Human Infectious Diseases Research Articles

Seaweed-Derived Phlorotannins: A Review of Multiple Biological Roles and Action Mechanisms.

Phlorotannins are a group of phenolic secondary metabolites isolated from a variety of brown algal species belonging to the Fucaceae, Sargassaceae, and Alariaceae families. The isolation of phlorotannins from various algal species has received a lot of interest owing to the fact that they have a range of biological features and are very biocompatible in their applications. Phlorotannins have a wide range of therapeutic biological actions, including antimicrobial, antidiabetic, antioxidant, anticancer, anti-inflammatory, anti-adipogenesis, and numerous other biomedical applications. The current review has extensively addressed the application of phlorotannins, which have been extensively investigated for the above-mentioned biological action and the underlying mechanism of action. Furthermore, the current review offers many ways to use phlorotannins to avoid certain downsides, such as low stability. This review article will assist the scientific community in investigating the greater biological significance of phlorotannins and developing innovative techniques for treating both infectious and non-infectious diseases in humans.

Phenotypically and genotypically estimation of virulence factors in Salmonella serovar typhi isolated from patients with enteric fever in Al- Najaf, Iraq

Abstract. Zghair LS, Motaweq ZY, Lafta HC. 2022. Phenotypically and genotypically estimation of virulence factors in Salmonella serovar typhi isolated from patients with enteric fever in Al-Najaf, Iraq. Nusantara Bioscience 14: 128-133. Salmonella serovar Typhi, often known as enteric fever, causes typhoid fever and has been a major human infectious disease for centuries, surviving in poor sanitation and overcrowding. Only 64 (58.1%) Gram-negative bacteria were found from the 110 total specimens, with 46 (41.8%) Gram-positive bacteria. The 64 samples were divided into 42 (65.6%) males and 22 (34.4%) females. This work presents the isolation and identification of 64 Salmonella typhi isolates obtained from specimens. In addition, the flagellin gene was found in 64 isolated probable typhoid fever patients (fliC-d). In this study, phenotypic techniques were used to detect several virulence factors. The results showed that small colonies of L-form bacteria grow on the edges of a petri dish when one of the ?-lactam antibiotics (a class of antibiotics that includes penicillin) is given to wild-type bacteria, showing 52 (81.3%) of isolates could produce L-form and observed in 44 (68.75%). The ability to generate CFA/I and CFA/II were found in 68.7% of isolates. The large percentage of CFA produced showed CFA/III production, 64 (100%).

Characterization of the complete mitochondrial genome of Ixodes granulatus (Ixodidae) and its phylogenetic implications.

Ticks are deemed to be second only to mosquitoes as the most common vector of human infectious diseases worldwide that give rise to human and animal diseases and economic losses to livestock production. Our understanding of the phylogenetic analysis between tick lineages has been restricted by the phylogenetic markers of individual genes. Genomic data research could help advance our understanding of phylogenetic analysis and molecular evolution. Mitochondrial genomic DNA facilitated the phylogenetic analysis of eukaryotes containing ticks. In this study, we sequenced and assembled the circular complete mitogenome information of Ixodes granulatus. The 14,540-bp mitogenome consists of 37 genes, including 13 protein-coding genes (PCGs), two genes for ribosomal RNA (rRNAs), and 22 genes for transfer RNA (tRNAs), and the origin of the L-strand replication region. The directions of the coding strand and component genes in the non-Australasian Ixodes mitochondrial genome were similar to those found in most other Australasian Ixodes, except for the loss of a lengthy control region. The phylogenetic tree based on maximum likelihood (ML) and Bayesian inference (BI) computational algorithms showed that I. granulatus exhibits a close relationship with I. hexagonus and I. ricinus. To our knowledge, this is the first study exploring the complete mitogenome for the species I. granulatus. Our results provide new insights for further research on the evolution, population genetics, systematics, and molecular ecology of ticks.

Vibrio cholerae: a pathogen shared by human and aquatic animals

Vibrio cholerae: a pathogen shared by human and aquatic animals

Lateral flow assays (LFA) for detection of pathogenic bacteria: A small point-of-care platform for diagnosis of human infectious diseases.

Up-to-date diagnostics is globally improved by point-of-care testing (POCT) analysis and bedside research works. Development in POCT analysis has been provided mostly by forward-looking engineering technology for biosensing and sensing assessments. Lately, lateral flow assays (LFAs) have attracted a lot of interest as a result of their noteworthy benefits including cost-effectiveness, better portability, being operator friendly and rapid detection. This technique has been employed broadly for monitoring diverse biomarkers linked to ultrasensitive detection of pathogenic bacteria, ecological monitoring, consumer protection, and infectious diseases. LFA analyses established on qualitative and optical outcomes have boosted the objectivity and data efficiency of the assessments. Therefore, developing novel methods with the capability of providing reliable and quantitative information regarding a target analyte in a model and preserving the qualities of LFAs is of great necessity. In this review, the main principles of LFAs, challenges, and prospects for more development in this field in sensing pathogenic bacteria have been summarized. Subsequently, visually-read LFAs improvement to further progressive platforms have been explored by considering the prospects of this very flexible method for ultrasensitive detection of pathogenic bacteria. In addition, novel labeling methodologies, electrochemical and optical transducers are described. Also, recent developments in these detection methods elements in combination with other considered approaches have been highlighted.

Diagnosis of dengue virus infection using spectroscopic images and deep learning.

Dengue virus (DENV) infection is one of the major health issues and a substantial epidemic infectious human disease. More than two billion humans are living in dengue susceptible regions with annual infection mortality rate is about 5%–20%. At initial stages, it is difficult to differentiate dengue virus symptoms with other similar diseases. The main objective of this research is to diagnose dengue virus infection in human blood sera for better treatment and rehabilitation process. A novel and robust approach is proposed based on Raman spectroscopy and deep learning. In this regard, the ResNet101 deep learning model is modified by exploiting transfer learning (TL) concept on Raman spectroscopic data of human blood sera. Sample size was selected using standard statistical tests. The proposed model is evaluated on 2,000 Raman spectra images in which 1,200 are DENV-infected of human blood sera samples, and 800 are healthy ones. It offers 96.0% accuracy on testing data for DENV infection diagnosis. Moreover, the developed approach demonstrated minimum improvement of 6.0% and 7.0% in terms of AUC and Kappa index respectively over the other state-of-the-art techniques. The developed model offers superior performance to capture minute Raman spectral variations due to the better residual learning capability and generalization ability compared to others deep learning models. The developed model revealed that it might be applied for diagnosis of DENV infection to save precious human lives.

Prediction of Pharmacokinetics of IDP-73152 in Humans Using Physiologically-Based Pharmacokinetics.

IDP-73152, a novel peptide deformylase inhibitor with an antibacterial effect against Gram-positive bacteria, is in phase I development. The objective of this study was to develop a physiologically-based pharmacokinetic model (PBPK) for IDP-73152 in animals, and to extend the model to humans. Biopharmaceutical properties of IDP-73152 are determined using in vitro/in vivo experimentations for the PBPK model. A transit model consisting of gastrointestinal segments is applied for an estimation of the intestinal absorption kinetics. The PBPK model of IDP-73152 in rats is able to appropriately predict the plasma concentration–time profiles after the administration of IDP-73152 at different doses and by different routes (combined absolute average fold error (cAAFE), 1.77). The model is also found to be adequate in predicting the plasma concentration–time profiles of IDP-73152 in mice (cAAFE 1.59) and dogs (cAAFE 1.42). Assuming the oral administration of IDP-73152 to humans at doses of 640 and 1280 mg, the model is able to reproduce the concentration–time profiles obtained in humans (cAAFE 1.38); therefore, these observations indicate that the PBPK model used for IDP-73152 is applicable to animal species and humans. This model may be useful in predicting efficacious doses of IDP-73152 for the management of infectious disease in humans.

High-throughput virtual screening of small-molecule inhibitors targeting immune cell checkpoints to discover new immunotherapeutics for human diseases.

Immunotherapy is widely used to treat various cancers, and the drugs used are called immune checkpoint (ICP) inhibitors. Overexpression of immune cell checkpoints is reported for other human diseases such as acute infections (malaria), chronic viral infection (HIV, hepatitis B virus, TB infections), allergy, asthma, neurodegeneration, and autoimmune diseases. Some mAbs (monoclonal antibodies) are available against ICPs, but they have side effects. Small molecule seems to be safer in comparison with mAbs. Three independent small-molecule inhibitor libraries consisting of 9466 compounds were screened against seven immune cell checkpoints by applying high-throughput virtual screening approach. A total of 13 ICP inhibitors were finalized based on docking, MM-GBSA scores, and ADME properties. Six compounds were selected for MD simulation, and then, rutin hydrate (targeting all seven immune cell checkpoints), amikacin hydrate (targeting six), and 6-hydroxyluteolin (targeting three) were found to be the best immune cell checkpoint inhibitors. These three potential inhibitors have shown the potential to activate human immune cells and thus may control the spread of human lifestyle or infectious diseases. Proposed inhibitors warrant the in vitro and in vivo validation to develop it as an immunotherapeutic.

Identification of ticks from an old collection by MALDI-TOF MS

Objective of this study is to find the optimal conditions for preparing the samples, resulting in quality, reproducible and specific MS spectra of the ticks, with a shelf life in 70% ethanol of more than ten years. Amblyomma (Am.) variegatum species which had been stored in alcohol for more than twenty years and for which numerous specimens were available were used to compare the performance of four protocols tested. Spectra of insufficient quality were obtained from Am. variegatum legs preserved in alcohol for long periods with the reference protocol, named DO that we had set up years ago. The same observation was made on the spectra from Am. variegatum legs from dry (evaporated alcohol, DO-mod protocol). With new protocols named ReDO and PReDO the spectra were of good quality with high intensities (> 3000 a.u.). Blind testing showed that 94%, and 93% of the spectra were correctly identified with relevant log score values (LSVs ≥1.8), respectively for ReDO and PReDO protocols. All soft ticks treated in this study by PReDO protocol exhibited low intensity spectra with background noise. This study revealed that MALDI-TOF MS is able to identify hard ticks stored during decades in alcohol or dry (evaporated alcohol). Significance of the studyThe correct identification of ticks, including vectors responsible for the transmission of infectious diseases in humans and animals is essential for their control. MALDI-TOF MS, a proteomic tool that has emerged in recent years, has become an innovative, accurate and alternative tool for the identification of arthropods, including ticks. However, previous studies reported that preservation of arthropods in alcohol modified the MS spectra obtained from specimens of the same species freshly collected or frozenly stored. In this study, a standard protocol was established for the identification of tick collections which had been stored for more than ten years in alcohol. Four different protocols were assessed. The analysis of the results showed that among the four protocols tested, two protocols named ReDO (Rehydration and incubation of the legs in 40 μl of HPLC water for 12 h in a dry bath at 37°) and PreDO (Drying of the legs for 12 h in a dry bath at 37 °C followed by rehydration and incubation in 40 μl of HPLC water for 12 h.) seem to be more appropriate for the MALDI-TOF MS identification of ticks from old collections preserved in alcohol or dry. This study is promising for the future, as it will make it possible to create a MALDI-TOF MS database from a wide range of ticks which have been stored for a long time in alcohol or which are dry stored in laboratories and museums around the world.

Effects of statins on the risks of ischemic stroke and heart disease in human immunodeficiency virus infection, influenza and severe acute respiratory syndrome–associated coronavirus: respiratory virus infection with steroid use

Objectives We sought to fill the research gap on the effects of statins on the risks of ischemic stroke and heart disease among individuals with human immunodeficiency virus infection, influenza, and severe acute respiratory syndrome associated–coronavirus (HIS) disorders. Methods We enrolled a HIS cohort treated with statins (n = 4921) and a HIS cohort not treated with statins (n = 4921). The cumulative incidence of ischemic stroke and heart disease was analyzed using a time-dependent Cox proportional regression analysis. We analyzed the adjusted hazard ratio (aHR) and 95% confidence interval (CI) of ischemic stroke and heart disease for statins users relative to nonusers based on sex, age, comorbidities and medications. Results The aHR (95% CI) was 0.38 (0.22–0.65) for ischemic stroke. The aHR (95% CI) of heart disease was 0.50 (0.46–0.55). The aHRs (95% CI) of statin users with low, medium, and high adherence (statin use covering <33%, 33%–66%, and >66%, respectively, of the study period) for the risks of ischemic stroke were 0.50 (0.27–0.92), 0.31 (0.10–1.01), and 0.16 (0.04–0.68) and for heart disease were 0.56 (0.51–0.61), 0.40 (0.33–0.48), and 0.44 (0.38–0.51), respectively, compared with statin nonusers. Conclusion Statin use was associated with lower aHRs for ischemic stroke and heart disease in those with HIS disorders with comorbidities.

Pulmonary Sporotrichosis Caused by Sporothrix brasiliensis: A 22-Year, Single-Center, Retrospective Cohort Study

Pulmonary sporotrichosis is a rare condition. It can present as a primary pulmonary disease, resulting from direct Sporothrix species (spp). conidia inhalation, or as part of multifocal sporotrichosis with multiple organ involvement, mainly in immunocompromised patients. This study aimed to describe the sociodemographic and epidemiological characteristics and clinical course of patients with positive cultures for Sporothrix spp. from pulmonary specimens (sputum and/or bronchoalveolar lavage) at a reference center in an area hyperendemic for zoonotic sporotrichosis. The clinical records of these patients were reviewed. Fourteen patients were included, and Sporothrix brasiliensis was identified in all cases. Disseminated sporotrichosis was the clinical presentation in 92.9% of cases, and primary pulmonary sporotrichosis accounted for 7.1%. Comorbidities included human immunodeficiency virus infection (78.6%), alcoholism (71.4%), and chronic obstructive pulmonary disease (14.3%). Treatment with amphotericin B followed by itraconazole was the preferred regimen and was prescribed in 92.9% of cases. Sporotrichosis-related death occurred in 42.9% while 35.7% of patients were cured. In five cases there was a probable contamination from upper airway lesions. Despite the significant increase in sporotrichosis cases, pulmonary sporotrichosis remains rare. The treatment of disseminated sporotrichosis is typically difficult. Prompt diagnosis and identification of all affected organs are crucial for better prognosis.

Antimicrobial Resistance Profile by Metagenomic and Metatranscriptomic Approach in Clinical Practice: Opportunity and Challenge

The burden of bacterial resistance to antibiotics affects several key sectors in the world, including healthcare, the government, and the economic sector. Resistant bacterial infection is associated with prolonged hospital stays, direct costs, and costs due to loss of productivity, which will cause policy makers to adjust their policies. Current widely performed procedures for the identification of antibiotic-resistant bacteria rely on culture-based methodology. However, some resistance determinants, such as free-floating DNA of resistance genes, are outside the bacterial genome, which could be potentially transferred under antibiotic exposure. Metagenomic and metatranscriptomic approaches to profiling antibiotic resistance offer several advantages to overcome the limitations of the culture-based approach. These methodologies enhance the probability of detecting resistance determinant genes inside and outside the bacterial genome and novel resistance genes yet pose inherent challenges in availability, validity, expert usability, and cost. Despite these challenges, such molecular-based and bioinformatics technologies offer an exquisite advantage in improving clinicians’ diagnoses and the management of resistant infectious diseases in humans. This review provides a comprehensive overview of next-generation sequencing technologies, metagenomics, and metatranscriptomics in assessing antimicrobial resistance profiles.

HMOX1 genetic polymorphisms and outcomes in infectious disease: A systematic review.

Heme-oxygenase 1 (HMOX1) is a critical stress response gene that catalyzes the multistep oxidation of heme. A GT(n) repeat of variable length in the promoter in has been associated with a wide range of human diseases, including infections. This paper aims to summarise and systematically review associations between the length of the HMOX1 GT(n) promoter and infectious disease in humans. A search using relevant terms was performed in PubMED and EMBASE through to 15/01/21 identifying all research that studied an association between the HMOX1 GT(n) repeat polymorphism and the incidence and/or outcome of any human infectious disease. Citations were screened for additional studies. Potential studies were screened for inclusion by two authors. Data was extracted on allele frequency, genotype, strength of association, mechanism of genotyping, and potential biases. A narrative review was performed across each type of infection. 1,533 studies were identified in the search, and one via citation screening. Sixteen studies were ultimately included, seven in malaria, three in HIV, three in sepsis, and one each in pneumonia, hepatitis C, and acute respiratory distress syndrome (ARDS). Sample sizes for nearly all studies were small (biggest study, n = 1,646). Allelic definition was different across all included studies. All studies were at some risk of bias. In malaria, three studies suggested that longer alleles were associated with reduced risk of severe malaria, particularly malaria-induced renal dysfunction, with four studies identifying a null association. In sepsis, two studies suggested an association with longer alleles and better outcomes. Despite the importance of HMOX1 in survival from infection, and the association between repeat length and gene expression, the clinical data supporting an association between repeat length and incidence and/or outcome of infection remain inconclusive.

Comparing the prevalence of Helicobacter pylori and virulence factors cagA, vacA, and dupA in supra-gingival dental plaques of children with and without dental caries: a case–control study

BackgroundHelicobacter pylori infection is one of the most common infectious diseases in humans. Dental plaque is considered as a reservoir of this bacterium, which could play an important role in the development of gastrointestinal problems. Our aim was to investigate the prevalence of H. pylori and its virulence factors in dental plaques in children with and without dental caries.MethodsAmong children aged 6 to 12 years, a total of 72 children were enrolled in the study, including 36 cases with total DMFT/dmft > 3 (case group) and 36 participants with total DMFT/dmft < 1 (control group). After removing supra-gingival plaques from the lower first permanent molar teeth, the samples were examined using PCR method for the presence of H. pylori and some of its virulence factors. Statistical analysis was performed using chi-square, Fisher' exact test, t-tests, and logistic regression.ResultsOf 72 participants, 40 cases were male, and 32 cases were female. The minimum and maximum values of total DMFT/dmft indices were zero and ten, respectively, and the mean ± SD value of total DMFT/dmft was 2.78 ± 3.22. Except for vegetable consumption (p = 0.045), there was no significant difference between the two groups regarding gastrointestinal disorders, feeding methods in infancy (p = 0.058), frequency of daily brushing (p = 0.808), frequency of dental visits (p = 0.101), and history of dental scaling (p = 0.246) and professional topical fluoride therapy (p = 0.5). Out of 72 samples, 15 cases were positive for H. pylori DNA (20.8%), and there was no significant association between the presence of this bacterium in dental plaque and dental caries (p = 0.281). The frequency of virulence factors detected in 15 H. pylori cases was as follows: cagA in six cases (40.0%), vacAm1 in three cases (20.0%), and vacAs1 in one case (6.7%). There was no significant difference between the groups regarding the prevalence of virulence factors.ConclusionOur results indicate the presence of H. pylori along with some virulence factors in dental plaques as a reservoir of this bacterium in children in Iran. Although there was no significant association between this bacterium and the incidence of dental caries, dental health in children needs to be seriously taken into consideration.

EVALUATION OF ANTI QUOROM SENSING ACTIVITIES USING Emblica officinalis ETHANOLIC LEAF EXTRACTS AGAINST MARINE MICROBES

Biofilm formation in pathogenic bacteria displays a major role in various human infectious diseases posing a major health problem in several countries. Biofilms contain colony of bacteria which are 1,000 folds more resistant to antibiotics and also they develop more insensitivity to innate and acquired immune responses. Quorum sensing (QS) is characterized well due to the interaction of bacterial cells, which is a dependent mechanism and acts its stimulus response related to population density. In the present study we tested the antiquorum sensing activity with leaf extracts of commonly used dietary supplement Emblica Officinalis (Amla) against marine microbes. In our method, we cultured Klebsilla, Proteus, E.coli, Shigella, Salmonella typhi from marine water source for quorum sensing activities and inhibitory effects through antimicrobial activities. Marine bacteria were isolated, identified based on physical and biochemical characterization. In our results we investigated the inhibitory effects of amla against pathogenic bacteria using swarming method. Further highest inhibitory bacterial isolates were examined under scanning electron microscopy (SEM). We conclude that amla exhibits potential inhibitory effects in biofilms formation from samples obtained from marine waters and further studies are needed in QS gene expression in more number of marine microbial samples.

Bio-hybrid nanoarchitectonics of nanoflower-based ELISA method for the detection of Staphylococcus aureus

Staphylococcus aureus is one of the crucial bacterial pathogens that cause food poisoning and human infectious diseases. Therefore, the establishment of a rapid and sensitive detection method for S. aureus is of great significance for the diagnosis, prevention, and control of the diseases caused by this pathogen. To this end, we have established a bio-hybrid nanoarchitectonics of nanoflower-based ELISA method for the detection of S. aureus with high specificity and sensitivity. The core of the method is to prepare a specific cell wall binding domain (CBD)-horseradish peroxidase (HRP)-Cu3(PO4)2 three-in-one organic-inorganic hybrid nanoflower complex through nanoarchitectonics. Detection consists of two main steps: we firstly coated an anti-S. aureus polyclonal antibody into the wells of a 96-well plate to specifically capture S. aureus, and then added customized CBD-HRP-Cu3(PO4)2 organic-inorganic hybrid nanoflower to the system. Due to the high specificity of the CBD from lysin PlyV12 of bacteriophage ϕ1 with S. aureus, a stable antibody-bacterium-hybrid nanoflower complex was formed. Then, the signal amplification of HRP enzyme activity in the hybrid nanoflower was carried out by using the TMB (3,3′,5,5′-tetramethylbenzidine)-hydrogen peroxide reporting system. The method has been proved to be capable of specifically detecting S. aureus ranging from 101 to 106 conoly-forming unit (CFU)/mL linearly with a detection limit down to 6 CFU/mL, which is arguably one of the best for all detection methods reported to date.

Colostrum of cattle in the prevention of human infectious disease (literature review)

Colostrum (or immune milk) is the first milk that mammals produce after childbirth, and its composition differs markedly from milk obtained later in lactation. Colostrum is a rich source of immunoglobulins and other biologically active components. The purpose of this literature review is to systematize research on methods of treatment and prevention of human infectious diseases using immunomodulatory and immunoprotective properties of colostrum. The open sources hosted in PubMed, Researchgate and eLibrary databases were studied. The history of the use of colostrum from hyperimmunized cows as a treatment for human diseases can be traced back to the 1950s. Many studies on the use of colostrum have explored its potential in both the prevention and treatment of various infectious diseases. The data obtained indicate the high efficiency of the use of cow colostrum and its components both for the prevention and treatment of infectious diseases. Colostrum is capable of producing a heterologous transfer of passive immunity. The immunization protocols used in the production of immune milk can be highly variable. This is especially true for the timing of immunization. Working on immunization protocols that expose animals to specific antigens can result in enhanced humoral immune responses in the mammary gland. The most relevant is the search for ways to use immune milk as a means to contain the SARS-CoV-2 pandemic. The literature review provides a description of antimicrobial, immunomodulatory and growth-stimulating factors in bovine colostrum. Examples and descriptions of homologous and heterologous transmission of passive immunity are given.

A non-canonical cGAS-STING-PERK pathway facilitates the translational program critical for senescence and organ fibrosis.

Innate DNA sensing via the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) mechanism surveys microbial invasion and cellular damage and thus participates in various human infectious diseases, autoimmune diseases and cancers. However, how DNA sensing rapidly and adaptively shapes cellular physiology is incompletely known. Here we identify the STING-PKR-like endoplasmic reticulum kinase (PERK)-eIF2α pathway, a previously unknown cGAS-STING mechanism, enabling an innate immunity control of cap-dependent messenger RNA translation. Upon cGAMP binding, STING at the ER binds and directly activates the ER-located kinase PERK via their intracellular domains, which precedes TBK1-IRF3 activation and is irrelevant to the unfolded protein response. The activated PERK phosphorylates eIF2α, forming an inflammatory- and survival-preferred translation program. Notably, this STING-PERK-eIF2α pathway is evolutionarily primitive and physiologically critical to cellular senescence and organ fibrosis. Pharmacologically or genetically targeting this non-canonical cGAS-STING pathway attenuated lung and kidney fibrosis. Collectively, the findings identify an alternative innate immune pathway and its critical role in organ fibrosis, report an innate immunity-directed translation program and suggest the therapeutic potential for targeting the STING-PERK pathway in treating fibrotic diseases.

Role of cervical cancer screening during prenatal checkups for infectious diseases: A retrospective, descriptive study.

ObjectiveThis study was conducted to evaluate the status and role of cervical cytology affected by human papillomavirus infection and other infectious diseases screened during routine prenatal checkups.MethodsWe retrospectively examined medical records containing the screening results for infectious diseases and cervical cancer in women who delivered neonates in our hospital from 2014 to 2017.ResultsAmong 3393 deliveries, 18.8% of women underwent a regular cervical cancer screening within 1 year of becoming pregnant, and 2641 women underwent a cervical cytology screening during this pregnancy. The cytological diagnostic results showed that 2562 women (97.0%) were negative for intraepithelial lesions or malignancy, whereas 79 (3.0%) had abnormal results. Of those with abnormal cytology results, 70 had abnormal cytology that was newly detected in this pregnancy, and 42 had grade ≥1 cervical intraepithelial neoplasia lesions. Spatulas were the most frequently used cytological sampling instruments, followed by cotton swabs. Cervical cytology revealed no major adverse reactions during these pregnancies.ConclusionsOur results confirm the importance of screening for infectious diseases during pregnancy. Only 20% of the women underwent a regular pre-pregnancy cervical cytology screening. Cervical cytology screening during pregnancy may currently be playing a crucial role in preventing cervical cancer in Japan.

Allosteric Probes for Modulating Essential Bacterial Chaperone‐Cofactor Interactions

DnaK is the bacterial homolog of Hsp70, an ATP‐dependent chaperone that assists cofactor proteins to catalyze nascent protein folding and salvage misfolded proteins. In the pathogen Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), DnaK and its cofactor proteins DnaJ1, DnaJ2 and GrpE are proposed drug targets. Despite the importance of chaperone function in human cancers and infectious disease, there are limited chemical probes or inhibitors that enable in vivo studies on the function of individual chaperones/cofactors. Here, we describe the discovery of small molecule inhibitors of mycobacterial DnaK from a re‐purposed drug library, most notably a peptidomimetic called telaprevir, which is able to inhibit chaperone function through interactions with the peptide‐binding cleft of DnaK. Binding of telaprevir leads to allosteric conformational changes that prevent ATP hydrolysis in a distal domain. We find that telaprevir also inhibits E. coli DnaK and human Hsp70 chaperones due to high conservation of Hsp70 sequences. Using in vitro and in vivo chaperone assays, we demonstrate that telaprevir modulates the function of mycobacterial DnaK and its cofactor protein DnaJ2 in cells, which disrupts cellular proteostasis. Co‐treatment of mycobacteria with telaprevir and aminoglycosides, which further stress the proteome, enhances the potency of these antibiotics. In addition, telaprevir combats mycobacterial resistance to the frontline TB drug rifampin, as DnaK‐DnaJ2 function is required for stabilization of protein mutants that confer drug tolerance. This work sets the stage for the design of peptide‐based inhibitors with higher selectivity for bacterial chaperones to probe chaperone‐protein interactions and explore resulting synergy with different classes of antibiotics.