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1.  Ethnobotanical appraisal and cultural values of medicinally important wild edible vegetables of Lesser Himalayas-Pakistan 
Background
The association among food and health is momentous as consumers now demand healthy, tasty and natural functional foods. Knowledge of such food is mainly transmitted through the contribution of individuals of households. Throughout the world the traditions of using wild edible plants as food and medicine are at risk of disappearing, hence present appraisal was conducted to explore ethnomedicinal and cultural importance of wild edible vegetables used by the populace of Lesser Himalayas-Pakistan.
Methods
Data was collected through informed consent semi-structured interviews, questionnaires, market survey and focus group conversation with key respondents of the study sites including 45 female, 30 children and 25 males. Cultural significance of each species was calculated based on use report.
Results
A total of 45 wild edible vegetables belonging to 38 genera and 24 families were used for the treatment of various diseases and consumed. Asteraceae and Papilionoideae were found dominating families with (6 spp. each), followed by Amaranthaceae and Polygonaceae. Vegetables were cooked in water (51%) followed by diluted milk (42%) and both in water and diluted milk (7%). Leaves were among highly utilized plant parts (70%) in medicines followed by seeds (10%), roots (6%), latex (4%), bark, bulb, flowers, tubers and rhizomes (2% each). Modes of preparation fall into seven categories like paste (29%), decoction (24%), powder (14%), eaten fresh (12%), extract (10%), cooked vegetable (8%) and juice (4%). Ficus carica was found most cited species with in top ten vegetables followed by Ficus palmata, Bauhinia variegata, Solanum nigrum, Amaranthus viridis, Medicago polymorpha, Chenopodium album, Cichorium intybus, Amaranthus hybridus and Vicia faba.
Conclusions
Patterns of wild edible plant usage depend mainly on socio-economic factors compare to climatic conditions or wealth of flora but during past few decades have harshly eroded due to change in the life style of the inhabitants. Use reports verified common cultural heritage and cultural worth of quoted taxa is analogous. Phytochemical analysis, antioxidant activities, pharmacological applications; skill training in farming and biotechnological techniques to improve the yield are important feature prospective regarding of wild edible vegetables.
doi:10.1186/1746-4269-9-66
PMCID: PMC3853161  PMID: 24034131
Ethno-medicinal; Cultural values; Wild edible vegetables; Lesser Himalayas
2.  Irrational use of antimalarial drugs in rural areas of eastern Pakistan: a random field study 
BMC Public Health  2012;12:941.
Background
Prescription of antimalarial drugs in the absence of malarial disease is a common practice in countries where malaria is endemic. However, unwarranted use of such drugs can cause side effects in some people and is a financial drain on local economies. In this study, we surveyed the prevalence of malaria parasites in humans, and the prevalence of the malaria transmitting mosquito vectors in the study area. We also investigated the use of antimalarial drugs in the local people. We focused on randomly selected rural areas of eastern Pakistan where no malaria cases had been reported since May 2004.
Methods
Mass blood surveys, active case detection, passive case detection, and vector density surveys were carried out in selected areas of Sargodha district from September 2008 to August 2009. Data pertaining to the quantities and types of antimalarial drugs used in these areas were collected from health centers, pharmacies, and the district CDC program of the Health Department of the Government of the Punjab.
Results
Seven hundred and forty four blood samples were examined, resulting in a Blood Examination Rate (BER) of 3.18; microscopic analysis of blood smears showed that none of the samples were positive for malaria parasites. Investigation of the mosquito vector density in 43 living rooms (bedrooms or rooms used for sleeping), 23 stores, and 32 animal sheds, revealed no vectors capable of transmitting malaria in these locations. In contrast, the density of Culex mosquitoes was high. Substantial consumption of a variety of antimalarial tablets, syrups, capsules and injections costing around 1000 US$, was documented for the region.
Conclusion
Use of antimalarial drugs in the absence of malarial infection or the vectors that transmit the disease was common in the study area. Continuous use of such drugs, not only in Pakistan, but in other parts of the world, may lead to drug-induced side effects amongst users. Better training of health care professionals is needed to ensure accurate diagnoses of malaria and appropriate prescription of antimalarial drugs delivered to communities.
doi:10.1186/1471-2458-12-941
PMCID: PMC3577451  PMID: 23116148
Malaria; Plasmodium; Eastern Pakistan; Antimalarial drugs; Mosquito vectors; Diagnosis; Blood Examination Rate (BER)
3.  Hypofractionated Radiotherapy as Local Hemostatic Agent in Advanced Cancer 
Indian Journal of Palliative Care  2011;17(3):219-221.
Purpose:
Tumor bleeding continues to remain a challenge in an oncological setting, and radiotherapy has been studied as a local hemostatic agent. We studied the role of local radiotherapy in controlling bleeding at our center.
Materials and Methods:
We reviewed 25 treated cases (cancer urinary bladder: 12, lung cancer: 5, cervical cancer: 4, uterine cancer: 1, rectal cancer: 2, schwanoma: 1) at our center from March 2008 to December 2010. All patients had either an advanced or recurrent disease. Radiotherapy schedule was either 20 Gray in 5 fractions or 15 Gray in 5 fractions and was delivered with Cobalt 60.
Results and Conclusion:
Of 25 patients, 22 (88%) responded, and there was complete cessation of bleeding. Both 15 Gray and 20 Gray dose schedule had equal efficacy. Treatment was well tolerated without any intermission. Radiotherapy is a safe and effective option in controlling tumor bleeding.
doi:10.4103/0973-1075.92339
PMCID: PMC3276819  PMID: 22346046
Hemostasis; Hypofractionation; Radiotherapy
4.  Descriptive distribution and phylogenetic analysis of feline infectious peritonitis virus isolates of Malaysia 
The descriptive distribution and phylogeny of feline coronaviruses (FCoVs) were studied in cats suspected of having feline infectious peritonitis (FIP) in Malaysia. Ascitic fluids and/or biopsy samples were subjected to a reverse transcription polymerase chain reaction (RT-PCR) targeted for a conserved region of 3'untranslated region (3'UTR) of the FCoV genome. Eighty nine percent of the sampled animals were positive for the presence of FCoV. Among the FCoV positive cats, 80% of cats were males and 64% were below 2 years of age. The FCoV positive cases included 56% domestic short hair (DSH), 40% Persian, and 4% Siamese cats. The nucleotide sequences of 10 selected amplified products from FIP cases were determined. The sequence comparison revealed that the field isolates had 96% homology with a few point mutations. The extent of homology decreased to 93% when compared with reference strains. The overall branching pattern of phylogenetic tree showed two distinct clusters, where all Malaysian isolates fall into one main genetic cluster. These findings provided the first genetic information of FCoV in Malaysia.
doi:10.1186/1751-0147-52-1
PMCID: PMC2828449  PMID: 20053278
5.  Incidence of post myocardial infarction left ventricular thrombus formation in the era of primary percutaneous intervention and glycoprotein IIb/IIIa inhibitors. A prospective observational study 
Background
Before the widespread use of primary percutaneous coronary intervention (PCI) and glycoprotein IIb/IIIa inhibitors (GP IIb/IIIa) left ventricular (LV) thrombus formation had been reported to complicate up to 20% of acute myocardial infarctions (AMI). The incidence of LV thrombus formation with these treatment modalities is not well known.
Methods
92 consecutive patients with ST-elevation AMI treated with PCI and GP IIb/IIIa inhibitors underwent 2-D echocardiograms, with and without echo contrast agent, within 24–72 hours.
Results
Only 4/92 (4.3%) had an LV thrombus, representing a significantly lower incidence than that reported in the pre-PCI era. Use of contrast agents did not improve detection of LV thrombi in our study.
Conclusion
The incidence of LV thrombus formation after acute MI, in the current era of rapid reperfusion, is lower than what has been historically reported.
doi:10.1186/1476-7120-4-20
PMCID: PMC1458359  PMID: 16600036
6.  Lifting the Mask: Identification of New Small Molecule Inhibitors of Uropathogenic Escherichia coli Group 2 Capsule Biogenesis 
PLoS ONE  2014;9(7):e96054.
Uropathogenic Escherichia coli (UPEC) is the leading cause of community-acquired urinary tract infections (UTIs), with over 100 million UTIs occurring annually throughout the world. Increasing antimicrobial resistance among UPEC limits ambulatory care options, delays effective treatment, and may increase overall morbidity and mortality from complications such as urosepsis. The polysaccharide capsules of UPEC are an attractive target a therapeutic, based on their importance in defense against the host immune responses; however, the large number of antigenic types has limited their incorporation into vaccine development. The objective of this study was to identify small-molecule inhibitors of UPEC capsule biogenesis. A large-scale screening effort entailing 338,740 compounds was conducted in a cell-based, phenotypic screen for inhibition of capsule biogenesis in UPEC. The primary and concentration-response assays yielded 29 putative inhibitors of capsule biogenesis, of which 6 were selected for further studies. Secondary confirmatory assays identified two highly active agents, named DU003 and DU011, with 50% inhibitory concentrations of 1.0 µM and 0.69 µM, respectively. Confirmatory assays for capsular antigen and biochemical measurement of capsular sugars verified the inhibitory action of both compounds and demonstrated minimal toxicity and off-target effects. Serum sensitivity assays demonstrated that both compounds produced significant bacterial death upon exposure to active human serum. DU011 administration in mice provided near complete protection against a lethal systemic infection with the prototypic UPEC K1 isolate UTI89. This work has provided a conceptually new class of molecules to combat UPEC infection, and future studies will establish the molecular basis for their action along with efficacy in UTI and other UPEC infections.
doi:10.1371/journal.pone.0096054
PMCID: PMC4077706  PMID: 24983234
7.  Crosstalk Between Microtubule Attachment Complexes Ensures Accurate Chromosome Segregation* 
Science (New York, N.Y.)  2013;342(6163):10.1126/science.1246232.
The microtubule-based mitotic spindle segregates chromosomes during cell division. During chromosome segregation, the centromeric regions of chromosomes build kinetochores that establish end-coupled attachments to spindle microtubules. Here, we used the C. elegans embryo as a model system to examine the crosstalk between two kinetochore protein complexes implicated in temporally distinct stages of attachment formation. The kinetochore dynein module, which mediates initial lateral microtubule capture, inhibited microtubule binding by the Ndc80 complex, which ultimately forms the end-coupled attachments that segregate chromosomes. The kinetochore dynein module directly regulated Ndc80, independently of phosphorylation by Aurora B kinase, and this regulation was required for accurate segregation. Thus, the conversion from initial dynein-mediated, lateral attachments to correctly oriented, Ndc80-mediated end-coupled attachments is actively controlled.
doi:10.1126/science.1246232
PMCID: PMC3885540  PMID: 24231804
9.  Development of a DNA sensor using a molecular logic gate 
Journal of Biological Physics  2013;39(3):387-394.
This communication reports the increase in fluorescence resonance energy transfer (FRET) efficiency between two laser dyes in the presence of deoxyribonucleic acid (DNA). Two types of molecular logic gates have been designed where DNA acts as input signal and fluorescence intensity of different bands are taken as output signal. Use of these logic gates as a DNA sensor has been demonstrated.
doi:10.1007/s10867-012-9295-3
PMCID: PMC3689364  PMID: 23860915
FRET; DNA; Molecular logic gate; Sensor
10.  Aluminium Induced Endoplasmic Reticulum Stress Mediated Cell Death in SH-SY5Y Neuroblastoma Cell Line Is Independent of p53 
PLoS ONE  2014;9(5):e98409.
Aluminium (Al) is the third most abundant element in the earth’s crust and its compounds are used in the form of house hold utensils, medicines and in antiperspirant etc. Increasing number of evidences suggest the involvement of Al+3 ions in a variety of neurodegenerative disorders including Alzheimer’s disease. Here, we have attempted to investigate the role of Al in endoplasmic reticulum stress and the regulation of p53 during neuronal apoptosis using neuroblastoma cell line. We observed that Al caused oxidative stress by increasing ROS production and intracellular calcium levels together with depletion of intracellular GSH levels. We also studied modulation of key pro- and anti-apoptotic proteins and found significant alterations in the levels of Nrf2, NQO1, pAKT, p21, Bax, Bcl2, Aβ1-40 and Cyt c together with increase in endoplasmic reticulum (ER) stress related proteins like CHOP and caspase 12. However, with respect to the role of p53, we observed downregulation of its transcript as well as protein levels while analysis of its ubiquitination status revealed no significant changes. Not only did Al increase the activities of caspase 9, caspase 12 and caspase 3, but, by the use of peptide inhibitors of specific and pan-caspases, we observed significant protection against neuronal cell death upon inhibition of caspase 12, demonstrating the prominent role of endoplasmic reticulum stress generated responses in Al toxicity. Overall our findings suggest that Al induces ER stress and ROS generation which compromises the antioxidant defenses of neuronal cells thereby promoting neuronal apoptosis in p53 independent pathway.
doi:10.1371/journal.pone.0098409
PMCID: PMC4039480  PMID: 24878590
11.  Circularly Polarized S Band Dual Frequency Square Patch Antenna Using Glass Microfiber Reinforced PTFE Composite 
The Scientific World Journal  2014;2014:345190.
Circularly polarized (CP) dual frequency cross-shaped slotted patch antenna on 1.575 mm thick glass microfiber reinforced polytetrafluoroethylene (PTFE) composite material substrate is designed and fabricated for satellite applications. Asymmetric cross-shaped slots are embedded in the middle of the square patch for CP radiation and four hexagonal slots are etched on the four sides of the square patch for desired dual frequency. Different substrate materials have been analysed to achieve the desired operating band. The experimental results show that the impedance bandwidth is approximately 30 MHz (2.16 GHz to 2.19 GHz) for lower band and 40 MHz (3.29 GHz to 3.33 GHz) for higher band with an average peak gain of 6.59 dBiC and 5.52 dBiC, respectively. Several optimizations are performed to obtain the values of the antenna physical parameters. Moreover, the proposed antenna possesses compactness, light weight, simplicity, low cost, and circularly polarized. It is an attractive candidate for dual band satellite antennas where lower band can be used for uplink and upper band can be used for downlink.
doi:10.1155/2014/345190
PMCID: PMC4055630  PMID: 24982943
12.  Therapeutic Implications of Black Seed and Its Constituent Thymoquinone in the Prevention of Cancer through Inactivation and Activation of Molecular Pathways 
The cancer is probably the most dreaded disease in both men and women and also major health problem worldwide. Despite its high prevalence, the exact molecular mechanisms of the development and progression are not fully understood. The current chemotherapy/radiotherapy regime used to treat cancer shows adverse side effect and may alter gene functions. Natural products are generally safe, effective, and less expensive substitutes of anticancer chemotherapeutics. Based on previous studies of their potential therapeutic uses, Nigella sativa and its constituents may be proved as good therapeutic options in the prevention of cancer. Black seeds are used as staple food in the Middle Eastern Countries for thousands of years and also in the treatment of diseases. Earlier studies have shown that N. sativa and its constituent thymoquinone (TQ) have important roles in the prevention and treatment of cancer by modulating cell signaling pathways. In this review, we summarize the role of N. sativa and its constituents TQ in the prevention of cancer through the activation or inactivation of molecular cell signaling pathways.
doi:10.1155/2014/724658
PMCID: PMC4052177  PMID: 24959190
13.  9-Amino­acridin-10-ium 4-amino­benzo­ate dihydrate 
The asymmetric unit of the title hydrated salt, C13H11N2 +·C7H6NO2 −·2H2O, consists of two independent 9-amino­acridinium cations, two 4-amino­benzoate anions and four water mol­ecules. Both 9-amino­acridinium cations are essentially planar, with maximum deviations of 0.034 (1) and 0.025 (2) Å, and are protonated at the pyridine N atoms. The 4-amino­benzoate anions are approximately planar, with dihedral angles of 9.16 (19) and 5.4 (2)° between the benzene ring and the carboxyl­ate group. In the crystal, the two independent anions are connected by N—H⋯O hydrogen bonds, forming a layer parallel to (100). The layers are connected through the cations by N—H⋯N and N—H⋯O hydrogen bonds. The water mol­ecules, which form O—H⋯O hydrogen-bonded chains along the b-axis direction, connect the anions and the cations by O—H⋯O, N—H⋯O and C—H⋯O hydrogen bonds. The crystal structure also features π–π inter­actions [centroid–centroid distances = 3.6343 (9)–3.8366 (10) Å] and a C—H⋯π inter­action.
doi:10.1107/S160053681401023X
PMCID: PMC4051093  PMID: 24940241
14.  Direct Binding of SAS-6 to ZYG-1 Recruits SAS-6 to the Mother Centriole for Cartwheel Assembly 
Developmental cell  2013;25(3):284-298.
SUMMARY
Assembly of SAS-6 dimers to form the centriolar cartwheel requires the ZYG-1/Plk4 kinase. Here we show that ZYG-1 recruits SAS-6 to the mother centriole independently of its kinase activity; kinase activity is subsequently required for cartwheel assembly. We identify a direct interaction between ZYG-1 and the SAS-6 coiled-coil that explains its kinase activity-independent function in SAS-6 recruitment. Perturbing this interaction, or the interaction between an adjacent segment of the SAS-6 coiled-coil and SAS-5, prevented SAS-6 recruitment and cartwheel assembly. SAS-6 mutants with alanine substitutions in a previously described ZYG-1 target site or in 37 other residues, either phosphorylated by ZYG-1 in vitro or conserved in closely related nematodes, all supported cartwheel assembly. We propose that ZYG-1 binding to the SAS-6 coiled-coil recruits the SAS-6—SAS-5 complex to the mother centriole, where a ZYG-1 kinase activity-dependent step, whose target is unlikely to be SAS-6, triggers cartwheel assembly.
doi:10.1016/j.devcel.2013.03.011
PMCID: PMC3655416  PMID: 23673331
Centriole; Plk4; Centrosome; Mitosis; Spindle
15.  The midbody ring scaffolds the abscission machinery in the absence of midbody microtubules 
The Journal of Cell Biology  2013;203(3):505-520.
The septins, but not midbody microtubules, are important for daughter cell cytoplasmic isolation and ESCRT-dependent midbody ring release during abscission.
Abscission completes cytokinesis to form the two daughter cells. Although abscission could be organized from the inside out by the microtubule-based midbody or from the outside in by the contractile ring–derived midbody ring, it is assumed that midbody microtubules scaffold the abscission machinery. In this paper, we assess the contribution of midbody microtubules versus the midbody ring in the Caenorhabditis elegans embryo. We show that abscission occurs in two stages. First, the cytoplasm in the daughter cells becomes isolated, coincident with formation of the intercellular bridge; proper progression through this stage required the septins (a midbody ring component) but not the membrane-remodeling endosomal sorting complex required for transport (ESCRT) machinery. Second, the midbody and midbody ring are released into a specific daughter cell during the subsequent cell division; this stage required the septins and the ESCRT machinery. Surprisingly, midbody microtubules were dispensable for both stages. These results delineate distinct steps during abscission and highlight the central role of the midbody ring, rather than midbody microtubules, in their execution.
doi:10.1083/jcb.201306036
PMCID: PMC3824018  PMID: 24217623
16.  Agrobacterium-Mediated Transformation of Tomato with rolB Gene Results in Enhancement of Fruit Quality and Foliar Resistance against Fungal Pathogens 
PLoS ONE  2014;9(5):e96979.
Tomato (Solanum lycopersicum L.) is the second most important cultivated crop next to potato, worldwide. Tomato serves as an important source of antioxidants in human diet. Alternaria solani and Fusarium oxysporum cause early blight and vascular wilt of tomato, respectively, resulting in severe crop losses. The foremost objective of the present study was to generate transgenic tomato plants with rolB gene and evaluate its effect on plant morphology, nutritional contents, yield and resistance against fungal infection. Tomato cv. Rio Grande was transformed via Agrobacterium tumefaciens harbouring rolB gene of Agrobacterium rhizogenes. rolB. Biochemical analyses showed considerable improvement in nutritional quality of transgenic tomato fruits as indicated by 62% increase in lycopene content, 225% in ascorbic acid content, 58% in total phenolics and 26% in free radical scavenging activity. Furthermore, rolB gene significantly improved the defence response of leaves of transgenic plants against two pathogenic fungal strains A. solani and F. oxysporum. Contrarily, transformed plants exhibited altered morphology and reduced fruit yield. In conclusion, rolB gene from A. rhizogenes can be used to generate transgenic tomato with increased nutritional contents of fruits as well as improved foliar tolerance against fungal pathogens.
doi:10.1371/journal.pone.0096979
PMCID: PMC4016209  PMID: 24817272
17.  Quantitative ethnomedicinal study of plants used in the skardu valley at high altitude of Karakoram-Himalayan range, Pakistan 
Background
The tribal inhabitants of the Skardu valley (Pakistan) live in an area of great endemic botanic diversity. This paper presents the first quantitative ethnomedicinal spectrum of the valley and information on the uses of medicinal plant. This paper aims to analyze and catalogue such knowledge based on Relative Frequency Citation (RFC) and Use Value (UV) of medicinal plants in addition to the configuration of the Pearson correlation coefficient.
Methods
The field study was carried out over a period of approximately 2 years (2011–2013) using semi-structured interviews with 71 informants (most of the informants belonged to an age between 50 and 70 years) in six remote locations in the valley. Ethnomedicinal data was analyzed using frequency citation (FC), relative frequency of citation (RFC) and use value (UV) along with a Pearson correlation coefficient (PCC). Demographic characteristics of participants, ethnobotanical inventory of plants and data on medicinal application and administration were recorded.
Results
A total of 50 medicinal plants belonging to 25 families were reported to be used against 33 different ailments in the valley. The maximum reported medicinal plant families were Asteraceae (7 report species), Lamiaceae (6) , Polygonaceae (4) and Rosaceae (4), the most dominant life form of the species includes herbs (38) followed by shrubs and subshrubs (12), the most frequent used part was leaves (41%) followed by root (26%), flower (14%), fruit (9%), seeds (8%), bulb (1%) and bark (1%), the most common preparation and administration methods were infusion (32%), decoction (26%), paste (18%), herbal juice (17%) and powder drug (7%). The Pearson correlation coefficient between RFC and UV was 0.732 showing highly positive significant association.
Conclusions
In this study, we have documented considerable indigenous knowledge about the native medicinal plants in Skardu valley for treating common ailments which are ready to be further investigated phytochemically and pharmacologically which leads to natural drug discovery development. The study has various socioeconomic dimensions which are associated with the local communities.
doi:10.1186/1746-4269-10-43
PMCID: PMC4039317  PMID: 24885937
Quantitative ethnobotany; Medicinal plants; Skardu valley; Northern Pakistan
18.  Mlh2 Is an Accessory Factor for DNA Mismatch Repair in Saccharomyces cerevisiae 
PLoS Genetics  2014;10(5):e1004327.
In Saccharomyces cerevisiae, the essential mismatch repair (MMR) endonuclease Mlh1-Pms1 forms foci promoted by Msh2-Msh6 or Msh2-Msh3 in response to mispaired bases. Here we analyzed the Mlh1-Mlh2 complex, whose role in MMR has been unclear. Mlh1-Mlh2 formed foci that often colocalized with and had a longer lifetime than Mlh1-Pms1 foci. Mlh1-Mlh2 foci were similar to Mlh1-Pms1 foci: they required mispair recognition by Msh2-Msh6, increased in response to increased mispairs or downstream defects in MMR, and formed after induction of DNA damage by phleomycin but not double-stranded breaks by I-SceI. Mlh1-Mlh2 could be recruited to mispair-containing DNA in vitro by either Msh2-Msh6 or Msh2-Msh3. Deletion of MLH2 caused a synergistic increase in mutation rate in combination with deletion of MSH6 or reduced expression of Pms1. Phylogenetic analysis demonstrated that the S. cerevisiae Mlh2 protein and the mammalian PMS1 protein are homologs. These results support a hypothesis that Mlh1-Mlh2 is a non-essential accessory factor that acts to enhance the activity of Mlh1-Pms1.
Author Summary
Lynch syndrome (hereditary nonpolyposis colorectal cancer or HNPCC) is a common cancer predisposition syndrome. In this syndrome, predisposition to cancer results from increased accumulation of mutations due to defective mismatch repair (MMR) caused by a mutation in one of the human mismatch repair genes MLH1, MSH2, MSH6 or PMS2. In addition to these genes, various DNA replication factors and the excision factor EXO1 function in the repair of damaged DNA by the MMR pathway. In Saccharomyces cerevisiae, the MLH2 gene encodes a MutL homolog protein whose role in DNA mismatch repair has been unclear. Here, we used phylogenetic analysis to demonstrate that the S. cerevisiae Mlh2 protein and the mammalian Pms1 protein are homologs. A combination of genetics, biochemistry and imaging studies were used to demonstrate that the Mlh1-Mlh2 complex is recruited to mispair-containing DNA by the Msh2-Msh6 and Msh2-Msh3 mispair recognition complexes where it forms foci that colocalize with Mlh1-Pms1 foci (note that scPms1 is the homolog of hPms2) and augments the function of the Mlh1-Pms1 complex. Thus, this work establishes the Mlh1-Mlh2 complex as a non-essential accessory factor that functions in MMR.
doi:10.1371/journal.pgen.1004327
PMCID: PMC4014439  PMID: 24811092
19.  Preterm birth, infant weight gain, and childhood asthma risk: A meta-analysis of 147,000 European children 
Background
Preterm birth, low birth weight, and infant catch-up growth seem associated with an increased risk of respiratory diseases in later life, but individual studies showed conflicting results.
Objectives
We performed an individual participant data meta-analysis for 147,252 children of 31 birth cohort studies to determine the associations of birth and infant growth characteristics with the risks of preschool wheezing (1-4 years) and school-age asthma (5-10 years).
Methods
First, we performed an adjusted 1-stage random-effect meta-analysis to assess the combined associations of gestational age, birth weight, and infant weight gain with childhood asthma. Second, we performed an adjusted 2-stage random-effect meta-analysis to assess the associations of preterm birth (gestational age <37 weeks) and low birth weight (<2500 g) with childhood asthma outcomes.
Results
Younger gestational age at birth and higher infant weight gain were independently associated with higher risks of preschool wheezing and school-age asthma (P < .05). The inverse associations of birth weight with childhood asthma were explained by gestational age at birth. Compared with term-born children with normal infant weight gain, we observed the highest risks of school-age asthma in children born preterm with high infant weight gain (odds ratio [OR], 4.47; 95% CI, 2.58-7.76). Preterm birth was positively associated with an increased risk of preschool wheezing (pooled odds ratio [pOR], 1.34; 95% CI, 1.25-1.43) and school-age asthma (pOR, 1.40; 95% CI, 1.18-1.67) independent of birth weight. Weaker effect estimates were observed for the associations of low birth weight adjusted for gestational age at birth with preschool wheezing (pOR, 1.10; 95% CI, 1.00-1.21) and school-age asthma (pOR, 1.13; 95% CI, 1.01-1.27).
Conclusion
Younger gestational age at birth and higher infant weight gain were associated with childhood asthma outcomes. The associations of lower birth weight with childhood asthma were largely explained by gestational age at birth.
doi:10.1016/j.jaci.2013.12.1082
PMCID: PMC4024198  PMID: 24529685
Gestational age; low birth weight; infant growth; wheezing; asthma; children; cohort studies; epidemiology; BMI, Body mass index; ISAAC, International Study on Asthma and Allergy in Childhood; OR, Odds ratio; pOR, Pooled odds ratio; SDS, Standard deviation scores
20.  Treatment with Thyroxine Restores Myelination and Clinical Recovery after Intraventricular Hemorrhage 
The Journal of Neuroscience  2013;33(44):17232-17246.
Intraventricular hemorrhage (IVH) remains a major cause of white matter injury in preterm infants with no viable therapeutic strategy to restore myelination. Maturation of oligodendrocytes and myelination is influenced by thyroid hormone (TH) signaling, which is mediated by TH receptor α (TRα) and TRβ. In the brain, cellular levels of TH are regulated by deiodinases, with deiodinase-2 mediating TH activation and deiodinase-3 TH inactivation. Therefore, we hypothesized that IVH would decrease TH signaling via changes in the expression of deiodinases and/or TRs, and normalization of TH signaling would enhance maturation of oligodendrocytes and myelination in preterm infants with IVH. These hypotheses were tested using both autopsy materials from human preterm infants and a rabbit model of IVH. We found that deiodinase-2 levels were reduced, whereas deiodinase-3 levels were increased in brain samples of both humans and rabbits with IVH compared with controls without IVH. TRα expression was also increased in human infants with IVH. Importantly, treatment with TH accelerated the proliferation and maturation of oligodendrocytes, increased transcription of Olig2 and Sox10 genes, augmented myelination, and restored neurological function in pups with IVH. Consistent with these findings, the density of myelinating oligodendrocytes was almost doubled in TH-treated human preterm infants compared with controls. Thus, in infants with IVH the combined elevation in deiodinase-3 and reduction in deiodinase-2 decreases TH signaling that can be worsened by an increase in unliganded TRα. Given that TH promotes neurological recovery in IVH, TH treatment might improve the neurodevelopmental outcome of preterm infants with IVH.
doi:10.1523/JNEUROSCI.2713-13.2013
PMCID: PMC3812500  PMID: 24174657
21.  Gain Enhancement of a Multiband Resonator Using Defected Ground Surface on Epoxy Woven Glass Material 
The Scientific World Journal  2014;2014:159468.
A multiband microstrip resonator is proposed in this study which is realized through a rectangular radiator with embedded symmetrical rectangular slots in it and a defected ground surface. The study is presented with detailed parametric analyses to understand the effect of various design parameters. The design and analyses are performed using the FIT based full-wave electromagnetic simulator CST microwave studio suite. With selected parameter values, the resonator showed a peak gain of 5.85 dBi at 5.2 GHz, 6.2 dBi at 8.3 GHz, 3.9 dBi at 9.5 GHz, 5.9 dBi at 12.2 GHz, and 4.7 dBi at 14.6 GHz. Meanwhile, the main lobe magnitude and the 3 dB angular beam width are 6.2 dBi and 86°, 5.9 dBi and 53.7°, 8.5 dBi and 43.9°, 8.6 dBi and 42.1°, and 4.7 dBi and 30.1°, respectively, at the resonant frequencies. The overall resonator has a compact dimension of 0.52λ  × 0.52λ  × 0.027λ at the lower resonant frequency. For practical validation, a lab prototype was built on a 1.6 mm thick epoxide woven glass fabric dielectric material which is measured using a vector network analyzer and within an anechoic chamber. The comparison between the simulated and measured results showed a very good understanding, which implies the practical suitability of the proposed multiband resonator design.
doi:10.1155/2014/159468
PMCID: PMC4030505  PMID: 24883354
22.  Impact of Hypertension on the Association of BMI with Risk and Age at Onset of Type 2 Diabetes Mellitus: Age- and Gender-Mediated Modifications 
PLoS ONE  2014;9(4):e95308.
Aims
Given that BMI correlates with risk of Type 2 diabetes mellitus (T2DM), and that hypertension is a common comorbid condition, we hypothesize that hypertension augments significantly the impact of obesity on T2DM onset.
Methods
We obtained data on T2DM in Kuwaiti natives from Kuwait Health Network Registry. We considered 1339 comorbid individuals with onset of hypertension preceding that of T2DM, and 3496 non-hypertensive individuals but with T2DM. Multiple linear regressions, ANOVA tests, and Cox proportional hazards models were used to quantify the impact of hypertension on correlation of BMI with age at onset and risk of T2DM.
Results
Impact of increasing levels of BMI on age at onset ot T2DM is seen augmented in patients diagnosed with hypertension. We find that the slope of the inverse linear relationship between BMI and onset age of T2DM is much steep in hypertensive patients (−0.69, males and −0.39, females) than in non-hypertensive patients (−0.36, males and −0.17, females). The decline in onset age for an unit increase of BMI is two-fold in males than in females. Upon considering BMI as a categorical variable, we find that while the mean onset age of T2DM in hypertensive patients decreases by as much as 5–12 years in every higher BMI categories, significant decrease in non-hypertensive patients exists only when severely obese. Hazard due to hypertension (against the baseline of non-hypertension and normal weight) increases at least two-fold in every obese category. While males have higher hazard due to hypertension in early adulthood, females have higher hazard in late adulthood.
Conclusion
Pre-existing condition of hypertension augments the association of BMI with Type 2 diabetes onset in both males and females. The presented results provide health professionals directives on the extent of weight-loss required to delay onset of Type 2 diabetes in hypertensive versus non-hypertensive patients.
doi:10.1371/journal.pone.0095308
PMCID: PMC3990699  PMID: 24743162
23.  What the Hec is up with Mouse Oocyte Meiosis? 
Developmental cell  2013;25(1):3-4.
In this issue of Developmental Cell, Gui and Homer (2013) report that the proper execution of meiosis I in mouse oocytes requires the stabilization of cyclin B2 by the kinetochore protein Hec1, revealing unanticipated functions for both proteins.
doi:10.1016/j.devcel.2013.03.018
PMCID: PMC3804012  PMID: 23597481
24.  Oxygen Limitation within a Bacterial Aggregate 
mBio  2014;5(2):e00992-14.
ABSTRACT
Cells within biofilms exhibit physiological heterogeneity, in part because of chemical gradients existing within these spatially structured communities. Previous work has examined how chemical gradients develop in large biofilms containing >108 cells. However, many bacterial communities in nature are composed of small, densely packed aggregates of cells (≤105 bacteria). Using a gelatin-based three-dimensional (3D) printing strategy, we confined the bacterium Pseudomonas aeruginosa within picoliter-sized 3D “microtraps” that are permeable to nutrients, waste products, and other bioactive small molecules. We show that as a single bacterium grows into a maximally dense (1012 cells ml−1) clonal population, a localized depletion of oxygen develops when it reaches a critical aggregate size of ~55 pl. Collectively, these data demonstrate that chemical and phenotypic heterogeneity exists on the micrometer scale within small aggregate populations.
IMPORTANCE
Before developing into large, complex communities, microbes initially cluster into aggregates, and it is unclear if chemical heterogeneity exists in these ubiquitous micrometer-scale aggregates. We chose to examine oxygen availability within an aggregate since oxygen concentration impacts a number of important bacterial processes, including metabolism, social behaviors, virulence, and antibiotic resistance. By determining that oxygen availability can vary within aggregates containing ≤105 bacteria, we establish that physiological heterogeneity exists within P. aeruginosa aggregates, suggesting that such heterogeneity frequently exists in many naturally occurring small populations.
doi:10.1128/mBio.00992-14
PMCID: PMC3994514  PMID: 24736225
25.  The interplay of DNA methylation over time with Th2 pathway genetic variants on asthma risk and temporal asthma transition 
Clinical Epigenetics  2014;6(1):8.
Background
Genetic effects on asthma of genes in the T-helper 2 (Th2) pathway may interact with epigenetic factors including DNA methylation. We hypothesized that interactions between genetic variants and methylation in genes in this pathway (IL4, IL4R, IL13, GATA3, and STAT6) influence asthma risk, that such influences are age-dependent, and that methylation of some CpG sites changes over time in accordance with asthma transition. We tested these hypotheses in subsamples of girls from a population-based birth cohort established on the Isle of Wight, UK, in 1989.
Results
Logistic regression models were applied to test the interaction effect of DNA methylation and SNP on asthma within each of the five genes. Bootstrapping was used to assess the models identified. From 1,361 models fitted at each age of 10 and 18 years, 8 models, including 4 CpGs and 8 SNPs, showed potential associations with asthma risk. Of the 4 CpGs, methylation of cg26937798 (IL4R) and cg23943829 (IL4) changes between ages 10 and 18 (both higher at 10; P = 9.14 × 10−6 and 1.07 × 10−5, respectively).
At age 10, the odds of asthma tended to decrease as cg12405139 (GATA3) methylation increased (log-OR = −12.15; P = 0.049); this effect disappeared by age 18. At age 18, methylation of cg09791102 (IL4R) was associated with higher risk of asthma among subjects with genotype GG compared to AG (P = 0.003), increased cg26937798 methylation among subjects with rs3024685 (IL4R) genotype AA (P = 0.003) or rs8832 (IL4R) genotype GG (P = 0.01) was associated with a lower asthma risk; these CpGs had no effect at age 10. Increasing cg26937798 methylation over time possibly reduced the risk of positive asthma transition (asthma-free at age 10 → asthma at age 18; log-OR = −3.11; P = 0.069) and increased the likelihood of negative transition (asthma at age 10 → asthma-free at age 18; log-OR = 3.97; P = 0.074).
Conclusions
The interaction of DNA methylation and SNPs in Th2 pathway genes is likely to contribute to asthma risk. This effect may vary with age. Methylation of some CpGs changed over time, which may influence asthma transition.
doi:10.1186/1868-7083-6-8
PMCID: PMC4023182  PMID: 24735657
Asthma risk; Asthma transition; DNA methylation and SNP interaction; Th2 pathway

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