Rapid response to pandemic threats: immunogenic epitope detection of pandemic pathogens for diagnostics and vaccine development using peptide microarrays

Emergence and re-emergence of pathogens bearing the risk of becoming a pandemic threat are on the rise. Increased travel and trade, growing population density, changes in urbanization, and climate have a critical impact on infectious disease spread. Currently, the world is confronted with the emergence of a novel coronavirus SARS-CoV-$_{2}$, responsible for yet more than 800 000 deaths globally. Outbreaks caused by viruses, such as SARS-CoV-$_{2}$, HIV, Ebola, influenza, and Zika, have increased over the past decade, underlining the need for a rapid development of diagnostics and vaccines. Hence, the rational identification of biomarkers for diagnostic measures on the one hand, and antigenic targets for vaccine development on the other, are of utmost importance. Peptide microarrays can display large numbers of putative target proteins translated into overlapping linear (and cyclic) peptides for a multiplexed, high-throughput antibody analysis. This enabled for example the identification of discriminant/diagnostic epitopes in Zika or influenza and mapping epitope evolution in natural infections versus vaccinations. In this review, we highlight synthesis platforms that facilitate fast and flexible generation of high-density peptide microarrays. We further outline the multifaceted applications of these peptide array platforms for the development of serological tests and vaccines to quickly encounter pandemic threats

Pole structure of the Hamiltonian ζ\zeta-function for a singular potential

We study the pole structure of the $\zeta$-function associated to the Hamiltonian $H$ of a quantum mechanical particle living in the half-line $\mathbf{R}^+$, subject to the singular potential $g x^{-2}+x^2$. We show that $H$ admits nontrivial self-adjoint extensions (SAE) in a given range of values of the parameter $g$. The $\zeta$-functions of these operators present poles which depend on $g$ and, in general, do not coincide with half an integer (they can even be irrational). The corresponding residues depend on the SAE considered.Comment: 12 pages, 1 figure, RevTeX. References added. Version to appear in Jour. Phys. A: Math. Ge

Auxin transport through non-hair cells sustains root-hair development.

The plant hormone auxin controls root epidermal cell development in a concentration-dependent manner. Root hairs are produced on a subset of epidermal cells as they increase in distance from the root tip. Auxin is required for their initiation and continued growth, but little is known about its distribution in this region of the root. Contrary to the expectation that hair cells might require active auxin influx to ensure auxin supply, we did not detect the auxin-influx transporter AUX1 in root-hair cells. A high level of AUX1 expression was detected in adjacent non-hair cell files. Non-hair cells were necessary to achieve wild-type root-hair length, although an auxin response was not required in these cells. Three-dimensional modelling of auxin flow in the root tip suggests that AUX1-dependent transport through non-hair cells maintains an auxin supply to developing hair cells as they increase in distance from the root tip, and sustains root-hair outgrowth. Experimental data support the hypothesis that instead of moving uniformly though the epidermal cell layer, auxin is mainly transported through canals that extend longitudinally into the tissue

Manifestation allergischer Krankheiten bei jungen Erwachsenen in Zusammenhang mit dem Eintritt in das Berufsleben - Untersuchungen zur Abhängigkeit von arbeitsbedingten Faktoren unter Berücksichtigung von Vorerkrankungen, Disposition und außerberuflichen Umweltfaktoren und Ableitung von Vorschlägen zur verbesserten Prävention: Studie in Ost- und Westdeutschland zu beruflichen Allergierisiken - SOLAR II -; Abschlussbericht

SOLAR II ist das zweite Follow-up einer bevölkerungsbezogenenden Kohorten-Studie. Diese Studie basiert auf einer Kohorte, die 1995/1996 aus damals 9-11jährigen Kindern aus Dresden und München zusammengestellt wurde. Die inzwischen erwachsenen Teilnehmer wurden nun erneut mit dem Ziel untersucht, Zusammenhänge zwischen beruflichen Expositionen und Allergien und Atemwegserkrankungen zu ermitteln. Ein Schwerpunkt der Auswertung galt der Frage, wie sich aus Risikofaktoren, die bereits in der Kindheit erkennbar sind, vorhersagen lässt, dass sich bei Tätigkeitsbeginn in Berufen mit hoher Exposition eine Allergie oder eine Atemwegserkrankung entwickeln wird. Mit den Ergebnissen der Studie kann nicht begründet werden, Jugendlichen mit Risikofaktoren für allergische Atemwegserkrankungen grundsätzlich von Tätigkeiten mit hohem Expositions-Potenzial abzuraten. Die Autoren sprechen sich aber für eine engmaschige arbeitsmedizinische Betreuung junger Erwachsener aus, die am Beginn einer solchen Tätigkeit stehen

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

A model for predicting effect of treatment on progression-free survival using MRD as a surrogate end point in CLL

Our objective was to evaluate minimal residual disease (MRD) at the end of induction treatment with chemoimmunotherapy as a surrogate end point for progression-free survival (PFS) in chronic lymphocytic leukemia (CLL) based on 3 randomized, phase 3 clinical trials (ClinicalTrials.gov identifiers NCT00281918, NCT00769522, and NCT02053610). MRD was measured in peripheral blood (PB) from treatment-naïve patients in the CLL8, CLL10, and CLL11 clinical trials, and quantified by 4-color flow cytometry or allele-specific oligonucleotide real-time quantitative polymerase chain reaction. A meta-regression model was developed to predict treatment effect on PFS using treatment effect on PB-MRD. PB-MRD levels were measured in 393, 337, and 474 patients from CLL8, CLL10, and CLL11, respectively. The model demonstrated a statistically significant relationship between treatment effect on PB-MRD and treatment effect on PFS. As the difference between treatment arms in PB-MRD response rates increased, a reduction in the risk of progression or death was observed; for each unit increase in the (log) ratio of MRD2 rates between arms, the log of the PFS hazard ratio decreased by 20.188 (95% confidence interval, 20.321 to 20.055; P 5 .008). External model validation on the REACH trial and sensitivity analyses confirm the robustness and applicability of the surrogacy model. Our surrogacy model supports use of PB-MRD as a primary end point in randomized clinical trials of chemoimmunotherapy in CLL. Additional CLL trial data are required to establish a more precise quantitative relationship between MRD and PFS, and to support general applicability of MRD surrogacy for PFS across diverse patient characteristics, treatment regimens, and different treatment mechanisms of action

Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances

We use a genome-wide association of 1 million parental lifespans of genotyped subjects and data on mortality risk factors to validate previously unreplicated findings near CDKN2B-AS1, ATXN2/BRAP, FURIN/FES, ZW10, PSORS1C3, and 13q21.31, and identify and replicate novel findings near ABO, ZC3HC1, and IGF2R. We also validate previous findings near 5q33.3/EBF1 and FOXO3, whilst finding contradictory evidence at other loci. Gene set and cell-specific analyses show that expression in foetal brain cells and adult dorsolateral prefrontal cortex is enriched for lifespan variation, as are gene pathways involving lipid proteins and homeostasis, vesicle-mediated transport, and synaptic function. Individual genetic variants that increase dementia, cardiovascular disease, and lung cancer - but not other cancers - explain the most variance. Resulting polygenic scores show a mean lifespan difference of around five years of life across the deciles.Peer reviewe