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1.  Comparison between open and closed methods of herniorrhaphy in calves affected with umbilical hernia 
Journal of Veterinary Science  2009;10(4):343-347.
Umbilical hernias in calves commonly present to veterinary clinics, which are normally secondary to failure of the normal closure of the umbilical ring, and which result in the protrusion of abdominal contents into the overlying subcutis. The aim of this study was to compare the suitability of commonly-used herniorrhaphies for the treatment of reducible umbilical hernia in calves. Thirty-four clinical cases presenting to the Veterinary Teaching Hospital, Chittagong Veterinary and Animal Sciences University, Chittagong, Bangladesh from July 2004 to July 2007 were subjected to comprehensive study including history, classification of hernias, size of the hernial rings, presence of adhesion with the hernial sacs, postoperative care and follow-up. They were reducible, non-painful and had no evidence of infection present on palpation. The results revealed a gender influence, with the incidence of umbilical hernia being higher in female calves than in males. Out of the 34 clinical cases, 14 were treated by open method of herniorrhaphy and 20 were treated by closed method. Complications of hernia were higher (21%) in open method-treated cases than in closed method-treated cases (5%). Hernia recurred in three calves treated with open herniorrhaphy within 2 weeks of the procedure, with swelling in situ and muscular weakness at the site of operation. Shorter operation time and excellent healing rate (80%) were found in calves treated with closed herniorrhaphy. These findings suggest that the closed herniorrhaphy is better than the commonly-used open method for the correction of reducible umbilical hernia in calves.
PMCID: PMC2807272  PMID: 19934601
calves; herniorrhaphy; reducible umbilical hernia
2.  Lack of Understanding of Cervical Cancer and Screening Is the Leading Barrier to Screening Uptake in Women at Midlife in Bangladesh: Population-Based Cross-Sectional Survey 
The Oncologist  2015;20(12):1386-1392.
A nationally representative, cross-sectional survey of women aged 30–59 years in Bangladesh showed that 81.6% of women had heard of cervical cancer (CCa) but only 48.6% were aware of CCa screening. Only 8.3% had ever been screened. Lack of CCa awareness and of understanding of the concept of screening are the key barriers to screening uptake in this cohort.
Cervical cancer (CCa) is the second most common cancer among women in Bangladesh. The uptake of CCa screening was less than 10% in areas where screening has been offered, so we investigated the awareness of CCa and CCa screening, and factors associated with women’s preparedness to be screened.
A nationally representative, cross-sectional survey of women aged 30–59 years was conducted in 7 districts of the 7 divisions in Bangladesh, using a multistage cluster sampling technique. Factors associated with the awareness of CCa and screening uptake were investigated separately, using multivariable logistic regression.
On systematic questioning, 81.3% and 48.6% of the 1,590 participants, whose mean age was 42.3 (±8.0) years, had ever heard of CCa and CCa screening, respectively. Having heard of CCa was associated with living in a rural area (adjusted odds ratio [OR]: 0.42; 95% confidence interval [CI]: 0.26–0.67), being 40–49 years old (OR: 1.59; 95% CI: 1.15–2.0), having no education (OR: 0.25; 95% CI: 0.16–0.38), and being obese (OR: 2.04; 95% CI: 1.23–3.36). Of the 773 women who had ever heard of CCa screening, 86% reported that they had not been screened because they had no symptoms and 37% did not know screening was needed. Only 8.3% had ever been screened. Having been screened was associated with being 40–49 years old (OR: 2.17; 95% CI: 1.19–3.94) and employed outside the home (OR: 3.83; 95% CI: 1.65–8.9), and inversely associated with rural dwelling (OR: 0.54; 95% CI: 0.30–0.98) and having no education (OR: 0.29; 95% CI: 0.10–0.85).
Lack of awareness of CCa and of understanding of the concept of screening are the key barriers to screening uptake in women at midlife in Bangladesh. Targeted educational health programs are needed to increase screening in Bangladesh with the view to reducing mortality.
Implications for Practice:
This is the first nationwide and population-based study in Bangladesh to collect detailed information pertaining to the awareness of cervical cancer and cervical cancer screening, and factors associated with women’s preparedness to undergo screening. Rather than cultural and religious barriers, lack of awareness and knowledge of cervical cancer and screening present the primary barriers to screening uptake. The results highlight the urgent need for health education programs that have the potential to increase cervical cancer awareness and screening uptake, and reduce cervical cancer mortality.
PMCID: PMC4679089  PMID: 26590177
Awareness; Barriers; Cervical cancer; Screening; Bangladesh
3.  Molecular Analysis of Glucose-6-Phosphate Dehydrogenase Gene Mutations in Bangladeshi Individuals 
PLoS ONE  2016;11(11):e0166977.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common X-linked human enzyme defect of red blood cells (RBCs). Individuals with this gene defect appear normal until exposed to oxidative stress which induces hemolysis. Consumption of certain foods such as fava beans, legumes; infection with bacteria or virus; and use of certain drugs such as primaquine, sulfa drugs etc. may result in lysis of RBCs in G6PD deficient individuals. The genetic defect that causes G6PD deficiency has been identified mostly as single base missense mutations. One hundred and sixty G6PD gene mutations, which lead to amino acid substitutions, have been described worldwide. The purpose of this study was to detect G6PD gene mutations in hospital-based settings in the local population of Dhaka city, Bangladesh. Qualitative fluorescent spot test and quantitative enzyme activity measurement using RANDOX G6PDH kit were performed for analysis of blood specimens and detection of G6PD-deficient participants. For G6PD-deficient samples, PCR was done with six sets of primers specific for G6PD gene. Automated Sanger sequencing of the PCR products was performed to identify the mutations in the gene. Based on fluorescence spot test and quantitative enzyme assay followed by G6PD gene sequencing, 12 specimens (11 males and one female) among 121 clinically suspected patient-specimens were found to be deficient, suggesting a frequency of 9.9% G6PD deficiency. Sequencing of the G6PD-deficient samples revealed c.C131G substitution (exon-3: Ala44Gly) in six samples, c.G487A substitution (exon-6:Gly163Ser) in five samples and c.G949A substitution (exon-9: Glu317Lys) of coding sequence in one sample. These mutations either affect NADP binding or disrupt protein structure. From the study it appears that Ala44Gly and Gly163Ser are the most common G6PD mutations in Dhaka, Bangladesh. This is the first study of G6PD mutations in Bangladesh.
PMCID: PMC5120827  PMID: 27880809
4.  Finding Potential Therapeutic Targets against Shigella flexneri through Proteome Exploration 
Background: Shigella flexneri is a gram negative bacteria that causes the infectious disease “shigellosis.” S. flexneri is responsible for developing diarrhea, fever, and stomach cramps in human. Antibiotics are mostly given to patients infected with shigella. Resistance to antibiotics can hinder its treatment significantly. Upon identification of essential therapeutic targets, vaccine and drug could be effective therapy for the treatment of shigellosis.
Methods: The study was designed for the identification and qualitative characterization for potential drug targets from S. flexneri by using the subtractive proteome analysis. A set of computational tools were used to identify essential proteins those are required for the survival of S. flexneri. Total proteome (13,503 proteins) of S. flexneri was retrieved from NCBI and further analyzed by subtractive channel analysis. After identification of the metabolic proteins we have also performed its qualitative characterization to pave the way for the identification of promising drug targets.
Results: Subtractive analysis revealed that a list of 53 targets of S. flexneri were human non-homologous essential metabolic proteins that might be used for potential drug targets. We have also found that 11 drug targets are involved in unique pathway. Most of these proteins are cytoplasmic, can be used as broad spectrum drug targets, can interact with other proteins and show the druggable properties. The functionality and drug binding site analysis suggest a promising effective way to design the new drugs against S. flexneri.
Conclusion: Among the 53 therapeutic targets identified through this study, 13 were found highly potential as drug targets based on their physicochemical properties whilst only one was found as vaccine target against S. flexneri. The outcome might also be used as module as well as circuit design in systems biology.
PMCID: PMC5118456  PMID: 27920755
S. flexneri; drug target; therapeutics; metabolic proteins; proteome
5.  Reduction in malaria prevalence and increase in malaria awareness in endemic districts of Bangladesh 
Malaria Journal  2016;15:552.
Malaria is endemic in 13 districts of Bangladesh. A baseline malaria prevalence survey across the endemic districts of Bangladesh was conducted in 2007, when the prevalence was reported around 39.7 per 1000 population. After two rounds of Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM)-funded intervention by the National Malaria Control Programme (NMCP) and a BRAC-led NGO consortium, a follow-up survey was conducted across the malaria-endemic districts of Bangladesh to measure the change in prevalence rate and in people’s knowledge of malaria.
The survey was carried out from August to November 2013 in 70 upazilas (sub-districts) of 13 malaria-endemic districts of Bangladesh, following the same multi-stage cluster sampling design and the same number of households enrolled during the baseline prevalence survey in 2007, to collect 9750 randomly selected blood samples. For on-the-spot diagnosis of malaria, a rapid diagnostic test was used. The household head or eldest person available was interviewed using a pre-coded structured questionnaire to collect data on the knowledge and awareness of malaria in the household.
Based on a weighted calculation, the overall malaria prevalence was found to be 1.41 per 1000 population. The proportion of Plasmodium falciparum mono-infection was 77.78% while both Plasmodium vivax mono-infection and mixed infection of the two species were found to be 11.11%. Bandarban had the highest prevalence (6.67 per 1000 population). Knowledge of malaria signs, symptoms and mode of transmission were higher in the follow-up survey (97.26%) than the baseline survey. Use of bed nets for prevention of malaria was found to be high (90.15%) at respondent level. People’s knowledge of selected parameters increased significantly during the follow-up survey compared to the baseline survey conducted in 2007.
A reduced prevalence rate of malaria and increased level of knowledge were observed in the present malaria prevalence survey in Bangladesh.
PMCID: PMC5105313  PMID: 27836016
Malaria; Prevalence; Survey; Awareness; Bangladesh
7.  Bangladesh national guidelines on the management of tuberculosis and diabetes mellitus co-morbidity (summary) 
Tuberculosis (TB) and diabetes mellitus (DM) have synergetic relationship. People with diabetes are 2–3 times at higher risk of getting active TB disease. On the other hand, TB or anti-TB treatment may cause glucose intolerance. The dual disease of DM and TB is more likely to be associated with atypical disease presentation, higher probability of treatment failure and complications. In most of the health-care delivery systems of the world, DM and TB are managed separately by two vertical health-care delivery programs in spite of clear interaction between the two diseases. Thus, there should be a uniform management service for TB-DM co-morbidity. Realizing this situation, Bangladesh Diabetic Samity (BADAS), a nonprofit, nongovernment organization for the management of diabetes in Bangladesh, with the patronization of TB CARE II Project funded by U.S. Agency for International Development (USAID), launched a project in 2013 titled BADAS-USAID TB Care II, Bangladesh with the goal of “Integrated approach to increase access to TB services for diabetic patients.” One of the project objective and activity was to develop a national guideline for the management of TB-DM comorbidity. Thus, under the guidance of National Tuberculosis Control Program, of the Directorate General of Health Services, Government of the People's Republic of Bangladesh and World Health Organization (WHO), this guideline was developed in 2014. It is based on the existing “National Guidelines and Operational Manual for TB Control” (5th edition) and guidelines for management of DM as per WHO and International Diabetes Federations. Along with that, expert opinions from public health experts and clinicians and “Medline”-searched literature were used to develop the guidelines. These guidelines illustrate the atypical presentation of the TB-DM co-morbidity, recommendations for screening, treatment, and follow-up of these patients and also recommendations in case of management of TB in patients with kidney and liver diseases. Thus, these guidelines will be a comprehensive tool for physicians to manage TB in diabetic patients.
PMCID: PMC5105572  PMID: 27867891
Bangladesh; co-morbidity; diabetes mellitus; guidelines; tuberculosis
8.  Chemical Analysis of Extracts from Newfoundland Berries and Potential Neuroprotective Effects 
Antioxidants  2016;5(4):36.
Various species of berries have been reported to contain several polyphenolic compounds, such as anthocyanins and flavonols, which are known to possess high antioxidant activity and may be beneficial for human health. To our knowledge, a thorough chemical analysis of polyphenolics in species of these plants native to Newfoundland, Canada has not been conducted. The primary objective of this study was to determine the polyphenolic compounds present in commercial extracts from Newfoundland berries, which included blueberries (V. angustifolium), lingonberries (V. vitis-idaea) and black currant (Ribes lacustre). Anthocyanin and flavonol glycosides in powdered extracts from Ribes lacustre and the Vaccinium species were identified using the high performance liquid chromatographic (HPLC) separation method with mass spectrometric (MS) detection. The identified compounds were extracted from dried berries by various solvents via ultrasonication followed by centrifugation. A reverse-phase analytical column was employed to identify the retention time of each chemical component before submission for LC–MS analysis. A total of 21 phenolic compounds were tentatively identified in the three species. Further, we tested the effects of the lingonberry extract for its ability to protect neurons and glia from trauma utilizing an in vitro model of cell injury. Surprisingly, these extracts provided complete protection from cell death in this model. These findings indicate the presence of a wide variety of anthocyanins and flavonols in berries that grow natively in Newfoundland. These powdered extracts maintain these compounds intact despite being processed from berry fruit, indicating their potential use as dietary supplements. In addition, these recent findings and previous data from our lab demonstrate the ability of compounds in berries to protect the nervous system from traumatic insults.
PMCID: PMC5187534  PMID: 27775557
anthocyanins; antioxidants; flavonols; Ribes lacustre; trauma; Vaccinium species
9.  Classification of a Hypervirulent Aeromonas hydrophila Pathotype Responsible for Epidemic Outbreaks in Warm-Water Fishes 
Lineages of hypervirulent Aeromonas hydrophila (vAh) are the cause of persistent outbreaks of motile Aeromonas septicemia in warm-water fishes worldwide. Over the last decade, this virulent lineage of A. hydrophila has resulted in annual losses of millions of tons of farmed carp and catfish in the People's Republic of China and the United States (US). Multiple lines of evidence indicate US catfish and Asian carp isolates of A. hydrophila affiliated with sequence type 251 (ST251) share a recent common ancestor. To address the genomic context for the putative intercontinental transfer and subsequent geographic spread of this pathogen, we conducted a core genome phylogenetic analysis on 61 Aeromonas spp. genomes, of which 40 were affiliated with A. hydrophila, with 26 identified as epidemic strains. Phylogenetic analyses indicate all ST251 strains form a coherent lineage affiliated with A. hydrophila. Within this lineage, conserved genetic loci unique to A. hydrophila were identified, with some genes present in consistently higher copy numbers than in non-epidemic A. hydrophila isolates. In addition, results from analyses of representative ST251 isolates support the conclusion that multiple lineages are present within US vAh isolated from Mississippi, whereas vAh isolated from Alabama appear clonal. This is the first report of genomic heterogeneity within US vAh isolates, with some Mississippi isolates showing closer affiliation with the Asian grass carp isolate ZC1 than other vAh isolated in the US. To evaluate the biological significance of the identified heterogeneity, comparative disease challenges were conducted with representatives of different vAh genotypes. These studies revealed that isolate ZC1 yielded significantly lower mortality in channel catfish, relative to Alabama and Mississippi vAh isolates. Like other Asian vAh isolates, the ZC1 lineage contains all core genes for a complete type VI secretion system (T6SS). In contrast, more virulent US isolates retain only remnants of the T6SS (clpB, hcp, vgrG, and vasH) which may have functional implications. Collectively, these results characterize a hypervirulent A. hydrophila pathotype that affects farmed fish on multiple continents.
PMCID: PMC5067525  PMID: 27803692
Aeromonas hydrophila; pathogenesis; comparative genomics; emerging disease; bacteria; catfish; carp
10.  Non-chemical proton-dependent steps prior to O2-activation limit Azotobacter vinelandii 3-mercaptopropionic acid dioxygenase (MDO) catalysis 
3-mercaptopropionate dioxygenase from Azotobacter vinelandii (Av MDO) is a non-heme mononuclear iron enzyme that catalyzes the O2-dependent oxidation of 3-mercaptopropionate (3mpa) to produce 3-sulfinopropionic acid (3spa). With one exception, the active site residues of MDO are identical to bacterial cysteine dioxygenase (CDO). Specifically, the CDO Arg-residue (R50) is replaced by Gln (Q67) in MDO. Despite this minor active site perturbation, substrate-specificity of Av MDO is more relaxed as compared to CDO. In order to investigate the relative timing of chemical and non-chemical events in Av MDO catalysis, the pH/D-dependence of steady-state kinetic parameters (kcat and kcat/KM) and viscosity effects are measured using two different substrates [3mpa and L-cysteine (cys)]. The pL-dependent activity of Av MDO in these reactions can be rationalized assuming a diprotic enzyme model in which three ionic forms of the enzyme are present [cationic, E(z+1); neutral, Ez; and anionic, E(z−1)]. The activities observed for each substrate appear to be dominated by electrostatic interactions within the enzymatic active site. Given the similarity between MDO and the more extensively characterized mammalian CDO, a tentative model for the role of the conserved ‘catalytic triad’ is proposed.
PMCID: PMC5036937  PMID: 27311613
Non-heme mononuclear iron; Thiol dioxygenase; Solvent isotope effects; Proton inventory; Viscosity effects
11.  Thirteen year retrospective review of the spectrum of inborn errors of metabolism presenting in a tertiary center in Saudi Arabia 
Inborn errors of metabolism (IEMs) are individually rare; however, they are collectively common. More than 600 human diseases caused by inborn errors of metabolism are now recognized, and this number is constantly increasing as new concepts and techniques become available for identifying biochemical phenotypes. The aim of this study was to determine the type and distribution of IEMs in patients presenting to a tertiary care center in Saudi Arabia. METHOD: We conducted a retrospective review of children diagnosed with IEMs presenting to the Pediatric Department of King Abdulaziz Medical City in Riyadh, Saudi Arabia over a 13-year period.
Over the 13- year period of this retrospective cohort, the total number of live births reached 110,601. A total of 187 patients were diagnosed with IEMs, representing a incidence of 169 in 100,000 births (1:591). Of these, 121 patients (64.7 %) were identified to have small molecule diseases and 66 (35.3 %) to have large molecule diseases. Organic acidemias were the most common small molecule IEMs, while lysosomal storage disorders (LSD) were the most common large molecule diseases. Sphingolipidosis were the most common LSD.
Our study confirms the previous results of the high rate of IEMs in Saudi Arabia and urges the health care strategists in the country to devise a long-term strategic plan, including an IEM national registry and a high school carrier screening program, for the prevention of such disorders. In addition, we identified 43 novel mutations that were not described previously, which will help in the molecular diagnosis of these disorders.
PMCID: PMC5024448  PMID: 27629047
Inborn errors of metabolism; IEMs; Saudi Arabia; Lysosomal; Organic acidemia; Mitochondrial; Fatty acid oxidation defects
12.  Identification of mutations through dominant screening for obesity using C57BL/6 substrains 
Scientific Reports  2016;6:32453.
The discovery of leptin substantiated the usefulness of a forward genetic approach in elucidating the molecular network regulating energy metabolism. However, no successful dominant screening for obesity has been reported, which may be due to the influence of quantitative trait loci between the screening and counter strains and the low fertility of obese mice. Here, we performed a dominant screening for obesity using C57BL/6 substrains, C57BL/6J and C57BL/6N, with the routine use of in vitro fertilization. The screening of more than 5000 mutagenized mice established two obese pedigrees in which single nucleotide substitutions in Mc4r and Sim1 genes were identified through whole-exome sequencing. The mutation in the Mc4r gene produces a premature stop codon, and the mutant SIM1 protein lacks transcriptional activity, showing that the haploinsufficiency of SIM1 and MC4R results in obesity. We further examined the hypothalamic neuropeptide expressions in the mutant pedigrees and mice with diet-induced obesity, which showed that each obesity mouse model has distinct neuropeptide expression profiles. This forward genetic screening scheme is useful and applicable to any research field in which mouse models work.
PMCID: PMC5009433  PMID: 27585985
13.  EWS Knockdown and Taxifolin Treatment Induced Differentiation and Removed DNA Methylation from p53 Promoter to Promote Expression of Puma and Noxa for Apoptosis in Ewing’s Sarcoma 
Journal of cancer therapy  2014;5(12):1092-1113.
Ewing’s sarcoma is a pediatric tumor that mainly occurs in soft tissues and bones. Malignant characteristics of Ewing’s sarcoma are correlated with expression of EWS oncogene. We achieved knockdown of EWS expression using a plasmid vector encoding EWS short hairpin RNA (shRNA) to increase anti-tumor mechanisms of taxifolin (TFL), a new flavonoid, in human Ewing’s sarcoma cells in culture and animal models. Immunofluorescence microscopy and flow cytometric analysis showed high expression of EWS in human Ewing’s sarcoma SK-N-MC and RD-ES cell lines. EWS shRNA plus TFL inhibited 80% cell viability and caused the highest decreases in EWS expression at mRNA and protein levels in both cell lines. Knockdown of EWS expression induced morphological features of differentiation. EWS shRNA plus TFL caused more alterations in molecular markers of differentiation than either agent alone. EWS shRNA plus TFL caused the highest decreases in cell migration with inhibition of survival, angiogenic and invasive factors. Knockdown of EWS expression was associated with removal of DNA methylation from p53 promoter, promoting expression of p53, Puma, and Noxa. EWS shRNA plus TFL induced the highest amounts of apoptosis with activation of extrinsic and intrinsic pathways in both cell lines in culture. EWS shRNA plus TFL also inhibited growth of Ewing’s sarcoma tumors in animal models due to inhibition of differentiation inhibitors and angiogenic and invasive factors and also induction of activation of caspase-3 for apoptosis. Collectively, knockdown of EWS expression increased various anti-tumor mechanisms of TFL in human Ewing’s sarcoma in cell culture and animal models.
PMCID: PMC4989871  PMID: 27547487
Apoptosis; Differentiation; Ewing’s Sarcoma; EWS shRNA; p53 Promoter; Taxifolin
14.  Antioxidant and anti-inflammatory agents mitigate pathology in a mouse model of pseudoachondroplasia 
Human Molecular Genetics  2015;24(14):3918-3928.
Pseudoachondroplasia (PSACH), a severe short-limb dwarfing condition, results from mutations that cause misfolding of the cartilage oligomeric matrix protein (COMP). Accumulated COMP in growth plate chondrocytes activates endoplasmic reticulum stress, leading to inflammation and chondrocyte death. Using a MT-COMP mouse model of PSACH that recapitulates the molecular and clinical PSACH phenotype, we previously reported that oxidative stress and inflammation play important and unappreciated roles in PSACH pathology. In this study, we assessed the ability of antioxidant and anti-inflammatory agents to affect skeletal and cellular pathology in our mouse model of PSACH. Treatment of MT-COMP mice with aspirin or resveratrol from birth to P28 decreased mutant COMP intracellular retention and chondrocyte cell death, and restored chondrocyte proliferation. Inflammatory markers associated with cartilage degradation and eosinophils were present in the joints of untreated juvenile MT-COMP mice, but were undetectable in treated mice. Most importantly, these treatments resulted in significantly increased femur length. This is the first and only therapeutic approach shown to mitigate both the chondrocyte and long-bone pathology of PSACH in a mouse model and suggests that reducing inflammation and oxidative stress early in the disease process may be a novel approach to treat this disorder.
PMCID: PMC4476442  PMID: 25859006
15.  Therapeutics Insight with Inclusive Immunopharmacology Explication of Human Rotavirus A for the Treatment of Diarrhea 
Rotavirus is the most common cause of severe infant and childhood diarrhea worldwide, and the morbidity and mortality rate is going to be outnumbered in developing countries like Bangladesh. To mitigate this substantial burden of disease, new therapeutics such as vaccine and drug are swiftly required against rotavirus. The present therapeutics insight study was performed with comprehensive immunoinformatics and pharmacoinformatics approach. T and B-cell epitopes were assessed in the conserved region of outer capsid protein VP4 among the highly reviewed strains from different countries including Bangladesh. The results suggest that epitope SU1 (TLKNLNDNY) could be an ideal candidate among the predicted five epitopes for both T and B-cell epitopes for the development of universal vaccine against rotavirus. This research also suggests five novel drug compounds from medicinal plant Rhizophora mucronata Lamk. for better therapeutics strategies against rotavirus diarrhea based on 3D structure building, pharmacophore, ADMET, and QSAR properties. The exact mode of action between drug compounds and target protein VP4 were revealed by molecular docking analysis. Drug likeness and oral bioavailability further confirmed the effectiveness of the proposed drugs against rotavirus diarrhea. This study might be implemented for experimental validation to facilitate the novel vaccine and drug design.
PMCID: PMC4917548  PMID: 27445802
human rotavirus; diarrhea; pharmacoinformatics; immunoinformatics; vaccine design; drug development
16.  Biological Control of Rice Bakanae by an Endophytic Bacillus oryzicola YC7007 
The Plant Pathology Journal  2016;32(3):228-241.
In our previous study, we reported that a novel endophytic bacterium Bacillus oryzicola YC7007 has suppressed bacterial diseases of rice via induced systemic resistance and antibiotic production. This endophytic strain, B. oryzicola YC7007 was used as a biological control agent against bakanae disease of rice caused by Fusarium fujikuroi, and its mechanism of interaction with the pathogen and the rice was further elucidated. Root drenching with B. oryzicola YC7007 suspension reduced the disease severity of bakanae significantly when compared with the untreated controls. The treatments of B. oryzicola YC7007 suspension (2.0 × 107 cfu/ml) to the rice rhizosphere reduced bakanae severity by 46–78% in pots and nursery box tests containing autoclaved and non-autoclaved soils. Moreover, in the detached rice leaves bioassay, the development of necrotic lesion and mycelial expansion of F. fujikuroi were inhibited significantly by spraying the culture filtrate of B. oryzicola YC7007. Drenching of ethyl acetate extracts of the culture filtrate to the rhizosphere of rice seedlings also reduced the bakanae disease severity in the plant culture dish tests. With the root drenching of B. oryzicola YC7007 suspension, the accumulation of hydrogen peroxide was observed at an early stage of rice seedlings, and a hormonal defense was elicited with and without pathogen inoculation. Our results showed that the strain B. oryzicola YC7007 had a good biocontrol activity against the bakanae disease of rice by direct inhibition, and was also capable of inducing systemic resistance against the pathogen via primed induction of the jasmonic acid pathway.
PMCID: PMC4892819  PMID: 27298598
Bacillus oryzicola; biocontrol; induced systemic resistance; rice bakanae disease
17.  Design and Implementation of a Novel Compatible Encoding Scheme in the Time Domain for Image Sensor Communication 
This paper presents a modulation scheme in the time domain based on On-Off-Keying and proposes various compatible supports for different types of image sensors. The content of this article is a sub-proposal to the IEEE 802.15.7r1 Task Group (TG7r1) aimed at Optical Wireless Communication (OWC) using an image sensor as the receiver. The compatibility support is indispensable for Image Sensor Communications (ISC) because the rolling shutter image sensors currently available have different frame rates, shutter speeds, sampling rates, and resolutions. However, focusing on unidirectional communications (i.e., data broadcasting, beacons), an asynchronous communication prototype is also discussed in the paper. Due to the physical limitations associated with typical image sensors (including low and varying frame rates, long exposures, and low shutter speeds), the link speed performance is critically considered. Based on the practical measurement of camera response to modulated light, an operating frequency range is suggested along with the similar system architecture, decoding procedure, and algorithms. A significant feature of our novel data frame structure is that it can support both typical frame rate cameras (in the oversampling mode) as well as very low frame rate cameras (in the error detection mode for a camera whose frame rate is lower than the transmission packet rate). A high frame rate camera, i.e., no less than 20 fps, is supported in an oversampling mode in which a majority voting scheme for decoding data is applied. A low frame rate camera, i.e., when the frame rate drops to less than 20 fps at some certain time, is supported by an error detection mode in which any missing data sub-packet is detected in decoding and later corrected by external code. Numerical results and valuable analysis are also included to indicate the capability of the proposed schemes.
PMCID: PMC4883427  PMID: 27213396
IEEE 802.15.7r1; TG7r1; optical wireless communication (OWC); image sensor communication (ISC); unidirectional mode; asynchronous communication; LED-to-rolling shutter camera; high-speed link; frame rate variation; image sensors compatibility; oversampling mode; undersampling mode; majority voting scheme; error detection
18.  G6PD Deficiency and Antimalarial Efficacy for Uncomplicated Malaria in Bangladesh: A Prospective Observational Study 
PLoS ONE  2016;11(4):e0154015.
The Bangladeshi national treatment guidelines for uncomplicated malaria follow WHO recommendations but without G6PD testing prior to primaquine administration. A prospective observational study was conducted to assess the efficacy of the current antimalarial policy.
Patients with uncomplicated malaria, confirmed by microscopy, attending a health care facility in the Chittagong Hill Tracts, Bangladesh, were treated with artemether-lumefantrine (days 0–2) plus single dose primaquine (0.75mg/kg on day2) for P. falciparum infections, or with chloroquine (days 0–2) plus 14 days primaquine (3.5mg/kg total over 14 days) for P. vivax infections. Hb was measured on days 0, 2 and 9 in all patients and also on days 16 and 30 in patients with P. vivax infection. Participants were followed for 30 days. The study was registered with the clinical trials website (NCT02389374).
Between September 2014 and February 2015 a total of 181 patients were enrolled (64% P. falciparum, 30% P. vivax and 6% mixed infections). Median parasite clearance times were 22.0 (Interquartile Range, IQR: 15.2–27.3) hours for P. falciparum, 20.0 (IQR: 9.5–22.7) hours for P. vivax and 16.6 (IQR: 10.0–46.0) hours for mixed infections. All participants were afebrile within 48 hours, two patients with P. falciparum infection remained parasitemic at 48 hours. No patient had recurrent parasitaemia within 30 days. Adjusted male median G6PD activity was 7.82U/gHb. One male participant (1/174) had severe G6PD deficiency (<10% activity), five participants (5/174) had mild G6PD deficiency (10–60% activity). The Hb nadir occurred on day 2 prior to primaquine treatment in P. falciparum and P. vivax infected patients; mean fractional fall in Hb was -8.8% (95%CI -6.7% to -11.0%) and -7.4% (95%CI: -4.5 to -10.4%) respectively.
The current antimalarial policy remains effective. The prevalence of G6PD deficiency was low. Main contribution to haemolysis in G6PD normal individuals was attributable to acute malaria rather than primaquine administration.
Trial Registration NCT02389374
PMCID: PMC4851315  PMID: 27128675
19.  A novel class of piperidones exhibit potent, selective and pro-apoptotic anti-leukemia properties 
Oncology Letters  2016;11(6):3842-3848.
In the present pre-clinical study, a series of 1-[3-(2-methoxyethylthio)-propionyl]-3,5- bis(benzylidene)-4 piperidones and structurally-related compounds were observed to be cytotoxic in vitro to three human leukemia cell lines, namely Nalm-6, CEM and Jurkat. The 50% cytotoxic concentration (CC50) values of the three cell lines ranged between 0.9–126.4 µM and 0.3–11.7 µM at 24 and 48 h subsequent to exposure, respectively. The two lead compounds with sub-micromolar CC50 concentrations, 1-(2-methoxyethylthio-propionyl)-3,5-bis(benzylidene)-4 piperidone (2a) and 3,5-bis(4-fluorobenzylidene)-1-[3-(2-methoxyethyl sulfinyl)-propionyl]-4-piperidone (3e), were selected for additional analyses. Several strategies were undertaken to determine whether the above piperidones caused cell death via apoptosis or necrosis on T-lymphocyte leukemia Jurkat cells. The results revealed that the two piperidones caused phosphatidylserine externalization, mitochondrial depolarization and activation of caspase-3, which are all biochemical hallmarks of apoptosis. In addition, the selected piperidones displayed selective cytotoxicity towards leukemia cells, and were less toxic in non-cancerous control cells. Therefore, the findings of the present study revealed that the novel piperidones 2a and 3e exert a selective cytotoxic effect on lymphocyte leukemia cells by favoring the activation of the intrinsic/mitochondrial apoptotic pathway.
PMCID: PMC4888252  PMID: 27313705
apoptosis; leukemia; lymphoma; piperidone
20.  Critical Role of Autophagy in the Processing of Adenovirus Capsid-Incorporated Cancer-Specific Antigens 
PLoS ONE  2016;11(4):e0153814.
Adenoviruses are highly immunogenic and are being examined as potential vectors for immunotherapy. Infection by oncolytic adenovirus is followed by massive autophagy in cancer cells. Here, we hypothesize that autophagy regulates the processing of adenoviral proteins for antigen presentation. To test this hypothesis, we first examined the presentation of viral antigens by infected cells using an antibody cocktail of viral capsid proteins. We found that viral antigens were processed by JNK-mediated autophagy, and that autophagy was required for their presentation. Consistent with these results, splenocytes isolated from virus-immunized mice were activated by infected cells in an MHC II-dependent manner. We then hypothesize that this mechanism can be utilized to generate an efficient cancer vaccine. To this end, we constructed an oncolytic virus encompassing an EGFRvIII cancer-specific epitope in the adenoviral fiber. Infection of cancer cells with this fiber-modified adenovirus resulted in recognition of infected cancer cells by a specific anti-EGFRvIII antibody. However, inhibition of autophagy drastically decreased the capability of the specific antibody to detect the cancer-related epitope in infected cells. Our data suggest that combination of adenoviruses with autophagy inducers may enhance the processing and presentation of cancer-specific antigens incorporated into capsid proteins.
PMCID: PMC4836716  PMID: 27093696
21.  Effects of conventional immunosuppressive treatment on CD244+ (CD28null) and FOXP3+ T cells in the inflamed muscle of patients with polymyositis and dermatomyositis 
T-cell infiltrates may persist in muscle tissue of polymyositis (PM) and dermatomyositis (DM) patients despite aggressive immunosuppressive treatment. Here, we investigated to what extent persistent T cells in affected muscle were FOXP3+, a marker for regulatory T cells (Tregs), or CD244+, a marker for CD28null T cells, and whether their presence correlated to clinical outcome. The sensitivity of CD28null T cells towards glucocorticoid and Treg-mediated immunosuppression was also investigated.
Muscle biopsies from 16 newly diagnosed or untreated patients with PM/DM were investigated by immunohistochemistry for expression of CD3, FOXP3 and CD244 before and after treatment with glucocorticoids and immunosuppressive agents. For clinical evaluation, serum levels of creatine kinase, muscle performance (FI and MMT8), disease activity (MITAX) and disability (HAQ) were measured. In vitro suppressive effects of glucocorticoids and Tregs on T-cell activation were measured by CD69 upregulation.
Before treatment, CD244+ cells were present at higher proportions compared to FOXP3+ cells in the inflamed muscle. Following treatment, FOXP3+ cell numbers decreased while CD244+ cells persisted. Patients with impaired muscle function (<75 % FI) post-treatment had higher levels of CD244+ cells in the follow-up biopsy compared to those with FI >75 %. MITAX and HAQ correlated with the number of CD244+ cells post-treatment. CD4+CD28null T cells displayed lower sensitivity towards both glucocorticoid and Treg-mediated immunosuppression in vitro compared to their CD28+ counterparts.
Poor outcome in patients with myositis following immunosuppressive therapy was linked to persistence of CD244+ (CD28null) T cells in muscle tissue, suggesting their resistance against immunosuppression. A relative loss of regulatory T cells could also contribute to poor clinical outcome given their recently ascribed role in muscle tissue regeneration.
PMCID: PMC4818535  PMID: 27039301
T-lymphocyte; Myositis; Treg cells; Glucocorticoids; Inflammation
22.  TIE2-mediated tyrosine phosphorylation of H4 regulates DNA damage response by recruiting ABL1 
Science Advances  2016;2(4):e1501290.
Membrane-bound enzyme relocates to the cell nucleus to modify chromatin, inducing cancer resistance to radiotherapy.
DNA repair pathways enable cancer cells to survive DNA damage induced after genotoxic therapies. Tyrosine kinase receptors (TKRs) have been reported as regulators of the DNA repair machinery. TIE2 is a TKR overexpressed in human gliomas at levels that correlate with the degree of increasing malignancy. Following ionizing radiation, TIE2 translocates to the nucleus, conferring cells with an enhanced nonhomologous end-joining mechanism of DNA repair that results in a radioresistant phenotype. Nuclear TIE2 binds to key components of DNA repair and phosphorylates H4 at tyrosine 51, which, in turn, is recognized by the proto-oncogene ABL1, indicating a role for nuclear TIE2 as a sensor for genotoxic stress by action as a histone modifier. H4Y51 constitutes the first tyrosine phosphorylation of core histones recognized by ABL1, defining this histone modification as a direct signal to couple genotoxic stress with the DNA repair machinery.
PMCID: PMC5065225  PMID: 27757426
Cell biology; DNA repair; oncogenes; TIE2; ABL1; ANG1; NHEJ
23.  Soluble Tie2 overrides the heightened invasion induced by anti-angiogenesis therapies in gliomas 
Oncotarget  2016;7(13):16146-16157.
Glioblastoma recurrence after treatment with the anti–vascular endothelial growth factor (VEGF) agent bevacizumab is characterized by a highly infiltrative and malignant behavior that renders surgical excision and chemotherapy ineffective. Our group has previously reported that Tie2-expressing monocytes (TEMs) are aberrantly present at the tumor/normal brain interface after anti-VEGF therapies and their significant role in the invasive outgrowth of these tumors. Here, we aimed to further understand the mechanisms leading to this pro-invasive tumor microenvironment. Examination of a U87MG xenogeneic glioma model and a GL261 murine syngeneic model showed increased tumor expression of angiopoietin 2 (Ang2), a natural ligand of Tie2, after anti-angiogenesis therapies targeting VEGF or VEGF receptor (VEGFR), as assessed by immunohistochemical analysis, immunofluorescence analysis, and enzyme-linked immunosorbent assays of tumor lysates. Migration and gelatinolytic assays showed that Ang2 acts as both a chemoattractant of TEMs and an enhancing signal for their tumor-remodeling properties. Accordingly, in vivo transduction of Ang2 into intracranial gliomas increased recruitment of TEMs into the tumor. To reduce invasive tumor outgrowth after anti-angiogenesis therapy, we targeted the Ang-Tie2 axis using a Tie2 decoy receptor. Using syngeneic models, we observed that overexpression of soluble Tie2 within the tumor prevented the recruitment of TEMs to the tumor and the development of invasion after anti-angiogenesis treatment. Taken together, these data indicate an active role for the Ang2-Tie2 pathway in invasive glioma recurrence after anti-angiogenesis treatment and provide a rationale for testing the combined targeting of VEGF and Ang-Tie2 pathways in patients with glioblastoma.
PMCID: PMC4941303  PMID: 26910374
anti-angiogenesis; glioma; invasion; angiopoietin 2; Tie2-expressing monocytes
24.  Reference-Free Assessment of Speech Intelligibility Using Bispectrum of an Auditory Neurogram 
PLoS ONE  2016;11(3):e0150415.
Sensorineural hearing loss occurs due to damage to the inner and outer hair cells of the peripheral auditory system. Hearing loss can cause decreases in audibility, dynamic range, frequency and temporal resolution of the auditory system, and all of these effects are known to affect speech intelligibility. In this study, a new reference-free speech intelligibility metric is proposed using 2-D neurograms constructed from the output of a computational model of the auditory periphery. The responses of the auditory-nerve fibers with a wide range of characteristic frequencies were simulated to construct neurograms. The features of the neurograms were extracted using third-order statistics referred to as bispectrum. The phase coupling of neurogram bispectrum provides a unique insight for the presence (or deficit) of supra-threshold nonlinearities beyond audibility for listeners with normal hearing (or hearing loss). The speech intelligibility scores predicted by the proposed method were compared to the behavioral scores for listeners with normal hearing and hearing loss both in quiet and under noisy background conditions. The results were also compared to the performance of some existing methods. The predicted results showed a good fit with a small error suggesting that the subjective scores can be estimated reliably using the proposed neural-response-based metric. The proposed metric also had a wide dynamic range, and the predicted scores were well-separated as a function of hearing loss. The proposed metric successfully captures the effects of hearing loss and supra-threshold nonlinearities on speech intelligibility. This metric could be applied to evaluate the performance of various speech-processing algorithms designed for hearing aids and cochlear implants.
PMCID: PMC4788356  PMID: 26967160
25.  Plasmodium vivax Tryptophan Rich Antigen PvTRAg36.6 Interacts with PvETRAMP and PvTRAg56.6 Interacts with PvMSP7 during Erythrocytic Stages of the Parasite 
PLoS ONE  2016;11(3):e0151065.
Plasmodium vivax is most wide spread and a neglected malaria parasite. There is a lack of information on parasite biology of this species. Genome of this parasite encodes for the largest number of tryptophan-rich proteins belonging to ‘Pv-fam-a’ family and some of them are potential drug/vaccine targets but their functional role(s) largely remains unexplored. Using bacterial and yeast two hybrid systems, we have identified the interacting partners for two of the P. vivax tryptophan-rich antigens called PvTRAg36.6 and PvTRAg56.2. The PvTRAg36.6 interacts with early transcribed membrane protein (ETRAMP) of P.vivax. It is apically localized in merozoites but in early stages it is seen in parasite periphery suggesting its likely involvement in parasitophorous vacuole membrane (PVM) development or maintenance. On the other hand, PvTRAg56.2 interacts with P.vivax merozoite surface protein7 (PvMSP7) and is localized on merozoite surface. Co-localization of PvTRAg56.2 with PvMSP1 and its molecular interaction with PvMSP7 probably suggest that, PvTRAg56.2 is part of MSP-complex, and might assist or stabilize the protein complex at the merozoite surface. In conclusion, the PvTRAg proteins have different sub cellular localizations and specific associated functions during intra-erythrocytic developmental cycle.
PMCID: PMC4783080  PMID: 26954579

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