MCPNet: a parallel maximum capacity-based genome-scale gene network construction framework.

MOTIVATION: Gene network reconstruction from gene expression profiles is a compute- and data-intensive problem. Numerous methods based on diverse approaches including mutual information, random forests, Bayesian networks, correlation measures, as well as their transforms and filters such as data processing inequality, have been proposed. However, an effective gene network reconstruction method that performs well in all three aspects of computational efficiency, data size scalability, and output quality remains elusive. Simple techniques such as Pearson correlation are fast to compute but ignore indirect interactions, while more robust methods such as Bayesian networks are prohibitively time consuming to apply to tens of thousands of genes. RESULTS: We developed maximum capacity path (MCP) score, a novel maximum-capacity-path-based metric to quantify the relative strengths of direct and indirect gene-gene interactions. We further present MCPNet, an efficient, parallelized gene network reconstruction software based on MCP score, to reverse engineer networks in unsupervised and ensemble manners. Using synthetic and real Saccharomyces cervisiae datasets as well as real Arabidopsis thaliana datasets, we demonstrate that MCPNet produces better quality networks as measured by AUPRC, is significantly faster than all other gene network reconstruction software, and also scales well to tens of thousands of genes and hundreds of CPU cores. Thus, MCPNet represents a new gene network reconstruction tool that simultaneously achieves quality, performance, and scalability requirements. AVAILABILITY AND IMPLEMENTATION: Source code freely available for download at https://doi.org/10.5281/zenodo.6499747 and https://github.com/AluruLab/MCPNet, implemented in C++ and supported on Linux.

Real-Space Infrared Spectroscopy of Ferroelectric Domain Walls in Multiferroic h-(Lu,Sc)FeO3.

We employ synchrotron-based near-field infrared spectroscopy to image the phononic properties of ferroelectric domain walls in hexagonal (h) Lu0.6Sc0.4FeO3, and we compare our findings with a detailed symmetry analysis, lattice dynamics calculations, and prior models of domain-wall structure. Rather than metallic and atomically thin as observed in the rare-earth manganites, ferroelectric walls in h-Lu0.6Sc0.4FeO3 are broad and semiconducting, a finding that we attribute to the presence of an A-site substitution-induced intermediate phase that reduces strain and renders the interior of the domain wall nonpolar. Mixed Lu/Sc occupation on the A site also provides compositional heterogeneity over micron-sized length scales, and we leverage the fact that Lu and Sc cluster in different ratios to demonstrate that the spectral characteristics at the wall are robust even in different compositional regimes. This work opens the door to broadband imaging of physical and chemical heterogeneity in ferroics and represents an important step toward revealing the rich properties of these flexible defect states.

EnGRaiN: a supervised ensemble learning method for recovery of large-scale gene regulatory networks.

MOTIVATION: Reconstruction of genome-scale networks from gene expression data is an actively studied problem. A wide range of methods that differ between the types of interactions they uncover with varying trade-offs between sensitivity and specificity have been proposed. To leverage benefits of multiple such methods, ensemble network methods that combine predictions from resulting networks have been developed, promising results better than or as good as the individual networks. Perhaps owing to the difficulty in obtaining accurate training examples, these ensemble methods hitherto are unsupervised. RESULTS: In this article, we introduce EnGRaiN, the first supervised ensemble learning method to construct gene networks. The supervision for training is provided by small training datasets of true edge connections (positives) and edges known to be absent (negatives) among gene pairs. We demonstrate the effectiveness of EnGRaiN using simulated datasets as well as a curated collection of Arabidopsis thaliana datasets we created from microarray datasets available from public repositories. EnGRaiN shows better results not only in terms of receiver operating characteristic and PR characteristics for both real and simulated datasets compared with unsupervised methods for ensemble network construction, but also generates networks that can be mined for elucidating complex biological interactions. AVAILABILITY AND IMPLEMENTATION: EnGRaiN software and the datasets used in the study are publicly available at the github repository: https://github.com/AluruLab/EnGRaiN. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

An alignment-free heuristic for fast sequence comparisons with applications to phylogeny reconstruction.

BACKGROUND: Alignment-free methods for sequence comparisons have become popular in many bioinformatics applications, specifically in the estimation of sequence similarity measures to construct phylogenetic trees. Recently, the average common substring measure, ACS, and its k-mismatch counterpart, ACSk, have been shown to produce results as effective as multiple-sequence alignment based methods for reconstruction of phylogeny trees. Since computing ACSk takes O(n logkn) time and hence impractical for large datasets, multiple heuristics that can approximate ACSk have been introduced. RESULTS: In this paper, we present a novel linear-time heuristic to approximate ACSk, which is faster than computing the exact ACSk while being closer to the exact ACSk values compared to previously published linear-time greedy heuristics. Using four real datasets, containing both DNA and protein sequences, we evaluate our algorithm in terms of accuracy, runtime and demonstrate its applicability for phylogeny reconstruction. Our algorithm provides better accuracy than previously published heuristic methods, while being comparable in its applications to phylogeny reconstruction. CONCLUSIONS: Our method produces a better approximation for ACSk and is applicable for the alignment-free comparison of biological sequences at highly competitive speed. The algorithm is implemented in Rust programming language and the source code is available at https://github.com/srirampc/adyar-rs .

Occupational Inhalation Exposures to Nanoparticles at Six Singapore Printing Centers.

Laser printers emit high levels of nanoparticles (PM0.1) during operation. Although it is well established that toners contain multiple engineered nanomaterials (ENMs), little is known about inhalation exposures to these nanoparticles and work practices in printing centers. In this report, we present a comprehensive inhalation exposure assessment of indoor microenvironments at six commercial printing centers in Singapore, the first such assessment outside of the United States, using real-time personal and stationary monitors, time-integrated instrumentation, and multiple analytical methods. Extensive presence of ENMs, including titanium dioxide, iron oxide, and silica, was detected in toners and in airborne particles collected from all six centers studied. We document high transient exposures to emitted nanoparticles (peaks of ∼500 000 particles/cm3, lung-deposited surface area of up to 220 µm2/cm3, and PM0.1 up to 16 µg/m3) with complex PM0.1 chemistry that included 40-60 wt % organic carbon, 10-15 wt % elemental carbon, and 14 wt % trace elements. We also record 271.6-474.9 pmol/mg of Environmental Protection Agency-priority polycyclic aromatic hydrocarbons. These findings highlight the potentially high occupational inhalation exposures to nanoparticles with complex compositions resulting from widespread usage of nano-enabled toners in the printing industry, as well as inadequate ENM-specific exposure control measures in these settings.

Diagnostic Yield of the Virtual Bronchoscopic Navigation System Guided Sampling of Peripheral Lung Lesions using Ultrathin Bronchoscope and Protected Bronchial Brush.

OBJECTIVES: The use of an ultrathin bronchoscope (UB) to diagnose peripheral pulmonary lesions is described. A virtual bronchoscopic navigation system was used to direct the ultrathin scope to the nodule. One of the constraints of this technique was the inability to confirm the target lesion position during biopsy by using a conventional linear endobronchial ultrasound probe, since the probe does not fit into a 1.2 mm working channel of this bronchoscope. The aim of the study was to review our institutional experience with the use of a UB for sampling peripheral pulmonary lesions using the transbronchial brush guided by virtual bronchoscopy. We describe a technique wherein we attempt to brush all the visible bronchial sub-segments once the bronchoscope has reached close to the nodule. MATERIALS AND METHODS: In total, 52 patients underwent the procedure between 2010 and 2017. A multiplanar computed tomography (CT) scan of the chest was obtained and subsequently uploaded to the Lung Point Virtual bronchoscopy navigation software. The UB was parked close to the lesion. All visible airway branches were then brushed using a protected bronchial brush. The data were retrospectively abstracted from the electronic medical records using standardized forms. RESULTS: A total of 52 lesions (40 solid, 8 part-solid, 3 cavitary, and 1 ground-glass) were sampled using a transbronchial brush (median, 2; range, 1-8). Twenty-four lesions were under 2 cm in size. The overall success rates were 67.3%. The average diameter of nodules was 2.7±1.01 cm; 65% lesions were in the outer-third of the lungs. The cancer-specific sensitivity was 72.5%. The presence of bronchus sign; location of the lesion; and the characteristics, size, and stage of cancer did not have any impact on the diagnostic yield. CONCLUSION: Virtual bronchoscopy-guided ultrathin bronchoscopy with bronchial brushing is safe and has a diagnostic yield comparable to other described techniques for evaluating peripheral pulmonary nodules.

Web-based Health Information Seeking and eHealth Literacy among Patients Living with Chronic Obstructive Pulmonary Disease (COPD).

Many people living with Chronic Obstructive Pulmonary Disease (COPD) have low general health literacy; however, there is little information available on these patients' eHealth literacy, or their ability to seek, find, understand, and appraise online health information and apply this knowledge to address or solve disease-related health concerns. A nationally representative sample of patients registered in the COPD Foundation's National Research Registry (N = 1,270) was invited to complete a web-based survey to assess socio-demographic (age, gender, marital status, education), health status (generic and lung-specific health-related quality of life), and socio-cognitive (social support, self-efficacy, COPD knowledge) predictors of eHealth literacy, measured using the 8-item eHealth literacy scale (eHEALS). Over 50% of the respondents (n = 176) were female (n = 89), with a mean age of 66.19 (SD = 9.47). Overall, participants reported moderate levels of eHealth literacy, with more than 70% feeling confident in their ability to find helpful health resources on the Internet. However, respondents were much less confident in their ability to distinguish between high- and low-quality sources of web-based health information. Very severe versus less severe COPD (ß = 4.15), lower lung-specific health-related quality of life (ß = -0.19), and greater COPD knowledge (ß = 0.62) were significantly associated with higher eHealth literacy. Higher COPD knowledge was also significantly associated with greater knowledge (ρ = 0.24, p = .001) and use (ρ = 0.24, p = .001) of web-based health resources. Findings emphasize the importance of integrating skill-building activities into comprehensive patient education programs that enable patients with severe cases of COPD to identify high-quality sources of web-based health information. Additional research is needed to understand how new social technologies can be used to help medically underserved COPD patients benefit from web-based self-management support resources.

A greedy alignment-free distance estimator for phylogenetic inference.

BACKGROUND: Alignment-free sequence comparison approaches have been garnering increasing interest in various data- and compute-intensive applications such as phylogenetic inference for large-scale sequences. While k-mer based methods are predominantly used in real applications, the average common substring (ACS) approach is emerging as one of the prominent alignment-free approaches. This ACS approach has been further generalized by some recent work, either greedily or exactly, by allowing a bounded number of mismatches in the common substrings. RESULTS: We present ALFRED-G, a greedy alignment-free distance estimator for phylogenetic tree reconstruction based on the concept of the generalized ACS approach. In this algorithm, we have investigated a new heuristic to efficiently compute the lengths of common strings with mismatches allowed, and have further applied this heuristic to phylogeny reconstruction. Performance evaluation using real sequence datasets shows that our heuristic is able to reconstruct comparable, or even more accurate, phylogenetic tree topologies than the kmacs heuristic algorithm at highly competitive speed. CONCLUSIONS: ALFRED-G is an alignment-free heuristic for evolutionary distance estimation between two biological sequences. This algorithm is implemented in C++ and has been incorporated into our open-source ALFRED software package ( http://alurulab.cc.gatech.edu/phylo ).

Efficient detection of viral transmissions with Next-Generation Sequencing data.

BACKGROUND: Hepatitis C is a major public health problem in the United States and worldwide. Outbreaks of hepatitis C virus (HCV) infections associated with unsafe injection practices, drug diversion, and other exposures to blood are difficult to detect and investigate. Molecular analysis has been frequently used in the study of HCV outbreaks and transmission chains; helping identify a cluster of sequences as linked by transmission if their genetic distances are below a previously defined threshold. However, HCV exists as a population of numerous variants in each infected individual and it has been observed that minority variants in the source are often the ones responsible for transmission, a situation that precludes the use of a single sequence per individual because many such transmissions would be missed. The use of Next-Generation Sequencing immensely increases the sensitivity of transmission detection but brings a considerable computational challenge because all sequences need to be compared among all pairs of samples. METHODS: We developed a three-step strategy that filters pairs of samples according to different criteria: (i) a k-mer bloom filter, (ii) a Levenhstein filter and (iii) a filter of identical sequences. We applied these three filters on a set of samples that cover the spectrum of genetic relationships among HCV cases, from being part of the same transmission cluster, to belonging to different subtypes. RESULTS: Our three-step filtering strategy rapidly removes 85.1% of all the pairwise sample comparisons and 91.0% of all pairwise sequence comparisons, accurately establishing which pairs of HCV samples are below the relatedness threshold. CONCLUSIONS: We present a fast and efficient three-step filtering strategy that removes most sequence comparisons and accurately establishes transmission links of any threshold-based method. This highly efficient workflow will allow a faster response and molecular detection capacity, improving the rate of detection of viral transmissions with molecular data.

Tracheobronchomalacia.

The term tracheobronchomalacia refers to excessively compliant and collapsible central airways leading to symptoms. Although seen as a coexisting condition with various other pulmonary condition, it may cause symptoms by itself. The condition is often misdiagnosed as asthma, bronchitis or just chronic cough due to a lack of specific pathognomonic history and clinical findings. The investigation revolves around different modes of imaging, lung function testing and usually confirmed by flexible bronchoscopy. The treatment widely varies based on the cause, with most cases treated conservatively with non-invasive ventilation. Some may require surgery or stent placement. In this article, we aim to discuss the pathophysiology behind this condition and recognize the common symptoms and causes of tracheobronchomalacia. The article will highlight the diagnostic steps as well as therapeutic interventions based on the specific cause.

A Case of Hepatopulmonary Syndrome.

We report the case of a 52-year-old female, a known case of Chronic Liver Disease with portal hypertension. She presented with dyspnoea, platypnoea, melena, cyanosis, clubbing and orthodeoxia. She had oesophageal varices and splenomegaly indicating portal hypertension. Her arterial blood gas revealed hypoxaemia and orthodeoxia. From this clinical background and investigation, a diagnosis of hepatopulmonary syndrome was made. Patient was managed conservatively as she was not willing for liver transplantation.

ALFRED: A Practical Method for Alignment-Free Distance Computation.

Alignment-free approaches are gaining persistent interest in many sequence analysis applications such as phylogenetic inference and metagenomic classification/clustering, especially for large-scale sequence datasets. Besides the widely used k-mer methods, the average common substring (ACS) approach has emerged to be one of the well-known alignment-free approaches. Two recent works further generalize this ACS approach by allowing a bounded number k of mismatches in the common substrings, relying on approximation (linear time) and exact computation, respectively. Albeit having a good worst-case time complexity [Formula: see text], the exact approach is complex and unlikely to be efficient in practice. Herein, we present ALFRED, an alignment-free distance computation method, which solves the generalized common substring search problem via exact computation. Compared to the theoretical approach, our algorithm is easier to implement and more practical to use, while still providing highly competitive theoretical performances with an expected run-time of [Formula: see text]. By applying our program to phylogenetic inference as a case study, we find that our program facilitates to exactly reconstruct the topology of the reference phylogenetic tree for a set of 27 primate mitochondrial genomes, at reasonably acceptable speed. ALFRED is implemented in C++ programming language and the source code is freely available online.

Rapid progression of pulmonary blastomycosis in an untreated patient of chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is associated with a state of immunosuppression characterized by hypogammaglobulinemia as well as B and T lymphocyte dysfunction. Though opportunistic infections are common in CLL patients, particularly after treatment, reports of infections by endemic dimorphic fungi are very few. Here we report a case of pulmonary blastomycosis in a CLL patient who initially presented with an indolent pulmonary mass lesion. The pulmonary lesions progressed rapidly over a two-week period. The diagnosis was established by transbronchial lung biopsy. He was treated with Amphotericin B lipid complex followed by oral itraconazole and recovered uneventfully. This case illustrates the importance of a timely diagnosis and treatment. The presentation of blastomycosis in immunocompromised patients, diagnosis, and treatment are discussed.

Malignant mesothelioma presenting as a gradually enlarging pneumothorax.

Malignant mesothelioma is an extremely aggressive tumor arising from the pleura with median survival of approximately 9-12 months. It can rarely present as a spontaneous pneumothorax. Less than 35 cases of malignant mesothelioma presenting as spontaneous pneumothorax have been reported in the literature. Pathology may show florid mesothelial hyperplasia. We herein report a case of mesothelioma presenting as a pneumothorax that gradually enlarged over a one-year period and also review the relevant literature.

Cerebellar atrophy in falciparum malaria.

Severe neurological complications are associated with falciparum malaria. We describe the case of an eight-year-old male child with severe falciparum malaria with high-level parasitemia and severe thrombocytopenia. There were features of abnormal gait, speech difficulty and altered behavior pattern during the recovery phase. This occurred even after receiving antimalarial therapy. MRI showed bilateral cerebellar atrophy.