MSO-GP: 3-D segmentation of large and complex conjoined tree structures.

Robust segmentation of large and complex conjoined tree structures in 3-D is a major challenge in computer vision. This is particularly true in computational biology, where we often encounter large data structures in size, but few in number, which poses a hard problem for learning algorithms. We show that merging multiscale opening with geodesic path propagation, can shed new light on this classic machine vision challenge, while circumventing the learning issue by developing an unsupervised visual geometry approach (digital topology/morphometry).

Hit-to-lead optimization of 2-aminoquinazolines as anti-microbial agents against Leishmania donovani.

Visceral leishmaniasis is a potentially fatal disease caused by infection by the intracellular protist pathogens Leishmania donovani or Leishmania infantum. Present therapies are ineffective because of high costs, variable efficacy against different species, the requirement for hospitalization, toxicity and drug resistance. Detailed analysis of previously published hit molecules suggested a crucial role of 'guanidine' linkage for their efficacy against L.

Intra-tumor ROS amplification by melatonin interferes in the apoptosis-autophagy-inflammation-EMT collusion in the breast tumor microenvironment.

Epidemiological as well as experimental studies have established that the pineal hormone melatonin has inhibitory effects on different types of cancers. Several mechanisms have been proposed for the anticancer activities of melatonin, but the fundamental molecular pathways still require clarity. We developed a mouse model of breast cancer using Ehrlich's ascites carcinoma (injected in the 4th mammary fat pad of female Swiss albino mice) and investigated the possibility of targeting the autophagy-inflammation-EMT colloquy to restrict breast tumor progression using melatonin as intervention.

Correction: Deep-Fuzz: A synergistic integration of deep learning and fuzzy water flows for fine-grained nuclei segmentation in digital pathology.

[This corrects the article DOI: 10.1371/journal.pone.

Deep-Fuzz: A synergistic integration of deep learning and fuzzy water flows for fine-grained nuclei segmentation in digital pathology.

Robust semantic segmentation of tumour micro-environment is one of the major open challenges in machine learning enabled computational pathology. Though deep learning based systems have made significant progress, their task agnostic data driven approach often lacks the contextual grounding necessary in biomedical applications. We present a novel fuzzy water flow scheme that takes the coarse segmentation output of a base deep learning framework to then provide a more fine-grained and instance level robust segmentation output.

Mitigating hERG Liability of Toll-Like Receptor 9 and 7 Antagonists through Structure-Based Design.

hERG is considered to be a primary anti-target in the drug development process, as the K channel encoded by hERG plays an important role in cardiac re-polarization. It is desirable to address the hERG safety liability during early-stage development to avoid the expenses of validating leads that will eventually fail at a later stage. We have previously reported the development of highly potent quinazoline-based TLR7 and TLR9 antagonists for possible application against autoimmune disease.

Arsenic-induced differential inflammatory responses in mouse thymus involves NF-κB/STAT-3 disruption, Treg bias and autophagy activation.

Aim: Arsenic contamination in drinking water is a world-wide public health concern. Sustained arsenic ingestion leads to immune alterations and subsequent development of inflammatory and autoimmune diseases; however, the underlying cellular and molecular intricacies of immunotoxicity remains uncharacterized. We aim to understand how exposure to arsenic at different concentrations affects the immune system differentially and whether arsenic-induced differential inflammation dictates altered T-regulatory cell bias and emphasize the role of autophagy in the pathway.

Development, Optimization, and In Vivo Validation of New Imidazopyridine Chemotypes as Dual TLR7/TLR9 Antagonists through Activity-Directed Sequential Incorporation of Relevant Structural Subunits.

Undesirable activation of endosomal toll-like receptors TLR7 and TLR9 present in specific immune cells in response to host-derived ligands is implicated in several autoimmune diseases and other contexts of autoreactive inflammation, making them important therapeutic targets. We report a drug development strategy identifying a new chemotype for incorporating relevant structural subunits into the basic imidazopyridine core deemed necessary for potent TLR7 and TLR9 dual antagonism. We established minimal pharmacophoric features in the core followed by hit-to-lead optimization, guided by in vitro and in vivo biological assays and ADME.

Hit-to-lead optimization of novel phenyl imidazole carboxamides that are active against Leishmania donovani.

Visceral leishmaniasis is a potentially fatal disease caused by the parasitic protists, Leishmania donovani and L. infantum. Current treatments remain unsuitable due to cost, the need for hospitalization, variable efficacy against different species, toxicity and emerging resistance.

3dSpAn: An interactive software for 3D segmentation and analysis of dendritic spines.

Three-dimensional segmentation and analysis of dendritic spine morphology involve two major challenges: 1) how to segment individual spines from the dendrites and 2) how to quantitatively assess the morphology of individual spines. To address these two issues, we developed software called 3dSpAn (3-dimensional Spine Analysis), based on implementing a previously published method, 3D multi-scale opening algorithm in shared intensity space. 3dSpAn consists of four modules: a) Preprocessing and Region of Interest (ROI) selection, b) Intensity thresholding and seed selection, c) Multi-scale segmentation, and d) Quantitative morphological feature extraction.

Systematic Optimization of Potent and Orally Bioavailable Purine Scaffold as a Dual Inhibitor of Toll-Like Receptors 7 and 9.

Several toll-like receptors (TLRs) reside inside endosomes of specific immune cells-among them, aberrant activation of TLR7 and TLR9 is implicated in myriad contexts of autoimmune diseases, making them promising therapeutic targets. However, small-molecule TLR7 and TLR9 antagonists are not yet available for clinical use. We illustrate here the importance of C2, C6, and N9 substitutions in the purine scaffold for antagonism to TLR7 and TLR9 through structure-activity relationship studies using cellular reporter assays and functional studies on primary human immune cells.

Structural Evolution and Translational Potential for Agonists and Antagonists of Endosomal Toll-like Receptors.

Toll-like receptors (TLRs) are members of a large family of evolutionarily conserved pattern recognition receptors (PRRs), which serve as key components of the innate immune system by playing a pivotal role in sensing "nonself" ligands. Endosomal TLRs (TLR3, TLR7, TLR8, and TLR9) can recognize pathogen-derived nucleic acid and initiate an innate immune response because they react against both self- and non-self-origin nucleic acid molecules. Accordingly, both receptor agonists and antagonists are potentially useful in disparate clinical contexts and thus are globally sought after.

PartSeg: a tool for quantitative feature extraction from 3D microscopy images for dummies.

Background: Bioimaging techniques offer a robust tool for studying molecular pathways and morphological phenotypes of cell populations subjected to various conditions. As modern high-resolution 3D microscopy provides access to an ever-increasing amount of high-quality images, there arises a need for their analysis in an automated, unbiased, and simple way. Segmentation of structures within the cell nucleus, which is the focus of this paper, presents a new layer of complexity in the form of dense packing and significant signal overlap.

Protein-templated gold nanoclusters as specific bio-imaging probes for the detection of Hg(ii) ions in in vivo and in vitro systems: discriminating between MDA-MB-231 and MCF10A cells.

Gold nanoclusters (AuNCs) synthesized within a protein (Human Serum Albumin, HSA) template exhibited intense red luminescence accompanied by a quantum yield >10% and remarkable photo and cluster-core stability for a prolonged period (more than a year). These photoluminescent nanoclusters (NCs) were resistant to chemical and thermal perturbations but break down selectively and highly sensitively in the presence of mercury, Hg(ii), ions. The AuNCs were efficient in quantifying Hg(ii) ions in solution as well as bound to the hormone insulin.

The Mixture of Autoregressive Hidden Markov Models of Morphology for Dentritic Spines During Activation Process.

The dendritic spines play a crucial role in learning and memory processes, epileptogenesis, drug addiction, and postinjury recovery. The shape of the dendritic spine is a morphological key to understand learning and memory process. The classification of the dendritic spines is based on their shapes but the major questions are how the shapes changes in time, how the synaptic strength changes, and is there a correlation between shapes and synaptic strength? Because the changes of the classes by dendritic spines during activation are time dependent, the forward-directed autoregressive hidden Markov model (ARHMM) can be used to model these changes.

Prophylactic Ketamine Treatment Promotes Resilience to Chronic Stress and Accelerates Recovery: Correlation with Changes in Synaptic Plasticity in the CA3 Subregion of the Hippocampus.

Ketamine is an -methyl-d-aspartate receptor antagonist that has gained wide attention as a potent antidepressant. It has also been recently reported to have prophylactic effects in animal models of depression and anxiety. Alterations of neuroplasticity in different brain regions; such as the hippocampus; prefrontal cortex; and amygdala; are a hallmark of stress-related disorders; and such changes may endure beyond the treatment of symptoms.

Author Correction: Quantitative 3-D morphometric analysis of individual dendritic spines.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Quantitative 3-D morphometric analysis of individual dendritic spines.

The observation and analysis of dendritic spines morphological changes poses a major challenge in neuroscience studies. The alterations of their density and/or morphology are indicators of the cellular processes involved in neural plasticity underlying learning and memory, and are symptomatic in neuropsychiatric disorders. Despite ongoing intense investigations in imaging approaches, the relationship between changes in spine morphology and synaptic function is still unknown.

Photostable Copper Nanoclusters: Compatible Förster Resonance Energy-Transfer Assays and a Nanothermometer.

To address the concern of material chemists over the issue of stability and photoluminescent (PL) characteristics of Cu nanoclusters (NCs), herein we present an efficient protocol discussing PL Cu NCs (Cu/HSA) having blue emission and high photostability. These PL NCs were illustrated as efficient probes for Förster resonance energy transfer (FRET) with a compatible fluorophore (Coumarin 153). Our spectroscopic results were well complemented by our molecular docking calculations, which also favored our proposed mechanism for Cu NC formation.

Temperature induced morphological transitions from native to unfolded aggregated States of human serum albumin.

The circulatory protein, human serum albumin (HSA), is known to have two melting point temperatures, 56 and 62 °C. In this present manuscript, we investigate the interaction of HSA with a synthesized bioactive molecule 3-pyrazolyl 2-pyrazoline (PZ). The sole tryptophan amino acid residue (Trp214) of HSA and PZ forms an excellent FRET pair and has been used to monitor the conformational dynamics in HSA as a function of temperature.

A new rhodamine based colorimetric 'off-on' fluorescence sensor selective for Pd2+ along with the first bound X-ray crystal structure.

A new fluorescence rhodamine derivative bearing an 8-aminoquinoline moiety has been designed and synthesized for selective sensing of Pd(2+) in the presence of other competing metal ions in aqueous media. Pd(2+) induced spirolactam ring opening of rhodamine is confirmed for the first time by the X-ray crystal structure of the bound Pd(2+)-complex.

A new highly selective, ratiometric and colorimetric fluorescence sensor for Cu(2+) with a remarkable red shift in absorption and emission spectra based on internal charge transfer.

A new 1,8-diaminonaphthalene based ratiometric and highly selective colorimetric "off-on" type of fluorescent probe, receptor 2 has been designed and synthesized that senses only Cu(2+) among the other heavy and transition metal ions examined on the basis of internal charge transfer (ICT). The visual sensitivity of the receptor 2 is remarkable, showing dual color changes from colorless (receptor) to purple followed by blue and a large red shift in emission upon Cu(2+) complexation.

N-(6-{2-[6-(2,2-Dimethyl-propanamido)-2-pyrid-yl]eth-yl}-2-pyrid-yl)-2,2-dimethyl-propanamide.

The title compound, C(22)H(30)N(4)O(2), lies about a crystallographic inversion center. The whole mol-ecule is disordered over two positions with a refined occupancy ratio of 0.636 (10):0.

N-(6-Bromo-meth-yl-2-pyrid-yl)acetamide.

The title acetamide compound, C(8)H(9)BrN(2)O, crystallizes with three crystallographically independent mol-ecules (A, B and C) in the asymmetric unit. In mol-ecule A, the mean plane through the acetamide unit is inclined at a dihedral angle of 4.40 (11)° with respect to the pyridine ring [10.