Discovery of inhibitors against mycobacterium branched-chain amino acid aminotransferases through in silico screening and experimental evaluation.

Tuberculosis (TB) is one of the most dangerous infectious diseases and is caused by Mycobacterium bovis (Mb) and Mycobacterium tuberculosis (Mt). Branched-chain amino acid aminotransferases (BCATs) were reported to be the key enzyme for methionine synthesis in Mycobacterium. Blocking the methionine synthesis in Mycobacterium can inhibit the growth of Mycobacterium. Therefore, in silico screening of inhibitors can be a good way to develop a potential drug for treating TB. A pyridoxal 5'-phosphate (PLP)-form of Mycobacterium bovis branched-chain amino acid aminotransferases (MbBCAT), an active form of MbBCAT, was constructed manually for docking approximately 150 000 compounds and the free energy was calculated in Autodock Vina. The 10 compounds which had the highest affinity to MbBCAT were further evaluated for their inhibitory effects against MbBCAT. Within the selected compounds, compound 4 (ZINC12359007) was found to be the best inhibitor against MbBCAT with the inhibitory constant Ki of 0·45 µmol l-1 and IC50 of 2·37 µmol l-1 . Our work provides potential candidates to develop effective drugs to prevent TB since the well-known structural information would be beneficial in the structure-based modification and design.

Regional Differences following Partial Salivary Gland Resection.

Regenerative medicine aims to repair, replace, or restore function to tissues damaged by aging, disease, or injury. Partial organ resection is not only a common clinical approach in cancer therapy but also an experimental injury model used to examine mechanisms of regeneration and repair in organs. We performed a partial resection, or partial sialoadenectomy, in the female murine submandibular salivary gland (SMG) to establish a model for investigation of repair mechanisms in salivary glands (SGs). After partial sialoadenectomy, we performed whole-gland measurements over a period of 56 d and found that the gland increased slightly in size. We used microarray analysis and immunohistochemistry (IHC) to examine messenger RNA and protein changes in glands over time. Microarray analysis identified dynamic changes in the transcriptome 3 d after injury that were largely resolved by day 14. At the 3-d time point, we detected gene signatures for cell cycle regulation, inflammatory/repair response, and extracellular matrix (ECM) remodeling in the partially resected glands. Using quantitative IHC, we identified a transient proliferative response throughout the gland. Both secretory epithelial and stromal cells expressed Ki67 that was detectable at day 3 and largely resolved by day 14. IHC also revealed that while most of the gland underwent a wound-healing response that resolved by day 14, a small region of the gland showed an aberrant sustained fibrotic response characterized by increased levels of ECM deposition, sustained Ki67 levels in stromal cells, and a persistent M2 macrophage response through day 56. The partial submandibular salivary gland resection model provides an opportunity to examine a normal healing response and an aberrant fibrotic response within the same gland to uncover mechanisms that prevent wound healing and regeneration in mammals. Understanding regional differences in the wound-healing responses may ultimately affect regenerative therapies for patients.

First report of the oil palm disease fungus Marasmius palmivorus from Taiwan causing stem rot disease on native Formosa palm Arenga engleri as new host.

Basidiomata were found on dead stems of wild native Formosa palm (Arenga engleri) in Taiwan. The fungus was identified based on morphology and internal transcribed spacer sequence comparison as the oil palm pathogen Marasmius palmivorus. A pathogenicity test with cultivated mycelium of M. palmivorus positively produced disease symptoms and death of non-wounded Formosa palm tree seedlings under excessive moisture conditions. These results indicate that mycelial inoculum may be more important for pathogenesis than spore inoculum and that the fungus does not require wounds for entry into the plant. Host records in the literature are critically revised. The extended geographical and host distribution indicate a greater risk by M. palmivorus in palm plantations than hitherto anticipated. SIGNIFICANCE AND IMPACT OF THE STUDY: Certain palm species are susceptible to disease caused by Marasmius palmivorus, particularly in oil and coconut palm plantations in tropical countries. Hitherto, there is no published information on the morphology and pathogenicity of the species in Taiwan.

The plant growth-promoting potential of the mesophilic wood-rot mushroom Pleurotus pulmonarius.

AIMS: To demonstrate the plant growth-promoting potential of a wood-decay mushroom. METHODS AND RESULTS: A wild strain of a white rot fungus (Pleurotus pulmonarius) was found to convert 10 mmol l-1 L-tryptophan (TRP) to approximately 15 µg ml-1 indole-3-acetic acid (IAA) under the optimal growth conditions of 30°C and pH 5 for 15 days. Results of gas chromatography-mass spectrometry indicated IAA synthesis through the indole-3-pyruvic acid pathway when using cellulose as a sole carbon source. The mycelium as well as the culture filtrate promoted the growth and chlorophyll content of seedlings. In a monocotyledonous plant (rice), the number of lateral roots was increased experimentally, whereas in a dicotyledonous plant (tomato), the fungus led to an increased length of shoots and roots. CONCLUSIONS: TRP-dependent IAA production was demonstrated for the first time for P. pulmonarius and may be responsible for enhancing plant growth in vitro. SIGNIFICANCE AND IMPACT OF THE STUDY: Synthesis of IAA as the most prevalent phytohormone in plants has been demonstrated for soil microfungi. Pleurotus pulmonarius is reported as an IAA-producing wood-decay macrofungus. The higher temperature optimum of P. pulmonarius isolated from subtropical environment compared to other Pleurotus species from temperate regions makes it more suitable for application in subtropical/tropical regions.

Community outbreak of invasive group A streptococcus infection in Ontario, Canada.

BACKGROUND: Outbreaks of invasive group A streptococcal infection (iGAS) have historically occurred in institutional settings. Increasingly, community-based outbreaks have been reported, often among marginalized populations, yet few guidelines exist for managing iGAS outbreaks in such settings. OBJECTIVE: To describe the ongoing outbreak of iGAS in Middlesex-London, Ontario, and the challenges that arose while applying current guidelines to a marginalized population in a community setting. METHODS: The outbreak investigation included all iGAS cases in Middlesex-London with an onset date from April 1, 2016 to February 28, 2018. Clinical specimens were submitted to provincial and federal laboratories for typing. Public health management of the outbreak involved environmental health inspections, contact tracing, chemoprophylaxis of close contacts, swabbing to determine colonization rates of Streptococcus pyogenes, and communicating with stakeholders and the public. RESULTS: A total of 156 confirmed cases of iGAS corresponding to 147 individuals were reported in less than two years. More than 60% of cases occurred in men (n=91) and almost half (n=71) of the total number of cases were persons who used drugs (PWUD) and/or were under-housed. Of the PWUD cases, 58 of 65 (89%) used injection drugs. Key challenges in controlling this outbreak included reaching PWUD and under-housed people; completing a case history and contact list; facilitating completion of treatment; dealing with concurrent infections such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV); and optimizing environmental health conditions. Guidelines were adapted so contacts who shared drugs or injection drug equipment with a known iGAS case would be offered chemoprophylaxis regardless of the clinical severity of the case. To optimize treatment completion, a single-dose of azithromycin for individuals in close contact with PWUD and/or under-housed cases was given. Cases with macrolide-resistant strain emm9 have recently emerged. CONCLUSION: The application of institution-based guidelines for iGAS outbreaks has been ineffective in controlling this particular community outbreak. There is a need for guidelines on managing outbreaks of iGAS in the community especially when an outbreak involves marginalized populations.

The use of an exoskeleton to investigate the self advantage phenomenon.

This paper presents an upper extremity exoskeleton with an original application in neuroscience. The novelty of this study is the investigation of the self-advantage phenomenon under various experimental conditions. Usually this kind of experiments lies only on human visual ability to explicitly and/or implicitly recognize their own arm movements. Using an exoskeleton to replay recorded trajectories allows to give another perspective to the previous studies in including the proprioceptive ability of humans. Twelve healthy subjects were involved in this study. The results show that the self advantage phenomenon is even more present in the implicit tasks.

Three-dimensional gesture comparison using curvature analysis of position and orientation.

This paper describes a new analysis method dedicated to the comparison of human gestures. The orientations and the positions of the gestures are first digitized using active 3D sensors and then compared to a 6-D template using curvature analysis. The proposed algorithm first starts by computing the invariant curvature of 3D position and orientation of a surgical tool using Frenet-Serret frames in 3D and quaternion space. The resulting curvature calculation is matched and compared to the template using a Dynamic Time Warping method. The proposed method is invariant to sensor position and orientation. An experimental study shows the efficiency of the new algorithm for an application in obstetrics, where the aim is to compare forceps blade placements between a senior medical doctor and a novice.

Gravity compensation of an upper extremity exoskeleton.

This paper presents a new gravity compensation method for an upper extremity exoskeleton mounted on a wheel chair. This new device is dedicated to regular and efficient rehabilitation training for post-stroke and injured people without the continuous presence of a therapist. The exoskeleton is a wearable robotic device attached to the human arm. The user provides information signals to the controller by means of the force sensors around the wrist and the arm, and the robot controller generates the appropriate control signals for different training strategies and paradigms. This upper extremity exoskeleton covers four basic degrees of freedom of the shoulder and the elbow joints with three additional adaptability degrees of freedom in order to match the arm anatomy of different users. For comfortable and efficient rehabilitation, a new heuristic method have been studied and applied on our prototype in order to calculate the gravity compensation model without the need to identify the mass parameters. It is based on the geometric model of the robot and accurate torque measurements of the prototype's actuators in a set of specifically chosen joint positions. The weight effect has been successfully compensated so that the user can move his arm freely while wearing the exoskeleton without feeling its mass.

Evaluation of medical gestures based on a global performance index.

This paper presents a method to evaluate medical gestures. The objective is to objectively assess a gesture carried out by novice doctors. The proposed method is based on the study of the curvature of the 3D gesture and provide a global performance index for one manipulation. The study of the number of peaks on the curvature indicates if the gesture is smooth or not. The application is the obstetric gestures linked to the forceps use but the method can be applied to different gestures without loss of generality. Seven residents carried out 30 forceps blade placements. The results clearly show a difference between the gestures carried out. This highlights the difficulty of the gesture according to the fetal head presentation.

Assessment of forceps blade orientations during their placement using an instrumented childbirth simulator.

This paper aims to highlight the benefits of simulator training in obstetric manipulations such as forceps blade placement. The BirthSIM simulator is used to mimic operative vaginal deliveries. To characterise forceps blade placement, we studied the curvature of forceps path. The orientation of the forceps blades are studied in the quaternion unit space to ensure time-independent analysis. The results showed progress for all novices in forceps blade placement. Simulator training helps them to develop their self-confidence and acquire experience before working in the delivery room.

Assessment of forceps use in obstetrics during a simulated childbirth.

BACKGROUND: In obstetrics, manipulations are mainly learned during real deliveries. To minimize the risks linked to such training, we propose a childbirth simulator as a teaching tool in hospitals. More specifically, we focus on training with forceps during obstetric manipulation. METHODS: The training method can be divided into two steps: the teaching of forceps placement, and the extraction manipulation. In this paper we focus on the extraction manipulation on the simulator and the analysis of the results, taking into account several parameters and using an evaluation function to obtain a global score. RESULTS: Experimental results reveal novice difficulty while proceeding to the fetus extraction. These results highlight the fact that novices need a personalized training which can be carried out on the BirthSIM simulator. CONCLUSION: Results lead to the conclusion that a simulator training offers benefit to novices by providing them with risk-free training to acquire initial experience before proceeding to conventional training in the delivery room.

A method to evaluate skill transfer and acquisition of obstetric gestures based on the curvatures analysis of the position and the orientation.

This paper focuses on the gesture analysis in order to compare two human gestures. The orientations and the positions of the gestures are both taken into account and the similarity rate between two gestures is calculated. In our case, the application is in obstetrics and the aim is to evaluate forceps blade placement. The method is based on the curvature analysis of the paths during the gesture. The 3-D position paths are expressed according to their cumulated chord length and the orientation paths in the quaternion unit space. These parameterizations lead to analyze data in space independently to time as requested by physicians. After filtering data in order to minimize sensor noises, the gestures are then compared by calculating the correlation between the position and the orientation curvatures of a novice gesture and an expert one. The results clearly show that novice skills in handling forceps increase in becoming smoother and closer to the reference placement. A childbirth simulator allows novices to acquire experience without any risks, however the training have to be completed with the extraction gesture evaluation and a compulsory training period in the delivery ward.

A medical simulator for subcutaneous contraceptive implant insertion.

New contraceptive methods like the subcutaneous implant offers a new kind of comfort for women with an efficiency similar to the contraceptive pill. Unfortunately the few numbers of unintended pregnancies that have been reported are generally due to a bad insertion of the implant. In order to give more security to patients, we have designed, in close collaboration with physicians, a new kind of medical simulator. This paper focuses on a device dedicated to a specific subcutaneous implant but it is worth noting that this simulator is relatively generic since it will be used for other subcutaneous techniques or other implant instruments. This simulator can be used for two purposes: one for training novice physicians in the correct manipulation and the other for physician certification which will help determine if they are capable of inserting the implant in vivo. This paper describes the approach which has led to the design of this simulator. It describes its functionalities, its several components but also methods used to analyze the manipulation of the implant insertion inside the patient. Finally first experimental results are reported and discussed. The system used in this paper makes possible to carry out training in a constraint-free context and provides the first mean of visualizing a maneuver that, until now, has been performed blindly.

Evaluation of obstetric gestures: an approach based on the curvature of quaternions.

This paper presents a method to evaluate a gesture carried out by a resident obstetrician by comparing it to a gesture carried out by an expert obstetrician. The studied gesture is the forceps blade placement. Resident paths were recorded on a childbirth simulator while placing forceps blades instrumented with six degrees of freedom sensors. The path is characterized by the positions and the orientations. In this paper we particularly focus on the orientations. Forceps orientations are expressed in the quaternion unit space and the curvature of quaternion path is compared by correlation to a reference defined by an expert. Residents have been trained on a simulator and their gestures are evaluated by comparing their orientation path curvatures to reference path curvatures. Quantitative results confirm the qualitative analysis, residents become more similar to the reference while training on simulator.

Design of a medical simulator for subcutaneous contraceptive implant insertion.

New contraceptive methods like the subcutaneous implant offers a new kind of comfort for women with an efficiency similar to the contraceptive pill. Unfortunately, the few numbers of unintended pregnancies that have been reported, are generally due to a bad insertion of the implant. In order to give more security to patients, we have designed, in close collaboration with physicians, a new kind of medical simulator. This simulator can be used for two purposes: one for training novice physicians in the correct gesture and the other for doctor certification which will help to determine if they are capable of inserting the implant in vivo. This paper describes the approach which has led to the design of this simulator. It describes its functionalities, its several components but also methods used to analyze the gesture of the implant insertion inside the patient. Finally, first experimental results are reported and discussed.

Evaluation of obstetric gestures: an approach based on the curvature of 3-D positions.

This paper presents a method to evaluate a gesture carried out by a resident obstetrician doctors by comparing it to a gesture carried out by an expert obstetrician doctors. The studied gesture is the forceps blade placement. Residents were recorded on a childbirth simulator while placing forceps blades. Their paths were compared in order to evaluate how similar they are to a reference path defined by an expert. The comparison method is developed with respect to expert requests: time independence and in considering the whole set of data and not only particular points. In order to respect these requests, the developed method lies on the correlation coefficient between the path curvatures. Residents have been trained on a simulator and their gestures were evaluated by comparing their path curvatures to reference path curvatures. Quantitative results confirm the qualitative analysis, residents become more similar to the reference while training on simulator.

Bioactivity of titanium following sodium plasma immersion ion implantation and deposition.

Bio-activation of titanium surface by Na plasma immersion ion implantation and deposition (PIII and D) is illustrated by precipitation of calcium phosphate and cell culture. The bioactivity of the plasma-implanted titanium is compared to that of the untreated, Na beam-line implanted and NaOH-treated titanium samples. Our data show that the samples can be classified into two groups: non-bioactive (untreated titanium and beam-line Na implanted titanium) and bioactive (Na-PIII and D and NaOH-treated titanium). None of the four types of surfaces exhibited major cell toxicity as determined by lactate dehydrogenase (LDH) release. However, the LDH release was higher on the more bioactive PIII and NaOH-treated surfaces. From a morphological point of view, cell adherence on the NaOH-treated titanium is the best. On the other hand, the cell activity and protein production were higher on the non-bioactive surfaces. The high alkaline phosphatase activity per cell suggests that the active surfaces support an osteogenic differentiation of the bone marrow cells at the expense of lower proliferation. The use of Na-PIII and D provides an environmentally cleaner technology to improve the bioactivity of Ti compared to conventional wet chemical processes. The technique is also particularly useful for the uniform and conforming treatment of medical implants that typically possess an irregular shape and are difficult to treat by conventional ion beam techniques.

Hydroxyapatite growth induced by native extracellular matrix deposition on solid surfaces.

Biological systems have a remarkable capability to produce perfect fine structures such as seashells, pearls, bones, teeth and corals. These structures are composites of interacting inorganic (calcium phosphate or carbonate minerals) and organic counterparts. It is difficult to say with certainty which part has the primary role. For example, the growth of molluscan shell crystals is thought to be initiated from a solution by the extracellular organic matrix (ECM). According to this theory, the matrix induces nucleation of calcium containing crystals. Recently, an alternative theory has been put forward, stating that a class of granulocytic hemocytes would be directly involved in shell crystal production in oysters. In the work presented here the surface of AISI 316 stainless steel was modified by deposition of ECM proteins. The ability of the modified substrates to induce nucleation and growth of hydroxyapatite (HA) from simulated body fluid (SBF) was examined by a kinetic study using two methods: (1) a simple soaking process in SBF and (2) a laser-liquid-solid interaction (LLSI) process which allows interaction between a scanning laser beam and a solid substrate immersed in SBF. The deposited HA layers were investigated by Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). It was found that a coating of stainless steel surface with native ECM proteins induced nucleation and growth of HA and facilitated its crystallization. By the process of simple soaking of the samples, irrespective of their horizontal or vertical position in the solution, HA layers were grown due to the reactive ECM-coated stainless steel surface. It was shown that the process occurring in the first stages of the growth was not only a result of the force of gravity. The application of the LLSI process strongly influenced HA formation on the ECM-modified substrates by promoting and enhancing the HA nucleation and growth through a synergistic effect of a few stimuli, i.e., the modified solid surface, the laser beam and the aqueous solution.

Ion beam treatment of titanium surfaces for enhancing deposition of hydroxyapatite from solution.

Surface coating with hydroxyapatite (HA) is a common way to improve the osseointegration of orthopaedic and dental titanium (Ti)-based materials. The main problems with current techniques are changes in composition during heating and poor adhesion to the surface. An alternative method is deposition of HA onto an activated surface out of a solution. The present work studies the surface treatment involving ion implantation of Na into Ti to induce a modification in chemistry and morphology, showing sodium titanate (Na(2)TiO(3)) incorporated within the surface layer with concentration, depth distribution, and morphology depending on the parameters of the ion implantation. Such ion-implanted Ti surfaces actively induce heterogeneous precipitation of HA from a simulated body fluid containing physiological concentrations of calcium and phosphate ions. This is compared with the activation by NaOH etching. The growth of bone forming cells on the pure Na implanted surface is oriented without an increased bone formation. Cell growth on the NaOH etched surface is reduced. After deposition of HA on both surfaces cell the growth pattern was improved.

Solution deposition of hydroxyapatite on titanium pretreated with a sodium ion implantation.

Titanium surfaces were treated by exposing them to a beam of sodium ions. Sodium titanate was shown to be incorporated within the oxidic titanium surface. The ion-implanted surfaces were examined for their reactivity by immersion in a simulated body fluid, which showed the formation of surface-bound hydroxyapatite. The surface was characterized by X-ray diffraction, Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and optical and electron microscopy. The surface hydroxyl concentration was determined using the nuclear reaction (1)H((15)N, alpha gamma)(12)C. Surface-related parameters that may affect hydroxyapatite nucleation are discussed in terms of the electrical double layer.