reComBat: batch-effect removal in large-scale multi-source gene-expression data integration

With the steadily increasing abundance of omics data produced all over the world under vastly different experimental conditions residing in public databases, a crucial step in many data-driven bioinformatics applications is that of data integration. The challenge of batch-effect removal for entire databases lies in the large number of batches and biological variation, which can result in design matrix singularity. This problem can currently not be solved satisfactorily by any common batch-correction algorithm.; We present; reComBat; , a regularized version of the empirical Bayes method to overcome this limitation and benchmark it against popular approaches for the harmonization of public gene-expression data (both microarray and bulkRNAsq) of the human opportunistic pathogen; Pseudomonas aeruginosa; . Batch-effects are successfully mitigated while biologically meaningful gene-expression variation is retained.; reComBat; fills the gap in batch-correction approaches applicable to large-scale, public omics databases and opens up new avenues for data-driven analysis of complex biological processes beyond the scope of a single study.; The code is available at https://github.com/BorgwardtLab/reComBat, all data and evaluation code can be found at https://github.com/BorgwardtLab/batchCorrectionPublicData.; Supplementary data are available at; Bioinformatics Advances; online

Avalanche of Bifurcations and Hysteresis in a Model of Cellular Differentiation

Cellular differentiation in a developping organism is studied via a discrete bistable reaction-diffusion model. A system of undifferentiated cells is allowed to receive an inductive signal emenating from its environment. Depending on the form of the nonlinear reaction kinetics, this signal can trigger a series of bifurcations in the system. Differentiation starts at the surface where the signal is received, and cells change type up to a given distance, or under other conditions, the differentiation process propagates through the whole domain. When the signal diminishes hysteresis is observed

Topoisomerase II inhibitors induce DNA damage-dependent interferon responses circumventing Ebola virus immune evasion

Ebola virus (EBOV) protein VP35 inhibits production of interferon alpha/beta (IFN) by blocking RIG-I-like receptor signaling pathways, thereby promoting virus replication and pathogenesis. A high-throughput screening assay, developed to identify compounds that either inhibit or bypass VP35 IFN-antagonist function, identified five DNA intercalators as reproducible hits from a library of bioactive compounds. Four, including doxorubicin and daunorubicin, are anthracycline antibiotics that inhibit topoisomerase II and are used clinically as chemotherapeutic drugs. These compounds were demonstrated to induce IFN responses in an ATM kinase-dependent manner and to also trigger the DNA-sensing cGAS-STING pathway of IFN induction. These compounds also suppress EBOV replication in vitro and induce IFN in the presence of IFN-antagonist proteins from multiple negative-sense RNA viruses. These findings provide new insights into signaling pathways activated by important chemotherapy drugs and identify a novel therapeutic approach for IFN induction that may be exploited to inhibit RNA virus replication

THEORY OF PHASE-LOCKING IN SMALL JOSEPHSON JUNCTION CELLS

Within the RSJ model, we performed a theoretical analysis of phase-locking in elementary strongly coupled Josephson junction cells. For this purpose, we developed a systematic method allowing the investigation of phase-locking in cells with small but non-vanishing loop inductance.The voltages across the junctions are found to be locked with very small phase difference for almost all values of external flux. However, the general behavior of phase-locking is found to be just contrary to that according to weak coupling. In case of strong coupling there is nearly no influence of external magnetic flux on the phases, but the locking-frequency becomes flux-dependent. The influence of parameter splitting is considered as well as the effect of small capacitive shunting of the junctions. Strongly coupled cells show synchronization even for large parameter splitting. Finally, a study of the behavior under external microwave radiation shows that the frequency locking-range becomes strongly flux-dependent, whereas the locking frequency itself turns out to be flux-independent.Comment: 26 pages, REVTEX, 9 PS figures appended in uuencoded form at the end, submitted to Phys. Rev. B

Three Distinct Roles for Notch in Drosophila R7 Photoreceptor Specification

During specification of the R7 photoreceptor in the <I>Drosophila</I> eye, activation of Notch signaling leads to multiple responses within the cell, including antagonistic ones

On the possibility of magneto-structural correlations: detailed studies of di-nickel carboxylate complexes

A series of water-bridged dinickel complexes of the general formula [Ni&lt;sub&gt;2&lt;/sub&gt;(μ&lt;sub&gt;2&lt;/sub&gt;-OH&lt;sub&gt;2&lt;/sub&gt;)(μ2- O&lt;sub&gt;2&lt;/sub&gt;C&lt;sup&gt;t&lt;/sup&gt;Bu)&lt;sub&gt;2&lt;/sub&gt;(O&lt;sub&gt;2&lt;/sub&gt;C&lt;sup&gt;t&lt;/sup&gt;Bu)2(L)(L0)] (L = HO&lt;sub&gt;2&lt;/sub&gt;C&lt;sup&gt;t&lt;/sup&gt;Bu, L0 = HO&lt;sub&gt;2&lt;/sub&gt;C&lt;sup&gt;t&lt;/sup&gt;Bu (1), pyridine (2), 3-methylpyridine (4); L = L0 = pyridine (3), 3-methylpyridine (5)) has been synthesized and structurally characterized by X-ray crystallography. The magnetic properties have been probed by magnetometry and EPR spectroscopy, and detailed measurements show that the axial zero-field splitting, D, of the nickel(ii) ions is on the same order as the isotropic exchange interaction, J, between the nickel sites. The isotropic exchange interaction can be related to the angle between the nickel centers and the bridging water molecule, while the magnitude of D can be related to the coordination sphere at the nickel sites

Diagnostic Accuracy of Fine Needle Biopsy for Metastatic Melanoma and Its Implications for Patient Management

The use of fine needle biopsy (FNB) for the diagnosis of metastatic melanoma can lead to the early removal and treatment of metastases, reduce the frequency of unnecessary surgery, and facilitate the staging of patients enrolled in clinical trials of adjuvant therapies. In this study, the accuracy of FNB for the diagnosis of metastatic melanoma was investigated. A retrospective cohort study was performed with 2204 consecutive FNBs performed on 1416 patients known or suspected to have metastatic melanoma. Almost three-quarters (1582) of these FNBs were verified by either histopathologic diagnosis following surgical resection or clinical follow-up. FNB for metastatic melanoma was found to have an overall sensitivity of 92.1% and a specificity of 99.2%, with 69 false-negative and 5 false-positive findings identified. The sensitivity of the procedure was found to be influenced by six factors. The use of immunostains, reporting of the specimen by a cytopathologist who had reported >500 cases, lesions located in the skin and subcutis, and patients with ulcerated primary melanomas were factors associated with a significant improvement in the sensitivity of the test. However, FNBs performed in masses located in lymph nodes of the axilla and FNBs that required more than one needle pass to obtain a sample were far more likely to result in false-negative results. FNB is a rapid, accurate, and clinically useful technique for the assessment of disease status in patients with suspected metastatic melanoma

Studying feasibility and effects of a two-stage nursing staff training in residential geriatric care using a 30 month mixed-methods design [ISRCTN24344776]

<p>Abstract</p> <p>Background</p> <p>Transfer techniques and lifting weights often cause back pain and disorders for nurses in geriatric care. The Kinaesthetics care conception claims to be an alternative, yielding benefits for nurses as well as for clients.</p> <p>Starting a multi-step research program on the effects of Kinaesthetics, we assess the feasibility of a two-stage nursing staff training and a pre-post research design. Using quantitative and qualitative success criteria, we address mobilisation from the bed to a chair and backwards, walking with aid and positioning in bed on the staff level as well as on the resident level. In addition, effect estimates should help to decide on and to prepare a controlled trial.</p> <p>Methods/Design</p> <p>Standard basic and advanced Kinaesthetics courses (each comprising four subsequent days and an additional counselling day during the following four months) are offered to n = 36 out of 60 nurses in a residential geriatric care home, who are in charge of 76 residents. N = 22 residents needing movement support are participating to this study.</p> <p>On the staff level, measurements include focus group discussions, questionnaires, physical strain self-assessment (Borg scale), video recordings and external observation of patient assistance skills using a specialised instrument (SOPMAS). Questionnaires used on the resident level include safety, comfort, pain, and level of own participation during mobilisation. A functional mobility profile is assessed using a specialised test procedure (MOTPA).</p> <p>Measurements will take place at baseline (T0), after basic training (T1), and after the advanced course (T2). Follow-up focus groups will be offered at T1 and 10 months later (T3).</p> <p>Discussion</p> <p>Ten criteria for feasibility success are established before the trial, assigned to resources (missing data), processes (drop-out of nurses and residents) and science (minimum effects) criteria. This will help to make rational decision on entering the next stage of the research program.</p> <p>Trial Registration</p> <p>Current Controlled Trials <a href="http://www.controlled-trials.com/ISRCTN24344776">ISRCTN24344776</a>.</p

Singular values of the Dirac operator in dense QCD-like theories

We study the singular values of the Dirac operator in dense QCD-like theories at zero temperature. The Dirac singular values are real and nonnegative at any nonzero quark density. The scale of their spectrum is set by the diquark condensate, in contrast to the complex Dirac eigenvalues whose scale is set by the chiral condensate at low density and by the BCS gap at high density. We identify three different low-energy effective theories with diquark sources applicable at low, intermediate, and high density, together with their overlapping domains of validity. We derive a number of exact formulas for the Dirac singular values, including Banks-Casher-type relations for the diquark condensate, Smilga-Stern-type relations for the slope of the singular value density, and Leutwyler-Smilga-type sum rules for the inverse singular values. We construct random matrix theories and determine the form of the microscopic spectral correlation functions of the singular values for all nonzero quark densities. We also derive a rigorous index theorem for non-Hermitian Dirac operators. Our results can in principle be tested in lattice simulations.Comment: 3 references added, version published in JHE

In Situ Photodegradation of Incorporated Polyanion Does Not Alter Prion Infectivity

Single-stranded polyanions ≥40 bases in length facilitate the formation of hamster scrapie prions in vitro, and polyanions co-localize with PrPSc aggregates in vivo [1], [2]. To test the hypothesis that intact polyanionic molecules might serve as a structural backbone essential for maintaining the infectious conformation(s) of PrPSc, we produced synthetic prions using a photocleavable, 100-base oligonucleotide (PC-oligo). In serial Protein Misfolding Cyclic Amplification (sPMCA) reactions using purified PrPC substrate, PC-oligo was incorporated into physical complexes with PrPSc molecules that were resistant to benzonase digestion. Exposure of these nuclease-resistant prion complexes to long wave ultraviolet light (315 nm) induced degradation of PC-oligo into 5 base fragments. Light-induced photolysis of incorporated PC-oligo did not alter the infectivity of in vitro-generated prions, as determined by bioassay in hamsters and brain homogenate sPMCA assays. Neuropathological analysis also revealed no significant differences in the neurotropism of prions containing intact versus degraded PC-oligo. These results show that polyanions >5 bases in length are not required for maintaining the infectious properties of in vitro-generated scrapie prions, and indicate that such properties are maintained either by short polyanion remnants, other co-purified cofactors, or by PrPSc molecules alone