An explainable machine learning platform for pyrazinamide resistance prediction and genetic feature identification of Mycobacterium tuberculosis

ObjectiveTuberculosis is the leading cause of death from a single infectious agent. The emergence of antimicrobial resistant Mycobacterium tuberculosis strains makes the problem more severe. Pyrazinamide (PZA) is an important component for short-course treatment regimens and first- and second-line treatment regimens. This research aims for fast diagnosis of M. tuberculosis resistance to PZA and identification of genetic features causing resistance.Materials and MethodsWe use clinically collected genomic data of M. tuberculosis that are resistant or susceptible to PZA. A machine learning platform is built to diagnose PZA resistance using the whole genome sequence data, and to identify resistance genes and mutations. The platform consists of a deep convolutional neural network (DCNN) model for resistance diagnosis and a support vector machine (SVM) model as a surrogate to identify resistance genes and mutations.ResultsThe DCNN model achieves a PZA resistance diagnosis accuracy of 93%. Each prediction takes less than a second. The SVM has revealed 2 novel genes, embB and gyrA, besides the well-known pncA gene, and 9 mutations that harbor PZA resistance.DiscussionThe DCNN and SVM machine learning platform, if used together with the real-time genome sequencing machines, could allow for rapid PZA diagnosis, allowing for critical time to ensure good patient outcomes, and preventing outbreaks of deadly infections. Furthermore, identifying pertinent resistance genes and mutations will help researchers better understand the biological mechanisms behind resistance.ConclusionsMachine learning can be used to achieve high-accuracy resistance prediction, and identify genes and mutations causing the resistance.     

Mitsuokella dentalis in human periodontitis

The occurrence of Mitsuokella dentalis in periodontitis was determined by culture and DNA probe detection. Subgingival paper-point samples from 480 periodontitis patients were transported in VMGA III, plated onto brucella agar with 5% sheep blood and incubated anaerobically for 7 days. Presumptive identification was based on a colony morphology resembling a water drop and biochemical characteristics. DNA probe detection was performed on paper-point samples using a digoxigenin-labeled cellular M. dentalis DNA probe in a dot-blot assay. Culture and DNA probe identified M. dentalis in 18.1% and in 80.7% of the study patients, respectively. M. dentalis isolates produced phosphatases, galactosidase, glucosidase and acetylglucosaminidase and showed high in vitro sensitivity to metronidazole. This study revealed that M. dentalis is a constituent of the pathogenic microbiota in human periodontitis. The periodontopathic potential of the organism is unknown.     

SD抗菌布的抗菌效果

研制出含有洗必泰的SD抗菌布,经整理后,有良好与持久的扰菌作用。用该布制作的床单与白大衣在烧伤病房试用,抑菌率达50％以上,洗涤15次仍有显著效果。     

Synthesis of certain mercapto-and aminopyrimidine derivatives as potential antimicrobial agents

Reaction of ethyl 4-chloro-2-phenylpyrimidine-4-carboxylate (4) with 5-chloro-2-methylthiophenol or 3-aryl-4-phenyl-1,2,4-triazole-5-thiol yielded the corresponding thioethers (5) and (8a, b), respectively. Careful alkaline hydrolysis of (5) yielded the corresponding carboxylic acid (6). Reaction of (4) withp-aminoacetophenone yielded compound (10) which was reacted with certain aromatic aldehydes to afford the α, β-unsaturated ketones (11a–d). Condensation of (11a–d) with malononitrile or phenylhydrazine yielded the 2-amino-3-cyanopyridines (12a–f) or the 2-pyrazolines (13a, b), respectively. Seven representative compounds were tested for theirin vitro antimicrobial activity against some pathogenic micro-organisms, some of them were proved to be active.     

伤寒杆菌的耐药性与伤寒的爆发流行

本文报道55株散发和38株爆发伤寒菌株的药物敏感试验、质粒检测及R质粒传递试验的结果。所有受检菌均出现不同程度的耐药现象,严重者耐药达8种之多;爆发株对常用抗菌素的耐药性明显高于散发株。R质粒的接合传递试验结果初步表明,散发株可传递性R质粒检测结果阴性,但发现一起爆发中,流行株携带有可传递性R质粒,由于检测菌株数尚少,其意义有待进一步探讨。     

噻二嗪硫酮衍生物的抗微生物活性

为筛选新的杀菌、抑霉药物，本文报导了１５种标题化合物对６种细菌和２种霉茵的生物活性。结果显示此类化合物对所试细菌的抑菌环直径多在１５ｍｍ以上，其中Ｎｏ３和Ｎｏ４的抑菌环直径均在２０ｍｍ以上；说明此类化合物有较强的生物活性，相比而言，对革兰氏阳性菌的抑制作用稍弱于对革兰氏阴件菌的作用．而对霉菌的作用则较弱。表明有望从此类化合物中筛选出可用于临床的新型抗菌药物。关键词     

Effects of sanguinarium, chlorhexidine and tetracycline on neutrophil viability and functions in vitro

The effectiveness of an ideal antimicrobial agent depends on its ability to kill microbes with minimal toxicity to host cells. Depending on the treatment regimen, antimicrobial agents come into contact with host cells for various intervals of time. Sanguinarium (SANG), chlorhexidine (CHX) and tetracycline (TET) are 3 antimicrobial agents frequently used in the management of periodontal infections. However, their effects on host immune cells during different treatment regimens are not known. Due to their ability to serve as the first line of host defense against microbial infections, we have compared the effects of these antimicrobial agents on human neutrophil functions and viability. The results show that SANG is not lytic to neutrophils from peripheral blood or crevicular fluid, at all concentrations tested. However, exposures of neutrophils to very low concentrations of SANG (0.001%) inhibits neutrophil chemotaxis, oxidative metabolism and degranulation within 5 min. Increasing the exposure time results in a similar inhibition of neutrophil functions, albeit at 50–100 fold lower concentrations of SANG. CHX rapidly disrupts the cell membrane of both crevicular and peripheral blood neutrophils at concentrations above 0.005% within 5 min, and inhibition of all neutrophil functions is due to its lytic properties. While TET is least toxic to neutrophils, a dose dependent inhibition of neutrophil functions is dependent on the calcium concentrations of the cellular environment, and is observed only above 0.04% or higher concentrations in the absence of calcium. The data suggest that a critical cumulative concentration of these drugs is essential for their toxicity and inhibition of neutrophil functions. Therefore, both the length of exposure and the dose of the drug both are critical while considering the effectiveness of SANG, CHX or TET in the treatment of infections. Furthermore, due to differences in their mechanisms of action, the consequences of their effects on neutrophils may have significant bearing on tissue pathology as well as on their therapeutic efficacy.