbeda-beda. Kemunculan bakteri resisten bisa disebabkan oleh dua faktor yaitu faktor lingkungan dan genetik. Lingkungan berperan sebagai environmental pressure yang menyeleksi makhluk hidup yang mampu bertahan hidup. Faktor genetik terjadi karena adanya mutasi bakteri dan transfer gen horizontal. Interaksi antara faktor lingkungan dan faktor genetik yang cocok bisa menentukan resistensi suatu bakteri. Salah satu protein yang berperan dalam resistensi terhadap logam adalah protein metallothionein. Metallothionein adalah protein yang kaya akan asam amino sistein yang memiliki kemampuan untuk mengikat ion logam berat. Bakteri yang memproduksi metallothionein memiliki kemampuan resistensi lebih besar terhadap logam berat daripada bakteri yang tidak memproduksi metallothionein. Gugus thiol pada asam amino sistein yang merupakan salah satu asam amino penyusun metallothionein akan mengikat ion logam berat sehingga ion logam terperangkap dan menjadi kurang reaktif. Metallothionein padav Cyanobacteria dikode oleh smt operon. Gen yang bertanggung jawab terhadap ekspresi metallothionein adalah smtB. Saat tidak terdapat ion logam berat, smtB akan terikat dengan operator sehingga RNA polymerase tidak dapat mentranskripsi kodon sehingga metallothionein tidak bisa diproduski. Saat terdapat ion logam berat maka ion logam akan berikatan dengan smtB sehingga konformasi smtB berubah. smtB kemudian akan terlepas sehingga RNA polymerase dapat melakukan transkripsi dan metallothionein bisa diproduksi oleh bakteri. Produksi metallothionein oleh bakteri dapat diinduksi oleh beberapa hal yaitu konsentrasi kontaminan, lama inkubasi, dan jenis metallothionein

Development of a stabilized trimer pre-fusion RSV F recombinant viral glycoprotein vaccine

It has been known that the RSV fusion protein F is a target vaccine protein to produce a protective immune response. The VRC has shown (Ngwuta, et.al.) through binding competition assays that the amount of pre-fusion site Ø–specific antibodies correlates with neutralizing (NT) activity, whereas the pre/post-fusion site II mAbs does not correlate with neutralization. Our results indicate that RSV NT activity in human sera is primarily derived from pre-F–specific antibodies, and therefore, inducing or boosting NT activity by vaccination will be facilitated by using pre-F antigens that preserve site Ø. Therefore, the instability of the RSV pre-fusion conformation has limited the potential of this as a vaccine antigen. Therefore, the VRC has designed a structurally stabilized glycoprotein pre-fusion RSV F trimer vaccine antigen and has shown it to be highly immunogenic in preclinical studies. A description of challenges in the development of a high productivity CHO cell line, production process and product quality and antigenic characterization assays for Phase I clinical material will be presented along with comparison of pre-clinical results of research to development material. Please click Additional Files below to see the full abstract

A green bio-organic catalyst (taurine) promoted one-pot synthesis of (R/S)-2-thioxo-3,4-dihydropyrimidine(TDHPM)-5-carboxanilides: chiral investigations using circular dichroism and validation by computational approaches

Owing to the massive importance of dihydropyrimidine (DHPMs) scaffolds in the pharmaceutical industry and other areas, we developed an effective and sustainable one-pot reaction protocol for the synthesis of (R/S)-2-thioxo-DHPM-5-carboxanilides via the Biginelli-type cyclo-condensation reaction of aryl aldehydes, thiourea and various acetoacetanilide derivatives in ethanol at 100 °C. In this protocol, taurine was used as a green and reusable bio-organic catalyst. Twenty-three novel derivatives of (R/S)-TDHPM-5-carboxanilides and their structures were confirmed by various spectroscopy techniques. The aforementioned compounds were synthesized via the formation of one asymmetric centre, one new C–C bond, and two new C–N bonds in the final product. All the newly synthesized compounds were obtained in their racemic form with up to 99% yield. In addition, the separation of the racemic mixture of all the newly synthesized compounds was carried out by chiral HPLC (Prep LC), which provided up to 99.99% purity. The absolute configuration of all the enantiomerically pure isomers was determined using a circular dichroism study and validated by a computational approach. With up to 99% yield of 4d, this one-pot synthetic approach can also be useful for large-scale industrial production. One of the separated isomers (4R)-(+)-4S developed as a single crystal, and it was found that this crystal structure was orthorhombic

A green bio-organic catalyst (taurine) promoted one-pot synthesis of (R/S)-2-thioxo-3,4-dihydropyrimidine(TDHPM)-5-carboxanilides: chiral investigations using circular dichroism and validation by computational approaches

Owing to the massive importance of dihydropyrimidine (DHPMs) scaffolds in the pharmaceutical industry and other areas, we developed an effective and sustainable one-pot reaction protocol for the synthesis of (R/S)-2-thioxo-DHPM-5-carboxanilides via the Biginelli-type cyclo-condensation reaction of aryl aldehydes, thiourea and various acetoacetanilide derivatives in ethanol at 100 °C. In this protocol, taurine was used as a green and reusable bio-organic catalyst. Twenty-three novel derivatives of (R/S)-TDHPM-5-carboxanilides and their structures were confirmed by various spectroscopy techniques. The aforementioned compounds were synthesized via the formation of one asymmetric centre, one new C–C bond, and two new C–N bonds in the final product. All the newly synthesized compounds were obtained in their racemic form with up to 99% yield. In addition, the separation of the racemic mixture of all the newly synthesized compounds was carried out by chiral HPLC (Prep LC), which provided up to 99.99% purity. The absolute configuration of all the enantiomerically pure isomers was determined using a circular dichroism study and validated by a computational approach. With up to 99% yield of 4d, this one-pot synthetic approach can also be useful for large-scale industrial production. One of the separated isomers (4R)-(+)-4S developed as a single crystal, and it was found that this crystal structure was orthorhombic

Reduced repair of 8-hydroxyguanine in the human breast cancer cell line, HCC1937

BACKGROUND: Breast cancer is the second leading cause of cancer deaths in women in the United States. Although the causes of this disease are incompletely understood, oxidative DNA damage is presumed to play a critical role in breast carcinogenesis. A common oxidatively induced DNA lesion is 8-hydroxyguanine (8-OH-Gua), which has been implicated in carcinogenesis. The aim of this study was to investigate the ability of HCC1937 and MCF-7 breast cancer cell lines to repair 8-OH-Gua relative to a nonmalignant human mammary epithelial cell line, AG11134. METHODS: We used oligonucleotide incision assay to analyze the ability of the two breast cancer cell lines to incise 8-OH-Gua relative to the control cell line. Liquid chromatography/mass spectrometry (LC/MS) was used to measure the levels of 8-OH-Gua as its nucleoside, 8-OH-dG in the cell lines after exposure to H(2)O(2 )followed by 30 min repair period. Protein expression levels were determined by Western blot analysis, while the hOGG1 mRNA levels were analyzed by RT-PCR. Complementation of hOGG1 activity in HCC1937 cells was assessed by addition of the purified protein in the incision assay, and in vivo by transfection of pFlagCMV-4-hOGG1. Clonogenic survival assay was used to determine sensitivity after H(2)O(2)-mediated oxidative stress. RESULTS: We show that the HCC1937 breast cancer cells have diminished ability to incise 8-OH-Gua and they accumulate higher levels of 8-OH-dG in the nuclear genome after H(2)O(2 )treatment despite a 30 min repair period when compared to the nonmalignant mammary cells. The defective incision of 8-OH-Gua was consistent with expression of undetectable amounts of hOGG1 in HCC1937 cells. The reduced incision activity was significantly stimulated by addition of purified hOGG1. Furthermore, transfection of pFlagCMV-4-hOGG1 in HCC1937 cells resulted in enhanced incision of 8-OH-Gua. HCC1937 cells are more sensitive to high levels of H(2)O(2 )and have up-regulated SOD1 and SOD2. CONCLUSION: This study provides evidence for inefficient repair of 8-OH-Gua in HCC1937 breast cancer cell line and directly implicates hOGG1 in this defect

A randomised fractional factorial screening experiment to predict effective features of audit and feedback

Background Audit and feedback aims to improve patient care by comparing healthcare performance against explicit standards. It is used to monitor and improve patient care, including through National Clinical Audit (NCA) programmes in the UK. Variability in effectiveness of audit and feedback is attributed to intervention design; separate randomised trials to address multiple questions about how to optimise effectiveness would be inefficient. We evaluated different feedback modifications to identify leading candidates for further “real-world” evaluation. Methods Using an online fractional factorial screening experiment, we randomised recipients of feedback from five UK NCAs to different combinations of six feedback modifications applied within an audit report excerpt: use effective comparators, provide multimodal feedback, recommend specific actions, provide optional detail, incorporate the patient voice, and minimise cognitive load. Outcomes, assessed immediately after exposure to the online modifications, included intention to enact audit standards (primary outcome, ranked on a scale of −3 to +3, tailored to the NCA), comprehension, user experience, and engagement. Results We randomised 1241 participants (clinicians, managers, and audit staff) between April and October 2019. Inappropriate repeated participant completion occurred; we conservatively excluded participant entries during the relevant period, leaving a primary analysis population of 638 (51.4%) participants. None of the six feedback modifications had an independent effect on intention across the five NCAs. We observed both synergistic and antagonistic effects across outcomes when modifications were combined; the specific NCA and whether recipients had a clinical role had dominant influences on outcome, and there was an antagonistic interaction between multimodal feedback and optional detail. Among clinical participants, predicted intention ranged from 1.22 (95% confidence interval 0.72, 1.72) for the least effective combination in which multimodal feedback, optional detail, and reduced cognitive load were applied within the audit report, up to 2.40 (95% CI 1.88, 2.93) for the most effective combination including multimodal feedback, specific actions, patient voice, and reduced cognitive load. Conclusion Potentially important synergistic and antagonistic effects were identified across combinations of feedback modifications, audit programmes, and recipients, suggesting that feedback designers must explicitly consider how different features of feedback may interact to achieve (or undermine) the desired effects

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication