Germinal center activity and B cell maturation are associated with protective antibody responses against Plasmodium pre-erythrocytic infection.

Blocking Plasmodium, the causative agent of malaria, at the asymptomatic pre-erythrocytic stage would abrogate disease pathology and prevent transmission. However, the lack of well-defined features within vaccine-elicited antibody responses that correlate with protection represents a major roadblock to improving on current generation vaccines. We vaccinated mice (BALB/cJ and C57BL/6J) with Py circumsporozoite protein (CSP), the major surface antigen on the sporozoite, and evaluated vaccine-elicited humoral immunity and identified immunological factors associated with protection after mosquito bite challenge. Vaccination achieved 60% sterile protection and otherwise delayed blood stage patency in BALB/cJ mice. In contrast, all C57BL/6J mice were infected similar to controls. Protection was mediated by antibodies and could be passively transferred from immunized BALB/cJ mice into naïve C57BL/6J. Dissection of the underlying immunological features of protection revealed early deficits in antibody titers and polyclonal avidity in C57BL/6J mice. Additionally, PyCSP-vaccination in BALB/cJ induced a significantly higher proportion of antigen-specific B-cells and class-switched memory B-cell (MBCs) populations than in C57BL/6J mice. Strikingly, C57BL/6J mice also had markedly fewer CSP-specific germinal center experienced B cells and class-switched MBCs compared to BALB/cJ mice. Analysis of the IgG γ chain repertoires by next generation sequencing in PyCSP-specific memory B-cell repertoires also revealed higher somatic hypermutation rates in BALB/cJ mice than in C57BL/6J mice. These findings indicate that the development of protective antibody responses in BALB/cJ mice in response to vaccination with PyCSP was associated with increased germinal center activity and somatic mutation compared to C57BL/6J mice, highlighting the key role B cell maturation may have in the development of vaccine-elicited protective antibodies against CSP.

Socioeconomic inequality among smoking and smokeless tobacco uses among males in India: a decomposition analysis.

OBJECTIVE: India is the third-largest tobacco manufacturer and its use in India is characterised by a high prevalence of smoking and smokeless (sl) tobacco use. This results in 1 million deaths per year in the country. Given the high burden of tobacco use, this study examines the regional variations and socio-economic correlates of tobacco use in India. METHODS: National Family Health Survey- 5 (2019-2020) have been analysed for the purpose of the study. A sample of 101,839 males aged 15-54 years was included in this study. Primary outcomes of tobacco use were categorised into smoking, smokeless and dual use of smoking and smokeless tobacco use. Bivariate analysis and decomposition analysis was done to study the socio-economic inequality. RESULTS: The prevalence of tobacco use among males in India is around 41 percent. As indicated by the results of the logistics regression, age is positively related to smoking among males. Males aged 45-54 years are 2.5 (95 % concentration index [CI]:2.30-2.63) times probable to smoke, 1.4 (95% CI: 1.30-1.47) times probable of smokeless tobacco consumption and 2.2 (95% CI: 2.10-2.35) times more prone to using both types of substances compared to the younger age group. Males who are widower use smokeless 1.69 times (95% CI: 1.44-1.99) higher with reference to unmarried males. Males belonging to Scheduled tribes are 1.2 (95% CI: 1.13-1.25) times more likely to smoke, 1.3 (95% CI: 1.24-1.37) times more likely to use smokeless substances and 1.4 (95% CI: 1.33-1.47) times more likely to have dual use of tobacco than other social groups. Manual workers (both skilled are unskilled) are likely to smoke (odds ratio [OR] = 1.1, 95% CI: 1.02-1.11), use smokeless tobacco (OR = 1.3, 95% CI: 1.23-1.34) and have dual use of tobacco (OR = 1.29, 95% CI: 1.24-1.34) more than that of other categories. The decomposition of the concentration index shows a significant contribution from factors like a no education, ST/SC caste and wealth index. Among the states and union territories, the prevalence of tobacco is high in West Bengal, Tripura, Mizoram, Manipur, Meghalaya and Sikkim. CONCLUSION: This study is useful for informing target-based prevention policies since it helps in highlighting regions, socio-economic and demographic groups especially vulnerable to tobacco addiction. In India, males from poorer and vulnerable socio-economic backgrounds are more likely to use tobacco. State wise, the eastern zone starting from West Bengal to the North-Eastern states have higher tobacco use than the rest of the country. There is an urgent need to frame policies for controlling the use of tobacco especially among high-risk groups.

Excited-State Charge Transfer in Push-Pull Platinum(II) π-Extended Porphyrins Fused with Pentacenequinone.

Platinum(II) π-extended porphyrins fused with pentacenequinone and dihydropentacene have been successfully synthesized. These porphyrins were investigated using various techniques including absorption, steady-state, and time-resolved phosphorescence spectroscopy and differential pulse voltammetry. UV-vis absorption spectra of pentacenequinone-fused porphyrins (SW-Pt1 and SW-Pt2) showed unusually broad and nontypical absorption patterns. Phosphorescence spectra of SW-Pt1, SW-Pt2, and SW-Pt3 displayed similar emissions in the 704-706 nm region indicating electronic transitions of similar origin; however, the triplet lifetimes were found to be quenched in the case of both SW-Pt1 and SW-Pt2, suggesting the occurrence of excited-state events. Facile reductions were obtained for both the pentacene-quinone-fused monomer (SW-Pt2) and dimer (SW-Pt1) and were identified to be located at the pentacenequinone components. The observed orbital segregations for SW-Pt2 and SW-Pt1 from DFT calculations supported the possibility of charge transfer in these push-pull systems. Interestingly, the established energy level diagram revealed that the charge transfer from the triplet excited Pt porphyrin is thermodynamically an uphill process. Systematic studies involving both femtosecond and nanosecond transient absorption techniques revealed that the singlet excited Pt porphyrins undergo an intermediate charge transfer state prior to populating the triplet state, providing a plausible explanation for phosphorescence quenching. The lifetime of the intermediate charge transfer states was found to be 25.9 and 5.68 ps, respectively, for SW-Pt1 and SW-Pt2.

Intramolecular Photoinduced Energy and Electron Transfer Reactions in Phenanthroimidazole-Boron Dipyromethane Donor-Acceptor Dyads.

Donor-acceptor systems in which a donor phenanthroimidazole (PhI) is directly connected to a BODIPY acceptor (Dyad1) and separated by an ethynyl bridge between PhI and BODIPY (Dyad2) have been designed, synthesized, and characterized by various spectroscopic and electrochemical techniques. Optical absorption and 1H NMR characteristics of both dyads with those of constituent individuals suggest that there exists a minimum π-π interaction between phenanthroimidazole and BODIPY. Quenched emission of both the dyads was observed when excited either at phenthaoimidazole absorption maxima or at BODIPY absorption maxima in all three investigated solvents. The detailed spectral analysis provided evidence for an intramolecular photoinduced excitation energy transfer (PEnT) from the singlet excited state of phenanthroimidazole to BODIPY and photoinduced electron transfer (PET) from the ground state of phenanthroimidazole to BODIPY. Transient absorption studies suggest that charge-separated species (PhI•+ - BODIPY•-) are generated at a rate constant of (1.16 ± 0.01) × 108 s-1 for the dyads Dyad1 and (5.15 ± 0.03) × 108 s-1 and for Dyad2 whereas energy transfer rate constants were much higher and were on the order of (1.1 ± 0.02) × 1010 s-1 and (1.6 ± 0.02) × 1010 s-1 for Dyad1 and Dyad2, respectively, signifying their usefulness in light energy harvesting applications.

π-Extended Pyrazinepyrene-Fused Zinc Phthalocyanines: Synthesis and Excited-State Charge Separation Involving Coordinated C60.

A series of pyrazinepyrene-fused zinc phthalocyanines (ZnPc-Pyrn) have been newly synthesized by reacting quinoxaline and the corresponding diamino-functionalized phthalocyanines as a new class of π-extended phthalocyanine systems. Bathochromically shifted absorption as a function of the number of pyrazinepyrene entities due to extended π-conjugation and quenched fluorescence due to the presence of fused pyrazinepyrene were witnessed. The electronic structures of these phthalocyanines were probed by systematic computational and electrochemical studies, while the excited-state properties were examined by pump-probe spectroscopies operating at the femto- and nanosecond time scales. Similar to the excited singlet lifetimes, the excited triplet states also revealed diminished lifetimes with an increased number of pyrazinepyrene entities. Further, the coordinatively unsaturated zinc in these molecules was coordinated with phenyl imidazole-functionalized fullerene, ImC60, to form a new series of donor-acceptor conjugates. Upon full characterization of these conjugates, the occurrence of excited-state charge separation was established by transient pump-probe spectroscopy, covering wide temporal and spatial regions. The lifetime of the final charge-separated states was ∼2 ns and decreased with an increase in the number of fused pyrazinepyrene units.

Stage-specific differential expression of zinc transporter SLC30A and SLC39A family proteins during prostate tumorigenesis.

Prostate cancer (PCa) initiation and progression uniquely modify the prostate milieu to aid unrestrained cell proliferation. One salient modification is the loss of the ability of prostate epithelial cells to accumulate high concentrations of zinc; however, molecular alterations associated with loss of zinc accumulating capability in malignant prostate cells remain poorly understood. Herein, we assessed the stage-specific expression of zinc transporters (ZNTs) belonging to the ZNT (SLC30A) and Zrt- and Irt-like protein (ZIP) (SLC39A) solute-carrier family in the prostate tissues of different genetically engineered mouse models (GEMM) of PCa (TMPRSS2-ERG.Ptenflox/flox , Hi-Myc+/- , and transgenic adenocarcinoma of mouse prostate), their age-matched wild-type controls, and 104 prostate core biopsies from human patients with different pathological lesions. Employing immunohistochemistry, differences in the levels of protein expression and spatial distribution of ZNT were evaluated as a function of the tumor stage. Results indicated that the expression of zinc importers (ZIP1, ZIP2, and ZIP3), which function to sequester zinc from circulation and prostatic fluid, was low to negligible in the membranes of the malignant prostate cells in both GEMM and human prostate tissues. Regarding zinc exporters (ZNT1, ZNT2, ZNT9, and ZNT10) that export excess zinc into the extracellular spaces or intracellular organelles, their expression was low in normal prostate glands of mice and humans; however, it was significantly upregulated in prostate adenocarcinoma lesions in GEMM and PCa patients. Together, our findings provide new insights into altered expression of ZNTs during the progression of PCa and indicate that changes in zinc homeostasis could possibly be an early-initiation event during prostate tumorigenesis and a likely prevention/intervention target.

Characterization of stage-specific tumor progression in TMPRSS2-ERG (fusion)-driven and non-fusion-driven prostate cancer in GEM models.

In the present study, we performed a comparative stage-specific pathological and molecular marker evaluation of TMPRSS2-ERG fusion and PTEN loss-driven (TMPRSS2-ERG. Ptenflox/flox ) versus non-fusion-driven prostate tumorigenesis (Hi-Myc) in mice. Anterior, ventral, and dorsolateral prostates were collected from mice at different ages (or time points post-Cre induction). Results indicated that growth and progression of prostatic intraepithelial lesions to adenocarcinoma stages occurred in both mice models albeit at different rates. In the TMPRSS2-ERG. Ptenflox/flox mice, the initiation of tumorigenesis was slow, but subsequent progression through different stages became increasingly faster. Adenocarcinoma stage was reached early on; however, no high-grade undifferentiated tumors were observed. Conversely, in the Hi-Myc+/- mice, tumorigenesis initiation was rapid; however, progression through different stages was relatively slower and it took a while to reach the more aggressive phenotype stage. Nevertheless, at the advanced stages in the Hi-Myc+/- mice, high-grade undifferentiated tumors were observed compared to the later stage tumors observed in the fusion-driven TMPRSS2-ERG. Ptenflox/flox mice. These results were corroborated by the stage specific-pattern in the molecular expression of proliferation markers (PCNA and c-Myc); androgen receptor (AR); fusion-resultant overexpression of ERG; Prostein (SLC45-A3); and angiogenesis marker (CD-31). Importantly, there was a significant increase in immune cell infiltrations, which increased with the stage of tumorigenesis, in the TMPRSS2-ERG fusion-positive tumors relative to fusion negative tumors. Together, these findings are both novel and highly significant in establishing a working preclinical model for evaluating the efficacy of interventions during different stages of tumorigenesis in TMPRSS2-ERG fusion-driven PCa.

Mechanisms and kinetics for the degradation of paclobutrazol and biocontrol action of a novel Pseudomonas putida strain T7.

The present study explores biodegradation kinetics and process optimization of plant growth retardant from triazole group paclobutrazol (PBZ; C15H20ClN3O mol. wt. 293.79 g mol-1) in a batch experiment. A gram-negative rod-shaped bacterium T7 was isolated from PBZ applied agricultural field by enrichment technique and characterized as Pseudomonas putida strain T7. Strain was tested for PBZ biodegradation and plant growth-promoting characteristics. Results revealed that strain T7 utilizes PBZ as a carbon and energy source and showing degradation up to 98.30% on the 15th day. First-order degradation kinetics and a linear model were well fitted and showing a maximum t1/2 value on 9th day. Biodegradation optimization by Box Behnken design (BBD) of Response surface methodology (RSM) showed maximum degradation at pH 7.0, 31 °C temperature, and 2 mL inoculum size (8 × 109 CFU mL-1). The bacterium was also able to solubilize Zn, K, and PO4 and produced a copious amount of IAA, HCN, and Ammonia. The biocontrol activity against plant pathogens like Fusarium oxysporum (MTCC-284), Colletotrichum gloeosporioides (MTCC 2190), Pythium aphanidermatum (MTCC - 1024), Tropical race-1 (TR -1), and Tropical race - 4 (TR-4) showed the great antagonistic effect. Hence, this strain can be employed as an effective bio-agent for eco-friendly cleanup strategies and pathogen suppressive agents in paclobutrazol contaminated soil.

Total body skeletal muscle mass estimated by magnetic resonance imaging and creatine (methyl-d3 ) dilution in athletes.

Creatine dilution (D3 -cr) is a technique for estimating total skeletal muscle mass (SMM) with practical utility, but has not been applied in athletic populations where body composition may differ to that in the normal population. This study aimed to assess the agreement between SMM derived from both D3 -cr and that obtained from whole-body magnetic resonance imaging (MRI) in 15 male and 5 female national level kayakers (stature: 182.0 ± 13.1 and 170.0 ± 9.0 cm; body mass: 80.6 ± 9.9 and 66.4 ± 6.0 kg; V̇O2 peak: 56.5 ± 7.0 and 49.6 ± 4.4 mL kg-1  min-1 , mean ± SD). SMM was determined following 60 mg of dosed D3 -cr and analysis of expelled urine collected on four subsequent days for creatine, creatinine, D3 -cr, and D3 -creatinine using liquid chromatography/mass spectroscopy. SMM was then estimated by assuming a creatine pool size of 4.3 g/kg. During the same time period, a whole-body MRI was undertaken to derive SMM from the analysis of multiple slices taken across the body. A strong positive correlation (F = 74.32; R = 0.90; P < .0001) between the two methods was observed, but the D3 -cr SMM was found to be significantly higher (43.3 ± 6.8 kg) when compared with MRI (36.3 ± 5.8 kg, P < .0001). However, the difference between the methods was removed when a higher intramuscular creatine pool (5.1 g/kg) was assumed. These data show that D3 -cr has potential utility in athletes, as referenced against MRI, but show that assumptions regarding creatine pool size need to be carefully considered.

Trunk Muscle Composition 2 Months After Hip Fracture: Findings From the Baltimore Hip Studies.

OBJECTIVE: To determine if hip fracture patients would have smaller cross-sectional area (CSA) and lower radiological attenuation (suggesting greater fat infiltration) in all trunk muscles as compared to older adults without hip fractures. DESIGN: Cross-sectional analysis of computed tomography (CT) scans. SETTING: Clinical imaging facility. PARTICIPANTS: Forty-one white participants (19 men, 22 women) from the Baltimore Hip Studies seventh cohort at 2 months postfracture were compared to 693 white participants (424 men, 269 women) from the Health, Aging and Body Composition (Health ABC) study at the year 6 visit (N=734). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Trunk muscle CSA and attenuation values were obtained from a single 10-mm, axial CT scan completed at the L4-L5 disc space in each participant. RESULTS: The hip fracture cohort had significantly smaller CSA for all trunk muscles (range: 12.1%-38% smaller) compared to the Health ABC cohort (P<.01), with the exception of the rectus abdominus muscle in men (P=.12). But, hip fracture patients, particularly female patients, had higher attenuation levels (lower intramuscular fat) in all trunk muscles (P<.0001). CONCLUSIONS: Findings are consistent with atrophy of the trunk muscles in the hip fracture population without a high level of intramuscular fat. Future work should evaluate the role of trunk muscle composition in the functional recovery of older adults after hip fracture.

Response surface methodology modeling of protein concentration, coagulum cut size, and set temperature on curd moisture loss kinetics during curd stirring.

The effects of the independent variables protein concentration (4-6%), coagulum cut size (6-18 mm3), and coagulation temperature (28-36°C) on curd moisture loss during in-vat stirring were investigated using response surface methodology. Milk (14 kg) in a cheese vat was rennet coagulated, cut, and stirred as per semihard cheesemaking conditions. During stirring, the moisture content of curd samples was determined every 10 min between 5 and 115 min after cutting. The moisture loss kinetics of curds cut to 6 mm3 followed a logarithmic trend, but the moisture loss of curds from larger cut sizes, 12 or 18 mm3, showed a linear trend. Response surface modeling showed that curd moisture level was positively correlated with cut size and negatively correlated with milk protein level. However, coagulation temperature had a significant negative effect on curd moisture up to 45 min of stirring but not after 55 min (i.e., after cooking). It was shown that curds set at the lower temperature had a slower syneresis rate during the initial stirring compared with curds set at a higher temperature, which could be accelerated by reducing the cut size. This study shows that keeping a fixed cut size at increasing protein concentration decreased the level of curd moisture at a given time during stirring. Therefore, to obtain a uniform curd moisture content at a given stirring time at increasing protein levels, an increased coagulum cut size is required. It was also clear that breakage of the larger curd particles during initial stirring can also significantly influence the curd moisture loss kinetics. Both transmission and scanning electron micrographs of cooked curds (i.e., after 45 min of stirring) showed that the casein micelles were fused at a higher degree in curds coagulated at 36°C compared with 28°C, which confirmed that coagulation temperature causes a marked change in curd microstructure during the earlier stages of stirring. The present study showed the dynamics of curd moisture content during stirring when using protein-concentrated milk at various set temperatures and cut sizes. This provides the basis for achieving a desired curd moisture loss during cheese manufacture using protein-concentrated milk as a means of reducing the effect of seasonal variation in milk for cheesemaking.

Influence of protein concentration and coagulation temperature on rennet-induced gelation characteristics and curd microstructure.

This study characterized the coagulation properties and defined the cutting window (CW; time between storage modulus values of 35 and 70 Pa) using rheometry for milk standardized to 4, 5, or 6% protein and set at 28, 32, or 36°C. Milks were standardized to a protein-to-fat ratio of approximately 1 by blending ultrafiltration retentate, skim milk, and whole milk. The internal curd microstructure for selected curd samples was analyzed with transmission electron microscopy and scanning electron microscopy. Lowering the coagulation temperature caused longer rennet coagulation time and time to reach storage modulus of 35 Pa, translating into a wider CW. It also led to a lower maximum curd-firming rate (MCFR) with lower firmness at 40 min at a given protein level. Increasing protein levels resulted in the opposite effect, although without an effect on rennet coagulation time at a given temperature. On coagulation at 28°C, milk with 5% protein resulted in a similar MCFR (∼4 Pa/min) and CW (∼8.25 min) compared with milk with 4% protein at 32°C, which reflects more standard conditions, whereas increasing milk to 6% protein resulted in more than doubling of the curd-firming rate (MCFR = 9.20 Pa/min) and a shorter CW (4.60 min). Gels set at 28°C had lower levels of rearrangement of protein network after 40 min compared with those set at 36°C. Protein levels, on the other hand, had no influence on the levels of protein network rearrangement, as indicated by loss tangent values. The internal structure of curd particles, as investigated by both scanning electron microscopy and transmission electron microscopy, appeared to have less cross-linking and smaller casein aggregates when coagulated at 28°C compared with 36°C, whereas varying protein levels did not show a marked effect on aggregate formation. Overall, this study showed a marked interactive effect between coagulation temperature and protein standardization of milk on coagulation properties, which subsequently requires adjustment of the CW during cheesemaking. Lowering of the coagulation temperature greatly altered the curd microstructure, with a tendency for less syneresis during cutting. Further research is required to quantify the changes in syneresis and in fat and protein losses to whey due to changes in the microstructure of curd particles arising from the different coagulation conditions applied to the protein-fortified milk.

A Bifunctional MOF Catalyst Containing Metal-Phosphine and Lewis Acidic Active Sites.

Post-synthetic modification of the hafnium metal-organic framework MOF-808(Hf) to include triarylphosphine ligands is reported. Sulfonated phenylphosphines are incorporated without oxidation to give a "MOF ligand" that can complex late transition metals such as Ir and Rh to give a bifunctional catalyst containing both metal-phosphine complexes and the Lewis acidic framework hafnium metal sites. The metallated phosphine-bearing MOFs act as fully heterogeneous bifunctional catalysts for tandem reductive amination and hydroaminomethylation reactions.

Modulator-Controlled Synthesis of Microporous STA-26, an Interpenetrated 8,3-Connected Zirconium MOF with the the-i Topology, and its Reversible Lattice Shift.

A fully interpenetrated 8,3-connected zirconium MOF with the the-i topology type, STA-26 (St Andrews porous material-26), has been prepared using the 4,4',4"-(2,4,6-trimethylbenzene-1,3,5-triyl)tribenzoate (TMTB) tritopic linker with formic acid as a modulating agent. In the as-prepared form STA-26 possesses Im3‾ m symmetry compared with the Pm3‾ m symmetry of the non-interpenetrated analogue, NU-1200, prepared using benzoic acid as a modulator. Upon removal of residual solvent there is a shift between the interpenetrating lattices and a resultant symmetry change to Cmcm which is fully reversible. This is observed by X-ray diffraction and 13 C MAS NMR is also found to be remarkably sensitive to the structural transition. Furthermore, heating STA-26(Zr) in vacuum dehydroxylates the Zr6 nodes leaving coordinatively unsaturated Zr4+ sites, as shown by IR spectroscopy using CO and CD3 CN as probe molecules. Nitrogen adsorption at 77 K together with grand canonical Monte Carlo simulations confirms a microporous, fully interpenetrated, structure with pore volume 0.53 cm3 g-1 while CO2 adsorption at 196 K reaches 300 cm3 STP g-1 at 1 bar. While the pore volume is smaller than that of its non-interpenetrated mesoporous analogue, interpenetration makes the structure more stable to moisture adsorption and introduces shape selectivity in adsorption.

46-Year Trends in Systemic Lupus Erythematosus Mortality in the United States, 1968 to 2013: A Nationwide Population-Based Study.

BACKGROUND: No large population-based studies have been done on systemic lupus erythematosus (SLE) mortality trends in the United States. OBJECTIVE: To identify secular trends and population characteristics associated with SLE mortality. DESIGN: Population-based study using a national mortality database and census data. SETTING: United States. PARTICIPANTS: All U.S. residents, 1968 through 2013. MEASUREMENTS: Joinpoint trend analysis of annual age-standardized mortality rates (ASMRs) for SLE and non-SLE causes by sex, race/ethnicity, and geographic region; multiple logistic regression analysis to determine independent associations of demographic variables and period with SLE mortality. RESULTS: There were 50 249 SLE deaths and 100 851 288 non-SLE deaths from 1968 through 2013. Over this period, the SLE ASMR decreased less than the non-SLE ASMR, with a 34.6% cumulative increase in the ratio of the former to the latter. The non-SLE ASMR decreased every year starting in 1968, whereas the SLE ASMR decreased between 1968 and 1975, increased between 1975 and 1999, and decreased thereafter. Similar patterns were seen in both sexes, among black persons, and in the South. However, statistically significant increases in the SLE ASMR did not occur among white persons over the 46-year period. Females, black persons, and residents of the South had higher SLE ASMRs and larger cumulative increases in the ratio of the SLE to the non-SLE ASMR (31.4%, 62.5%, and 58.6%, respectively) than males, other racial/ethnic groups, and residents of other regions, respectively. Multiple logistic regression showed independent associations of sex, race, and region with SLE mortality risk and revealed significant racial/ethnic differences in associations of SLE mortality with sex and region. LIMITATIONS: Underreporting of SLE on death certificates may have resulted in underestimates of SLE ASMRs. Accuracy of coding on death certificates is difficult to ascertain. CONCLUSION: Rates of SLE mortality have decreased since 1968 but remain high relative to non-SLE mortality, and significant sex, racial, and regional disparities persist. PRIMARY FUNDING SOURCE: None.

A common variant association study in ethnic Saudi Arabs reveals novel susceptibility loci for hypertriglyceridemia.

Hypertriglyceridemia (hTG) is a lipid disorder, resulting from an elevation in triglyceride levels, with a strong genetic component. It constitutes a significant risk factor for coronary artery disease (CAD), a leading cause of death worldwide. In this study, we performed a common variant association study for hTG in ethnic Saudi Arabs. We genotyped 5501 individuals in a two-phase experiment using Affymetrix Axiom® Genome-Wide CEU 1 Array (Affymetrix, Santa Cruz, CA) that contains a total of 587,352 single nucleotide polymorphisms (SNPs). The lead variant was the rs1558861 [1.99 (1.73-2.30); p = 7.37 × 10-22 ], residing on chromosome (chr) 11 at the apolipoprotein A-I/A-5 (APOA1/APOA5) locus. The rs780094 [1.34 (1.21-1.49); p = 8.57 × 10-8 ] on chr 2 at the glucokinase regulatory protein (GCKR) locus was similarly significantly associated, while the rs10911205 [1.29 (1.16-1.44); p = 3.52 × 10-6 ] on chr1 at the laminin subunit gamma-1 (LAMC1) locus showed suggestive association with disease. Furthermore, the rs17145738 [0.68 (0.60-0.77); p = 6.69 × 10-9 ] on chr7 at the carbohydrate-responsive element-binding protein-encoding (MLXIPL) gene locus displayed significant protective characteristics, while another variant rs6982502 [0.76 (0.68-0.84); p = 5.31 × 10-7 ] on chr8 showed similar but weaker properties. These findings were replicated in 317 cases vs 1415 controls from the same ethnic Arab population. Our study identified several variants across the human genome that are associated with hTG in ethnic Arabs.

Expression of prophage-encoded endolysins contributes to autolysis of Lactococcus lactis.

Analysis of autolysis of derivatives of Lactococcus lactis subsp. cremoris MG1363 and subsp. lactis IL1403, both lacking the major autolysin AcmA, showed that L. lactis IL1403 still lysed during growth while L. lactis MG1363 did not. Zymographic analysis revealed that a peptidoglycan hydrolase activity of around 30 kDa is present in cell extracts of L. lactis IL1403 that could not be detected in strain MG1363. A comparison of all genes encoding putative peptidoglycan hydrolases of IL1403 and MG1363 led to the assumption that one or more of the 99 % homologous 27.9-kDa endolysins encoded by the prophages bIL285, bIL286 and bIL309 could account for the autolysis phenotype of IL1403. Induced expression of the endolysins from bIL285, bIL286 or bIL309 in L. lactis MG1363 resulted in detectable lysis or lytic activity. Prophage deletion and insertion derivatives of L. lactis IL1403 had a reduced cell lysis phenotype. RT-qPCR and zymogram analysis showed that each of these strains still expressed one or more of the three phage lysins. A homologous gene and an endolysin activity were also identified in the natural starter culture L. lactis subsp. cremoris strains E8, Wg2 and HP, and the lytic activity could be detected under growth conditions that were identical as those used for IL1403. The results presented here show that these endolysins of L. lactis are expressed during normal growth and contribute to autolysis without production of (lytic) phages. Screening for natural strains expressing homologous endolysins could help in the selection of strains with enhanced autolysis and, thus, cheese ripening properties.

Exploring quinolone resistance-determining region in Neisseria gonorrhoeae isolates from across India.

BACKGROUND & OBJECTIVES: Antimicrobial resistance in Neisseria gonorrhoeae, the causative agent of gonorrhoea, is a subject of worldwide attention. The present study was undertaken to examine the rates of ciprofloxacin resistance, to correlate mutations in gyrA and parC genes with the level of resistance and to look for a variation in mutation pattern, if any, in isolates from across the country. METHODS: A total of 113 isolates of N. gonorrhoeae collected from sexually transmitted infection patients in six centres during November 2010 to October 2013 were investigated. Minimum inhibitory concentration (MIC) determination was done by E-test and results interpreted as per Calibrated Dichotomous Sensitivity criteria. DNA sequence analysis of gyrA and parC genes was done. RESULTS: Of the 113 isolates, only three (2.6%) were susceptible whereas eight (7.07%) were less susceptible, 32 [28.3%, 95% confidence interval (CI): 20.4-37.6%] resistant (MIC 1-3 µg/ml) and 70 (61.9%, 95% CI: 52.2-70.7%) exhibited high-level resistance (HLR) (MIC ≥4 µg/ml) to ciprofloxacin. A S91F substitution in gyrA gene was demonstrated in all ciprofloxacin non-susceptible isolates. All resistant and HLR isolates had a double mutation in gyrA gene. However, only 5.7 per cent of HLR isolates showed double mutations in parC gene. One isolate (MIC 32 µg/ml) had a previously undescribed G85D substitution in the parC gene. INTERPRETATION & CONCLUSIONS: A S91F substitution in gyrA gene was seen in all non-susceptible isolates of N. gonorrhoeae. It may be used as a marker for ciprofloxacin resistance for molecular surveillance approaches to complement the culture-based methods.

Measurement of muscle mass in sarcopenia: from imaging to biochemical markers.

Sarcopenia encompasses the loss of muscle mass and strength/function during aging. Several methods are available for the estimation of muscle or lean body mass. Popular assessment tools include body imaging techniques (e.g., magnetic resonance imaging, computed tomography, dual X-ray absorptiometry, ultrasonography), bioelectric impedance analysis, anthropometric parameters (e.g., calf circumference, mid-arm muscle circumference), and biochemical markers (total or partial body potassium, serum and urinary creatinine, deuterated creatine dilution method). The heterogeneity of the populations to be evaluated as well as the setting in which sarcopenia is investigated impacts the definition of "gold standard" assessment techniques. The aim of this article is to critically review available methods for muscle mass estimation, highlighting strengths and weaknesses of each of them as well as their proposed field of application.