ALBERT

Description: The Green's function (GF) for the scalar wave equation is numerically constructed by an advanced geometric ray-tracing method based on the eikonal approximation related to the semiclassical propagator. The underlying theory is first briefly introduced, and then it is applied to acoustics and implemented in a ray-tracing-type numerical simulation. The so constructed numerical method is systematically used to calculate the sound field in a rectangular (cuboid) room, yielding also the acoustic modes of the room. The simulated GF is rigorously compared to its analytic approximation. Good agreement is found, which proves the devised numerical approach potentially useful also for low frequency acoustic modeling, which is in practice not covered by geometrical methods.

Description: by Jacquelyn Freund, Rebecca M. May, Enjun Yang, Hongchuan Li, Matthew McCullen, Bin Zhang, Todd Lenvik, Frank Cichocki, Stephen K. Anderson, Taku Kambayashi

Description: by Yael Bar-Lavan, Netta Shemesh, Shiran Dror, Rivka Ofir, Esti Yeger-Lotem, Anat Ben-Zvi Safeguarding the proteome is central to the health of the cell. In multi-cellular organisms, the composition of the proteome, and by extension, protein-folding requirements, varies between cells. In agreement, chaperone network composition differs between tissues. Here, we ask how chaperone expression is regulated in a cell type-specific manner and whether cellular differentiation affects chaperone expression. Our bioinformatics analyses show that the myogenic transcription factor HLH-1 (MyoD) can bind to the promoters of chaperone genes expressed or required for the folding of muscle proteins. To test this experimentally, we employed HLH-1 myogenic potential to genetically modulate cellular differentiation of Caenorhabditis elegans embryonic cells by ectopically expressing HLH-1 in all cells of the embryo and monitoring chaperone expression. We found that HLH-1-dependent myogenic conversion specifically induced the expression of putative HLH-1-regulated chaperones in differentiating muscle cells. Moreover, disrupting the putative HLH-1-binding sites on ubiquitously expressed daf-21(Hsp90) and muscle-enriched hsp-12 . 2(sHsp) promoters abolished their myogenic-dependent expression. Disrupting HLH-1 function in muscle cells reduced the expression of putative HLH-1-regulated chaperones and compromised muscle proteostasis during and after embryogenesis. In turn, we found that modulating the expression of muscle chaperones disrupted the folding and assembly of muscle proteins and thus, myogenesis. Moreover, muscle-specific over-expression of the DNAJB6 homolog DNJ-24, a limb-girdle muscular dystrophy-associated chaperone, disrupted the muscle chaperone network and exposed synthetic motility defects. We propose that cellular differentiation could establish a proteostasis network dedicated to the folding and maintenance of the muscle proteome. Such cell-specific proteostasis networks can explain the selective vulnerability that many diseases of protein misfolding exhibit even when the misfolded protein is ubiquitously expressed.

Description: by Jianxin Shi, Ju-Hyun Park, Jubao Duan, Sonja T. Berndt, Winton Moy, Kai Yu, Lei Song, William Wheeler, Xing Hua, Debra Silverman, Montserrat Garcia-Closas, Chao Agnes Hsiung, Jonine D. Figueroa, Victoria K. Cortessis, Núria Malats, Margaret R. Karagas, Paolo Vineis, I-Shou Chang, Dongxin Lin, Baosen Zhou, Adeline Seow, Keitaro Matsuo, Yun-Chul Hong, Neil E. Caporaso, Brian Wolpin, Eric Jacobs, Gloria M. Petersen, Alison P. Klein, Donghui Li, Harvey Risch, Alan R. Sanders, Li Hsu, Robert E. Schoen, Hermann Brenner, MGS (Molecular Genetics of Schizophrenia) GWAS Consortium , GECCO (The Genetics and Epidemiology of Colorectal Cancer Consortium) , The GAME-ON/TRICL (Transdisciplinary Research in Cancer of the Lung) GWAS Consortium , PRACTICAL (PRostate cancer AssoCiation group To Investigate Cancer Associated aLterations) Consortium , PanScan Consortium , The GAME-ON/ELLIPSE Consortium , Rachael Stolzenberg-Solomon, Pablo Gejman, Qing Lan, Nathaniel Rothman, Laufey T. Amundadottir, Maria Teresa Landi, Douglas F. Levinson, Stephen J. Chanock, Nilanjan Chatterjee Recent heritability analyses have indicated that genome-wide association studies (GWAS) have the potential to improve genetic risk prediction for complex diseases based on polygenic risk score (PRS), a simple modelling technique that can be implemented using summary-level data from the discovery samples. We herein propose modifications to improve the performance of PRS. We introduce threshold-dependent winner’s-curse adjustments for marginal association coefficients that are used to weight the single-nucleotide polymorphisms (SNPs) in PRS. Further, as a way to incorporate external functional/annotation knowledge that could identify subsets of SNPs highly enriched for associations, we propose variable thresholds for SNPs selection. We applied our methods to GWAS summary-level data of 14 complex diseases. Across all diseases, a simple winner’s curse correction uniformly led to enhancement of performance of the models, whereas incorporation of functional SNPs was beneficial only for selected diseases. Compared to the standard PRS algorithm, the proposed methods in combination led to notable gain in efficiency (25–50% increase in the prediction R 2 ) for 5 of 14 diseases. As an example, for GWAS of type 2 diabetes, winner’s curse correction improved prediction R 2 from 2.29% based on the standard PRS to 3.10% ( P = 0.0017) and incorporating functional annotation data further improved R 2 to 3.53% ( P = 2×10 −5 ). Our simulation studies illustrate why differential treatment of certain categories of functional SNPs, even when shown to be highly enriched for GWAS-heritability, does not lead to proportionate improvement in genetic risk-prediction because of non-uniform linkage disequilibrium structure.

Description: by Ivana Gudelj, Margie Kinnersley, Peter Rashkov, Karen Schmidt, Frank Rosenzweig Cross-feeding, a relationship wherein one organism consumes metabolites excreted by another, is a ubiquitous feature of natural and clinically-relevant microbial communities and could be a key factor promoting diversity in extreme and/or nutrient-poor environments. However, it remains unclear how readily cross-feeding interactions form, and therefore our ability to predict their emergence is limited. In this paper we developed a mathematical model parameterized using data from the biochemistry and ecology of an E . coli cross-feeding laboratory system. The model accurately captures short-term dynamics of the two competitors that have been observed empirically and we use it to systematically explore the stability of cross-feeding interactions for a range of environmental conditions. We find that our simple system can display complex dynamics including multi-stable behavior separated by a critical point. Therefore whether cross-feeding interactions form depends on the complex interplay between density and frequency of the competitors as well as on the concentration of resources in the environment. Moreover, we find that subtly different environmental conditions can lead to dramatically different results regarding the establishment of cross-feeding, which could explain the apparently unpredictable between-population differences in experimental outcomes. We argue that mathematical models are essential tools for disentangling the complexities of cross-feeding interactions.

Description: by Kathryn French, Jason Evans, Hannah Tanner, Savita Gossain, Abid Hussain Background Faster identification of bacterial isolates from blood cultures can enable earlier clinical intervention for patients with sepsis. We evaluated the clinical impact of direct identification of micro-organisms from positive blood cultures using MALDI-ToF. Method Positive blood cultures with organisms seen on Gram stain were included over a four week period. For each patient case, comparison was made between the clinical advice given on day one with only a Gram stain result, and the follow up advice given on day two with the benefit of organism identification. Culture results were then compared with direct MALDI-ToF identification. Results For 73 of 115 cases (63.5%), direct organism identification was obtained by MALDI-ToF. Of those 73, 70 (95.5%) had a result concordant with that of the plate culture. In 28 of the 115 cases (24.3%) direct MALDI-ToF identification on day one would have had a clear clinical benefit. In 11 cases it would have helped to identify the potential source of bacteraemia. In 11 cases it would have indicated a different antibiotic regimen on day one, with five patients receiving appropriate antibiotics 24 hours earlier. For 14 cases the blood culture isolate could have been designated as unlikely to be clinically significant. Conclusion We have demonstrated that organism identification on day one of blood culture positivity can have a direct clinical impact. Faster identification using MALDI-ToF assists the clinician in assessing the significance of a blood culture isolate on day one. It can allow earlier appropriate choice of antimicrobial agent, even in the absence of susceptibility testing, and help narrow down the potential source of infection providing a focus for further investigation in a more timely way than conventional techniques alone.

Description: by Katharine Kripke, Jason Reed, Catherine Hankins, Gregory Smiley, Catey Laube, Emmanuel Njeuhmeli

Description: by Ana Alfaro, Eligia Juárez-Torres, Ingrid Medina-Martínez, Norma Mateos-Guerrero, Maura Bautista-Huerta, Edgar Román-Bassaure, Nicolás Villegas-Sepúlveda, Jaime Berumen The median age of cervical cancer (CC) presentation coincides with the mean age of menopause presentation (49 years) in Mexico. Here, we investigated the association between different HPV16 variants and early (≤ 49 years) or delayed (≥ 50 years) CC presentation. We conducted a case-case study that included 462 CCs, 386 squamous cell carcinomas (SCC), 63 adenocarcinomas (ACC), and 13 additional cell types. Variants were identified by PCR and DNA sequencing. The risk conferred by each variant for developing CC earlier than 50 years was analyzed using a univariate logistic regression model considering old-aged patients (≥ 50 years) and non-HPV16 cases as the reference variables. Overall, the frequency of HPV16 was 50.9%, and the only identified variants were the European A1/2 (31.2%) and the Asian-American D2 (10.8%), and D3 (8.9%). D2 was mainly associated with ≤ 49-year-old patients (15.9%); A1/2 was uniformly distributed between the two age groups (~31%), whereas D3 increased with age to a frequency of 11.8% in the older group. Only the D2 variant conferred a 3.3-fold increase in the risk of developing CC before 50 years of age (OR = 3.3, 95% CI = 1.7–6.6, p 〈 0.001) in relation with non-HPV16 cases. Remarkably, this risk was higher for ACC (OR = 6.0, 95% CI = 1.1–33, p 〈 0.05) than for SCC (OR = 2.8, 95% CI = 1.3–5.9, p 〈 0.01). Interestingly, when analyzing only the HPV16-positive CC, D2 increases (OR = 2.5, 95% CI = 1.2–5, p 〈 0.05) and D3 decreases (OR = 0.45, 95% CI 0.2–0.9, p 〈 0.05) the risk to develop CC before 50 years old in relation with A1/2 variant. These results indicated that D2 variant is associated with early and D3 with delayed CC presentation, whereas A1/2 variant was uniformly distributed between the two age groups.

Description: by Hyo Geun Choi, Bumjung Park, Songyong Sim, Soon-Hyun Ahn Objectives The objective of this study was to compare post-operative visits for upper respiratory infections (URIs) between tonsillectomy and non-tonsillectomy participants (controls). Methods Using the national cohort study from the Korean Health Insurance Review and Assessment Service, 1:4 matched (age, sex, income, region, and pre-operative URI visit) tonsillectomy participants (5,831) and control participants (23,324) were selected. Post-operative visits for URI were measured from 1 to 9 years post-op. The equivalence test was used. The margin of equivalence of the difference (Tonsillectomy—Control group group) was set to -0.5 to 0.5. Results There was no difference between the tonsillectomy and control group in 1- to 9-year post-op visits (-0.5 〈 95% CI of difference 〈 0.5). URI visits gradually decreased from 5.5/2 years (pre-op) to 2.1/year (at 1 year post-op) and 1.4/year (at 9 years post-op) in both tonsillectomy and control groups. In the subgroup analysis (children Vs adolescent and adults; rare Vs frequent pre-operative URI), there was no difference in the number of post-op visits for URI between the tonsillectomy and control groups (-0.5 〈 95% CI of difference 〈 0.5). Conclusion Tonsillectomy does not provide a decrease in the number of post-operative visits for URI, and URI decreased over time whether or not a tonsillectomy was performed.

Description: by Catherine Hankins, Mitchell Warren, Emmanuel Njeuhmeli