Genome-scale analysis of positional clustering of mouse testis-specific genes

BACKGROUND: Genes are not randomly distributed on a chromosome as they were thought even after removal of tandem repeats. The positional clustering of co-expressed genes is known in prokaryotes and recently reported in several eukaryotic organisms such as Caenorhabditis elegans, Drosophila melanogaster, and Homo sapiens. In order to further investigate the mode of tissue-specific gene clustering in higher eukaryotes, we have performed a genome-scale analysis of positional clustering of the mouse testis-specific genes. RESULTS: Our computational analysis shows that a large proportion of testis-specific genes are clustered in groups of 2 to 5 genes in the mouse genome. The number of clusters is much higher than expected by chance even after removal of tandem repeats. CONCLUSION: Our result suggests that testis-specific genes tend to cluster on the mouse chromosomes. This provides another piece of evidence for the hypothesis that clusters of tissue-specific genes do exist

Structural Simplification of Bedaquiline: the Discovery of 3-(4-(N,N-dimethylaminomethyl)phenyl)quinoline Derived Antitubercular Lead Compounds

Bedaquiline (BDQ) is a novel and highly potent last-line antituberculosis drug that was approved by the US FDA in 2013. Owing to its stereo-structural complexity, chemical synthesis and compound optimization are rather difficult and expensive. This study describes the structural simplification of bedaquiline while preserving antitubercular activity. The compound's structure was split into fragments and reassembled in various combinations while replacing the two chiral carbon atoms with an achiral linkage instead. Four series of analogues were designed; these candidates retained their potent antitubercular activity at sub-microgram per mL concentrations against both sensitive and multidrug-resistant (MDR) Mycobacterium tuberculosis strains. Six out of the top nine MIC-ranked candidates were found to inhibit mycobacterial ATP synthesis activity with IC50 values between 20 and 40 μm, one had IC50>66 μm, and two showed no inhibition, despite their antitubercular activity. These results provide a basis for the development of chemically less complex, lower-cost bedaquiline derivatives and describe the identification of two derivatives with antitubercular activity against non-ATP synthase related targets

Methylation profiling of SOCS1, SOCS2, SOCS3, CISH and SHP1 in Philadelphia-negative myeloproliferative neoplasm

published_or_final_versio

Retraction-based first-order feasible methods for difference-of-convex programs with smooth inequality and simple geometric constraints

In this paper, we propose first-order feasible methods for difference-of-convex (DC) programs with smooth inequality and simple geometric constraints. Our strategy for maintaining feasibility of the iterates is based on a "retraction" idea adapted from the literature of manifold optimization. When the constraints are convex, we establish the global subsequential convergence of the sequence generated by our algorithm under strict feasibility condition, and analyze its convergence rate when the objective is in addition convex according to the Kurdyka-Lojasiewicz (KL) exponent of the extended objective (i.e., sum of the objective and the indicator function of the constraint set). We also show that the extended objective of a large class of Euclidean norm (and more generally, group LASSO penalty) regularized convex optimization problems is a KL function with exponent $\frac12$; consequently, our algorithm is locally linearly convergent when applied to these problems. We then extend our method to solve DC programs with a single specially structured nonconvex constraint. Finally, we discuss how our algorithms can be applied to solve two concrete optimization problems, namely, group-structured compressed sensing problems with Gaussian measurement noise and compressed sensing problems with Cauchy measurement noise, and illustrate the empirical performance of our algorithms

Carbon nanotube four-terminal devices for pressure sensing applications

Carbon nanotubes (CNTs) are of high interest for sensing applications,owing to their superior mechanical strength, high Young’s modulus and low density. In this work, we report on a facile approach for the fabrication of carbon nanotube devices using a four terminal configuration. Oriented carbon nanotube films were pulled out from a CNT forest wafer and then twisted into a yarn. Both the CNT film and yarn were arranged on elastomer membranes/diaphragms which were arranged on a laser cut acrylic frame to form pressure sensors. The sensors were calibrated using a precisely controlled pressure system, showing a large change of the output voltage of approximately 50 mV at a constant supply current of 100 μA and under a low applied pressure of 15 mbar. The results indicate the high potential of using CNT films and yarns for pressure sensing applications

Palladium-catalyzed directed meta-selective C-H allylation of arenes: unactivated internal olefins as allyl surrogates

Palladium(II)-catalyzed meta-selective C-H allylation of arenes has been developed utilizing synthetically inert unactivated acyclic internal olefins as allylic surrogates. The strong σ-donating and π-accepting ability of pyrimidine-based directing group facilitates the olefin insertion by overcoming inertness of the typical unactivated internal olefins. Exclusive allyl over styrenyl product selectivity as well as E-stereoselectivity were achieved with broad substrate scope, wide functional group tolerance and good to excellent yields. Late-stage functionalisations of pharmaceuticals were demonstrated. Experimental and computational studies shed insights on the mechanism and pointed to key palladacyclic steric control in determining product selectivities

Mechanistic Investigation of the Specific Anticancer Property of Artemisinin and Its Combination with Aminolevulinic Acid for Enhanced Anticolorectal Cancer Activity.

The antimalarial artemisinin (ART) possesses anticancer activity, but its underlying mechanism remains largely unclear. Using a chemical proteomics approach with artemisinin-based activity probes, we identified over 300 specific ART targets. This reveals an anticancer mechanism whereby ART promiscuously targets multiple critical biological pathways and leads to cancer cell death. The specific cytotoxicity of ART against colorectal cancer (CRC) cells rather than normal colon epithelial cells is due to the elevated capacity of heme synthesis in the cancer cells. Guided by this mechanism, the specific cytotoxicity of ART toward CRC cells can be dramatically enhanced with the addition of aminolevulinic acid (ALA), a clinically used heme synthesis precursor, to increase heme levels. Importantly, this novel ART/ALA combination therapy proves to be more effective than an ART monotherapy in a mouse xenograft CRC model. Thus, ART can be repurposed and potentiated by exploitation of its mechanism of action and the metabolic features of the CRC cells

Mp1p Is a Virulence Factor in Talaromyces (Penicillium) marneffei

published_or_final_versio

Coexistence of the topological state and a two-dimensional electron gas on the surface of Bi2Se3

Topological insulators are a recently discovered class of materials with fascinating properties: While the inside of the solid is insulating, fundamental symmetry considerations require the surfaces to be metallic. The metallic surface states show an unconventional spin texture, electron dynamics and stability. Recently, surfaces with only a single Dirac cone dispersion have received particular attention. These are predicted to play host to a number of novel physical phenomena such as Majorana fermions, magnetic monopoles and unconventional superconductivity. Such effects will mostly occur when the topological surface state lies in close proximity to a magnetic or electric field, a (superconducting) metal, or if the material is in a confined geometry. Here we show that a band bending near to the surface of the topological insulator Bi$_2$Se$_3$ gives rise to the formation of a two-dimensional electron gas (2DEG). The 2DEG, renowned from semiconductor surfaces and interfaces where it forms the basis of the integer and fractional quantum Hall effects, two-dimensional superconductivity, and a plethora of practical applications, coexists with the topological surface state in Bi$_2$Se$_3$. This leads to the unique situation where a topological and a non-topological, easily tunable and potentially superconducting, metallic state are confined to the same region of space.Comment: 12 pages, 3 figure

Plasma biomarkers identify older adults at risk of Alzheimer's disease and related dementias in a real-world population-based cohort

Introduction: Plasma biomarkers—cost effective, non-invasive indicators of Alzheimer's disease (AD) and related disorders (ADRD)—have largely been studied in clinical research settings. Here, we examined plasma biomarker profiles and their associated factors in a population-based cohort to determine whether they could identify an at-risk group, independently of brain and cerebrospinal fluid biomarkers. Methods: We measured plasma phosphorylated tau181 (p-tau181), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and amyloid beta (Aβ)42/40 ratio in 847 participants from a population-based cohort in southwestern Pennsylvania. Results: K-medoids clustering identified two distinct plasma Aβ42/40 modes, further categorizable into three biomarker profile groups: normal, uncertain, and abnormal. In different groups, plasma p-tau181, NfL, and GFAP were inversely correlated with Aβ42/40, Clinical Dementia Rating, and memory composite score, with the strongest associations in the abnormal group. Discussion: Abnormal plasma Aβ42/40 ratio identified older adult groups with lower memory scores, higher dementia risks, and higher ADRD biomarker levels, with potential implications for population screening. Highlights: Population-based plasma biomarker studies are lacking, particularly in cohorts without cerebrospinal fluid or neuroimaging data. In the Monongahela-Youghiogheny Healthy Aging Team study (n = 847), plasma biomarkers associated with worse memory and Clinical Dementia Rating (CDR), apolipoprotein E ε4, and greater age. Plasma amyloid beta (Aβ)42/40 ratio levels allowed clustering participants into abnormal, uncertain, and normal groups. Plasma Aβ42/40 correlated differently with neurofilament light chain, glial fibrillary acidic protein, phosphorylated tau181, memory composite, and CDR in each group. Plasma biomarkers can enable relatively affordable and non-invasive community screening for evidence of Alzheimer's disease and related disorders pathophysiology