Visualizing the dynamic mechanical power and time burden of mechanical ventilation patients: an analysis of the MIMIC-IV database.

BACKGROUND: Limiting driving pressure and mechanical power is associated with reduced mortality risk in both patients with and without acute respiratory distress syndrome. However, it is still poorly understood how the intensity of mechanical ventilation and its corresponding duration impact the risk of mortality. METHODS: Critically ill patients who received mechanical ventilation were identified from the Medical Information Mart for Intensive Care (MIMIC)-IV database. A visualization method was developed by calculating the odds ratio of survival for all combinations of ventilation duration and intensity to assess the relationship between the intensity and duration of mechanical ventilation and the mortality risk. RESULTS: A total of 6251 patients were included. The color-coded plot demonstrates the intuitive concept that episodes of higher dynamic mechanical power can only be tolerated for shorter durations. The three fitting contour lines represent 0%, 10%, and 20% increments in the mortality risk, respectively, and exhibit an exponential pattern: higher dynamic mechanical power is associated with an increased mortality risk with shorter exposure durations. CONCLUSIONS: Cumulative exposure to higher intensities and/or longer duration of mechanical ventilation is associated with worse outcomes. Considering both the intensity and duration of mechanical ventilation may help evaluate patient outcomes and guide adjustments in mechanical ventilation to minimize harmful exposure.

PD-1 blockade and radiotherapy combination for advanced Epstein-Barr virus-associated intrahepatic cholangiocarcinoma: a case report and literature review.

Advanced intrahepatic cholangiocarcinoma (ICC) is a rare malignant tumor of biliary epithelial cells, known for its extremely unfavorable prognosis. In the absence of intervention, patients typically survive for less than 5 months. Current guidelines from the Chinese Society of Clinical Oncology (CSCO), National Comprehensive Cancer Network (NCCN), and European Society for Medical Oncology (ESMO) recommend chemotherapy-based systemic therapy as the standard treatment for advanced ICC. However, the first-line regimen, consisting of gemcitabine in combination with cisplatin, generally results in a median survival of approximately one year, which is considered suboptimal. Significant progress has been made in radiotherapy techniques, molecular diagnostics, and tumor immune microenvironments. The integration of immune and radiation therapies has revolutionized treatment strategies for cholangiocarcinoma. Moreover, combined therapeutic regimens have shown promising results in improving survival rates among patients with advanced ICC. In this study, we present a case report of a 70-year-old male patient diagnosed with stage IV ICC, featuring metastases to the retroperitoneal, left adrenal, and left supraclavicular lymph nodes. The patient exhibited a high tumor mutational load, significant microsatellite instability, and hyper-expression of PD-L1 (90%), along with positive Epstein-Barr virus-encoded RNA (EBER). Pembrolizumab, a programmed cell death 1 (PD-1) inhibitor, was administered in conjunction with radiotherapy. As a result, considerable shrinkage and inactivation of the primary foci were observed, accompanied by the disappearance of metastases. Ultimately, the patient achieved complete remission and maintained progression-free survival for 41 months following the initial treatment. To the best of our knowledge, this represents the longest case of complete remission using a combination of immunotherapy and radiotherapy as a first-line regimen for the high tumor mutational load, microsatellite instability, and PD-L1 expression (90%) subtype of Epstein-Barr virus-associated ICC (EBVaICC). These findings suggest that the combination of PD-1 inhibitors with radiotherapy may serve as a promising therapeutic strategy for treating this particular cancer subtype.

Identifying duplications and lateral gene transfers simultaneously and rapidly.

This paper deals with the problem of enumerating all minimum-cost LCA-reconciliations involving gene duplications and lateral gene transfers (LGTs) for a given species tree [Formula: see text] and a given gene tree [Formula: see text]. Previously, [Tofigh A, Hallett M, Lagergren J, Simultaneous identification of duplications and lateral gene transfers, IEEE/ACM Trans Comput Biol Bioinf 517-535, 2011.] gave a fixed-parameter algorithm for this problem that runs in [Formula: see text] time, where [Formula: see text] is the number of vertices in [Formula: see text], [Formula: see text] is the number of vertices in [Formula: see text], and [Formula: see text] is the minimum cost of an LCA-reconciliation between [Formula: see text] and [Formula: see text]. In this paper, by refining their algorithm, we obtain a new one for the same problem that finds and outputs the solutions in a compact form within [Formula: see text] time. In the most interesting case where [Formula: see text], our algorithm is [Formula: see text] times faster.

Improved Practical Algorithms for Rooted Subtree Prune and Regraft (rSPR) Distance and Hybridization Number.

The problem of computing the rooted subtree prune and regraft (rSPR) distance of two phylogenetic trees is computationally hard and so is the problem of computing the hybridization number of two phylogenetic trees (denoted by Hybridization Number Computation [HNC]). Since they are important problems in phylogenetics, they have been studied extensively in the literature. Indeed, quite a number of exact or approximation algorithms have been designed and implemented for them. In this article, we design and implement several approximation algorithms for them and one exact algorithm for HNC. Our experimental results show that the resulting exact program is much faster (namely, more than 80 times faster for the easiest dataset used in the experiments) than the previous best and its superiority in speed becomes even more significant for more difficult instances. Moreover, the resulting approximation program's output has much better results than the previous bests; indeed, the outputs are always nearly optimal and often optimal. Of particular interest is the usage of the Monte Carlo tree search (MCTS) method in the design of our approximation algorithms. Our experimental results show that with MCTS, we can often solve HNC exactly within short time.

Computing a Consensus Phylogeny via Leaf Removal.

Given a set [Formula: see text]. of phylogenetic trees with the same leaf-label set X, we wish to remove some leaves from the trees so that there is a tree T with leaf-label set X displaying all the resulting trees. Note that the labels of leaves removed from one input tree may be different from those of leaves removed from another input tree. One objective is to minimize the total number of leaves removed from the trees, whereas the other is to minimize the maximum number of leaves removed from an input tree. Chauve et al. refer to the problem with the first (respectively, second) objective as AST-LR (respectively, AST-LR-d), and they show that both problems are NP-hard, where NP is the class of problems solvable in non-deterministic polynomial time. They further present algorithms for the parameterized versions of both problems. In this article, we point out that their algorithm for the parameterized version of AST-LR is flawed and present a new algorithm. Since neither Chauve et al.'s algorithm for AST-LR-d nor our new algorithm for AST-LR looks practical, we further design integer-linear programming (ILP for short) models for AST-LR and AST-LR-d, and we discuss speedup issues when using popular ILP solvers (say, GUROBI or CPLEX) to solve the models. Our experimental results show that our ILP approach is quite efficient.

CircPAN3 contributes to drug resistance in acute myeloid leukemia through regulation of autophagy.

The aim of this study was to investigate the role and underlying mechanism of circular RNA (circRNA) circPAN3 in mediating drug resistance in acute myeloid leukemia (AML). We first established two doxorubicin (ADM)-resistant AML cell lines and then utilized high-throughput RNA sequencing (RNA-seq) to compare their circRNA expression profiles with those of the parental cell lines. With bioinformatic analysis, we identified key circRNA molecules involved in drug resistance and validated our findings in clinical specimens. The target microRNAs (miRNAs) and downstream mRNAs were also explored bioinformatically. Using RNA interference technique, the potential mechanism was further investigated. Twenty-nine circRNAs were identified to be differentially expressed between ADM-resistant and sensitive cells. We found that circPAN3 is most likely a key mediator in the development of AML drug resistance, evidenced by the increased expression in ADM-resistant cell lines and BM samples from relapsed patients. Additionally, downregulation of circPAN3 by small interfering RNA (siRNA) significantly restored drug sensitivity to ADM in the two ADM-resistant cell lines, but lentivirus-mediated circPAN3 overexpression had the opposite effect. Subsequent bioinformatic analysis and mechanistic experiments revealed that circPAN3 may facilitate AML drug resistance through regulating autophagy and influencing expression of apoptosis-related proteins, while AMPK/mTOR signaling plays a key role in the regulation of circPAN3 on autophagy. These findings may provide new important insights into the role of circRNAs in mediating AML drug resistance, and suggest that circPAN3 might be a potential target for treatment of drug-resistance AML, which merits further investigation and validation.

CircPAN3 mediates drug resistance in acute myeloid leukemia through the miR-153-5p/miR-183-5p-XIAP axis.

The contribution and role of circular RNAs (circRNAs) in mediating chemoresistance in acute myeloid leukemia (AML) are still poorly understood and need further investigation. In this study, we established a doxorubicin (ADM)-resistant THP-1 AML cell line (THP-1/ADM). A high-throughput microarray was used to identify circRNA expression profiles of THP-1/ADM cells and naive THP-1 cells. The identified potential functional circRNA molecule was further validated in THP-1/ADM cells and bone marrow (BM) specimens from 42 AML patients. The interactions with target microRNAs (miRNAs) and downstream messenger RNAs (mRNAs) were also explored. As a result, 49 circRNAs that are significantly differentially expressed between THP-1/ADM and THP-1 cells were identified. Of these circRNAs, downregulation of circPAN3 by small interfering RNA significantly restored ADM sensitivity of THP-1/ADM cells. Furthermore, BM samples from patients with refractory and recurrent AML showed increased expression of circPAN3. A detailed circRNA/miRNA/mRNA interaction network was predicated for this circRNA. Subsequent mechanistic experiments showed that downregulation of circPAN3 could decrease the expression of X-linked inhibitor of apoptosis protein (XIAP), but this effect was counteracted by miR-153-3p or miR-183-5p specific inhibitors. Luciferase experiments further demonstrated that these molecules are involved in the circPAN3 regulatory network. Our results revealed that circPAN3 may be a key mediator for chemoresistance of AML cells, which may depend on the circPAN3-miR-153-5p/miR-183-5p-XIAP axis. Our findings provide evidence that circPAN3 can be a valuable indicator for predicting clinical efficacy of chemotherapy in AML patients and also can serve as a potential target for reversing drug resistance in AML.

[Effect of Expression Levels of MiRNA-132, -125, -143 and -145 on Autophagy and Apoptosis of Multiple Myeloma Cells].

OBJECTIVE: To investigate relationship of miRNA-132, miRNA-256, miRNA-143 and miRNA-145 level with antophagy and apoptosis of multiple mgeloma cells. METHODS: Human myeloma cell line U266 and normal CD138+ plasma cells were selected and used for study and detection, the 45 cases of MM were enrolled in MM group, and 40 normal persons were sellectod in control group. The expression of miRNA-132, miRNA-125b, miRNA-143 and miRNA-145 were measured by using qPCR, the expressions of autophagy-related protein (LC3-Ⅱ, LC3-Ⅰ, P62, beclin-1) and apoptosis-related molecules (cleaved-Caspase3, cleaved-Caspase7, BCL-2, BAX) were measured by using Western blot, respectively. The rate of apoptosis was measured by using flow cytometry. The correlation of miRNA expression level with clinical-related indexes including M protein, hemoglobin, ß2-MG, lactate dehydrogenase, albumin, creatinine and serum calcium was analyzed. RESULTS: Compared with normal plasma cells, the expression of miRNA-132 and miRNA-125b in myeloma cells increased significantly (P<0.05), and the expression of miRNA-143 and miRNA-145 decreased significantly (P<0.05), but the expression of LC3-Ⅱ/LC3-Ⅰ and Beclin-1 increased significantly (P<0.05). The expression of P62. BAX, cleaved-Caspase3 and cleaved-Caspase7 decreased significantly (P<0.05), the BCL-2 expression increased significantly (P<0.05), but the rate of apoptosis decreased (P<0.05). After transfection with miRNA-125b mimic or miRNA-143 inhibitor by using the cationic liposomes, the LC3-Ⅱ /LC3-Ⅰ of normal plasma cells increased significantly (P<0.05), the expression of Beclin-1 significantly increased (P<0.05), the expression of P62 decreased significantly (P<0.05), and the apoptosis rate decreased (P<0.05). However, the apoptosis rate was not significantly changed after addition of the autophagic inhibitor 3-MA in the reaction system(P>0.05). The expressions of miRNA-132, miRNA-125b, miRNA-143 and miRNA-145 were significantly different between DS and ISS staging group, also between the patients with abnormal and normal chromosome karyotype (P<0.05). The miRNA-125b and miRNA-143 significantly correlated with the levels of ß2-MG, albumin and hemoglobin (P<0.05). CONCLUSION: The expressions of miRNA-132, miRNA-125b, miRNA-143 and miRNA-145 in patients with multiple myeloma closely relate with the clinical characteristics. Both over-expression of miRNA-125b and down-expression of miRNA-143 inhibit the apoptosis of myeloma cells by up-regulation of autophagy.

Faster Exact Computation of rSPR Distance via Better Approximation.

Due to hybridization events in evolution, studying two different genes of a set of species may yield two related but different phylogenetic trees for the set of species. In this case, we want to measure the dissimilarity of the two trees. The rooted subtree prune and regraft (rSPR) distance of the two trees has been used for this purpose. The problem of computing the rSPR distance of two given trees has many applications but is NP-hard. Accordingly, a number of programs have been developed for solving the problem either exactly or approximately. In this paper, we develop two new programs one of which solves the problem exactly and outperforms the previous best (namely, Whidden et al.'s rSPR-v1.3.0) significantly, while the other solves the problem approximately and outputs significantly better lower and upper bounds on the rSPR distance of the two given trees than the previous best due to Schalekamp et al. Our programs can be downloaded at http://rnc.r.dendai.ac.jp/rspr.html.

Better ILP models for haplotype assembly.

BACKGROUND: The haplotype assembly problem for diploid is to find a pair of haplotypes from a given set of aligned Single Nucleotide Polymorphism (SNP) fragments (reads). It has many applications in association studies, drug design, and genetic research. Since this problem is computationally hard, both heuristic and exact algorithms have been designed for it. Although exact algorithms are much slower, they are still of great interest because they usually output significantly better solutions than heuristic algorithms in terms of popular measures such as the Minimum Error Correction (MEC) score, the number of switch errors, and the QAN50 score. Exact algorithms are also valuable because they can be used to witness how good a heuristic algorithm is. The best known exact algorithm is based on integer linear programming (ILP) and it is known that ILP can also be used to improve the output quality of every heuristic algorithm with a little decline in speed. Therefore, faster ILP models for the problem are highly demanded. RESULTS: As in previous studies, we consider not only the general case of the problem but also its all-heterozygous case where we assume that if a column of the input read matrix contains at least one 0 and one 1, then it corresponds to a heterozygous SNP site. For both cases, we design new ILP models for the haplotype assembly problem which aim at minimizing the MEC score. The new models are theoretically better because they contain significantly fewer constraints. More importantly, our experimental results show that for both simulated and real datasets, the new model for the all-heterozygous (respectively, general) case can usually be solved via CPLEX (an ILP solver) at least 5 times (respectively, twice) faster than the previous bests. Indeed, the running time can sometimes be 41 times better. CONCLUSIONS: This paper proposes a new ILP model for the haplotype assembly problem and its all-heterozygous case, respectively. Experiments with both real and simulated datasets show that the new models can be solved within much shorter time by CPLEX than the previous bests. We believe that the models can be used to improve heuristic algorithms as well.

Dual-Hole Excitons Activated Photoelectrolysis in Neutral Solution.

II-VI semiconductors exhibit unique behaviors that can generate dual-holes ("heavy and light"), but the application in photocatalysis is still missing. Herein, an empirical utilization of light/heavy holes in a hybrid metal cluster-2D semiconductor nanoplatelets is reported. This hybrid material can boost the hole-transfer at the surface and suppress the recombination. Different roles are enacted by light-holes and heavy-holes, in which the light-holes with higher energy and mobility can facilitate the slow kinetics of water oxidation and further reduce the onset voltage, while the massive heavy-holes can increase the resulting photocurrent by about five times, achieving a photocurrent of 2 mA cm-2 at 1.23 V versus RHE under AM 1.5 G illumination in nonsacrificial neutral solution. These strategies can be the solutions for photoelectrolysis and be beneficial for sustainable development in solar conversion.

Algorithms for Pedigree Comparison.

Reconstruction of ancestral relationships among genera, species, and populations is a core task in evolutionary biology. At the population level, pedigrees have been commonly used. Reconstruction of pedigree is required in practice due to legal or medical reasons. Pedigrees are very important to geneticists for inferring haplotype segments, recombination, and allele sharing status with which disease loci can be identified. Evaluating reconstruction methods requires comparing the inferred pedigree and the known pedigrees. Moreover, comparison of pedigrees is required in studying relationships among crops such as maize, wheat and barley, etc. In this paper, we discuss three models for comparison of pedigrees, the maximum pedigree isomorphism problem, the maximum paternal-path-preserved mapping problem, and the minimum edge-cutting mapping problem. For the maximum pedigree isomorphism problem, we prove that the problem is NP-hard and give a fixed-parameter algorithm for the problem. For the maximum paternal-path-preserved mapping problem, we give a dynamic-programming algorithm to find the mapping that preserves the maximum number of paternal paths between the two input pedigrees. For the minimum edge-cutting mapping problem, we prove that the problem is NP-hard and give a fixed-parameter algorithm with running time , where is the number of vertices in the two input pedigrees and is the number of edges to be cut. This algorithm is useful in practice when comparing two similar pedigrees.

[Expression of Apoptosis-related Protein Livin and Caspase-3 in Diffuse Large B Cell Lymphoma and Its Clinical Significance].

OBJECTIVE: To detect the expression levels of Livin and Caspase-3 proteins in diffuse large B cell lymphoma (DLBCL), and to explore its correlation with clinicopathological characteristics, so as to provide a reference for clinical treatment and evaluation prognosis of DLBCL. METHODS: Immunohisto-chemical staining was performed to detect the expression of Livin and Caspase-3 in the samples from 51 DLBCL patients and 20 patients with reactive hyperplasia of lymph node (RHL). The relation between Livin and Caspase-3 with the factors influencing the prognosis of DLBCL was analyzed. RESULTS: Livin+ was not expressed in the tissues of RHL, but its expression rates reached to 58.82%(30/51) in 51 cases of DLBCL(P<0.05). The expression rats of Caspase-3 in DLBCL and RHL were 25.49%(13/51) and 85.0%(17/20) respectively, and the difference was statistically significant(P<0.05). The expression level of Livin in DLBCL tissues was related with clinical stage and pathological type(P<0.01, P<0.01). The expression of Livin was not obviously related with sex, age and extranodal involvement. The expression level of Caspase-3 in DLBCL tissues was related with clinical stage (P<0.05). The expression of Caspase-3 was not obviously related with sex, age, pathological type and extranodal involvement. There was a negative correlation between Livin and Caspase-3 in DLBCL(γs=-0.333,P=0.017). Kaplan-meier survival analysis revealed that the expressions of Livin and Caspase-3 were related stalistically significantly with the patients prognosis (P<0.01, P<0.05). CONCLUSION: Over-expression of Livin in DLBCL and DLBCL of non-GCB subtypes, and low-expression of Caspase-3 in DLBCL may play a significant role in clinical prognosis of DLBCL.

Better ILP-Based Approaches to Haplotype Assembly.

Haplotype assembly is to directly construct the haplotypes of an individual from sequence fragments (reads) of the individual. Although a number of programs have been designed for computing optimal or heuristic solutions to the haplotype assembly problem, computing an optimal solution may take days or even months while computing a heuristic solution usually requires a trade-off between speed and accuracy. This article refines a previously known integer linear programming-based (ILP-based) approach to the haplotype assembly problem in twofolds. First, the read-matrices of some datasets (such as NA12878) come with a quality for each base in the reads. We here propose to utilize the qualities in the ILP-based approach. Secondly, we propose to use the ILP-based approach to improve the output of any heuristic program for the problem. Experiments with both real and simulated datasets show that the qualities of read-matrices help us find more accurate solutions without significant loss of speed. Moreover, our experimental results show that the proposed hybrid approach improves the output of ReFHap (the current leading heuristic) significantly (say, by almost 25% of the QAN50 score) without significant loss of speed, and can even find optimal solutions in much shorter time than the original ILP-based approach. Our program is available upon request to the authors.

Mutual blood donation is safer at small blood collection stations in China.

BACKGROUND: The assumption that the level of safety of voluntary non-remunerated donors is significantly higher than that of family replacement donors is supported by global data without stratifying for first-time or repeat volunteer, or according to age, but the viral marker prevalence between replacement donors and first-time voluntary non-remunerated donors is similar. MATERIALS AND METHODS: From 2006 to 2013, replacement and voluntary donors were respectively recruited by the hospitals and the Center Blood Station in Zhaoqing, Guangdong, according to the existing procedures, and all the donors were screened for hepatitis B virus (HBV) surface antigen (HBsAg), antibodies against hepatitis C virus (anti-HCV), human immunodeficiency virus (anti-HIV) (1 + 2) and Treponema pallidum (anti-TP) by the enzyme immunoassays (EIAs), and alanine aminotransferase (ALT) in the Center Blood Station by kinetic analysis method. The risk factors related to blood safety were analyzed by Binary logistic regression analysis. RESULTS: Between 252,202 volunteers and 2771 replacement donors, the prevalences of ALT > 40 U/L and anti-HIV (4.88% and 0.01% vs 4.44% and 0.07%, respectively) were not significantly different. The prevalences of HBsAg, anti-HCV and anti-syphilis in replacement group were higher than those in voluntary group, which were related to donor's sex, age and donation time. Overall prevalence of serological markers was higher in male replacement donors than in female, and in replacement donor over 30 years than in those below 30 years, but the positive prevalence in repeated replacement donors was lower than that in first-time replacement donors. CONCLUSIONS: With appropriate intervention measures, such as pre-donor screening and other donor selection policy, replacement donors and voluntary donors provide a similar level of viral safety. Our donor selection policy in future should focus on retaining both young replacement and young voluntary donors as repeat donors and promoting the donation proportion of females, which will improve blood safety.

Trehalose attenuates the gait ataxia and gliosis of spinocerebellar ataxia type 17 mice.

Spinocerebellar ataxia type 17 (SCA17) is caused by CAG/CAA repeat expansion on the gene encoding a general transcription factor, TATA-box-binding protein (TBP). The CAG repeat expansion leads to the reduced solubility of polyglutamine TBP and induces aggregate formation. The TBP aggregation, mostly present in the cell nuclei, is distinct from that in most other neurodegenerative diseases, in which the aggregation is formed in cytosol or extracellular compartments. Trehalose is a disaccharide issued by the Food and Drug Administration with a Generally Recognized As Safe status. Lines of evidence suggest trehalose could prevent protein aggregate formation in several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease. In this study, we evaluated the therapeutic potential of trehalose on SCA17 using cerebellar primary and organotypic culture systems and a mouse model. Our results showed that TBP nuclear aggregation was significantly decreased in both the primary and slice cultures. Trehalose (4 %) was further supplied in the drinking water of SCA17 transgenic mice. We found both the gait behavior in the footprint analysis and motor coordination in the rotarod task were significantly improved in the trehalose-treated SCA17 mice. The cerebellar weight was increased and the astrocyte gliosis was reduced in SCA17 mice after trehalose treatment. These data suggest that trehalose could be a potential nontoxic treatment for SCA17.

[Clinical and molecular characteristics of hemoglobin New York in Guangxi populations].

OBJECTIVE: To analyze the clinical and molecular characteristics of hemoglobin New York in populations from Guangxi and provide reference data for screening thalassemia. METHODS: A total of 30 691 samples were screened by capillary electrophoresis, and then suspicious samples of Hb New York were identified by DNA sequencing and analysis of blood cell count. Gap-PCR and reverse dot blot hybridization method were used for the detection of common mutations of α and ß thalassemia in Chinese. RESULTS: The incidence of Hb New York was 0.12% in Guangxi. The hematological phenotype index (MCV, MCH, Hb New York, Hb A2) of 32 Hb New York heterozygous cases were (91.00±5.19)fl, (29.42±2.04)pg, (44.10±3.12)% and (2.80±0.29)% , respectively. The hematological phenotype index of 4 Hb New York composited SEA heterozygous patients were (68.20±5.26) fl, (21.78±2.15) pg, (36.60±2.00)% and (2.90±0.14)% , of 2 Hb New York composited WS heterozygous patients were (83.90±2.69) fl, (27.70±1.70) pg, (39.70±1.70)% and (3.50±0.21)%. There were statistical differences between three groups (P<0.05). HGB, MCV and MCH of Hb New York heterozygous and Hb New York composited WS heterozygous were normal, and patients with Hb New York composited SEA heterozygous showed mild anemia, decreased MCV and MCH. CONCLUSION: Most of Hb New York were heterozygous and no homozygotes in Guangxi. There were different hematological characteristics in different Hb New York heterozygous patients. Hb New York heterozygous had normal hematological phenotype, ant combined with other types of thalassemia could exhibit symptoms such as anemia.

Exact algorithms for haplotype assembly from whole-genome sequence data.

MOTIVATION: Haplotypes play a crucial role in genetic analysis and have many applications such as gene disease diagnoses, association studies, ancestry inference and so forth. The development of DNA sequencing technologies makes it possible to obtain haplotypes from a set of aligned reads originated from both copies of a chromosome of a single individual. This approach is often known as haplotype assembly. Exact algorithms that can give optimal solutions to the haplotype assembly problem are highly demanded. Unfortunately, previous algorithms for this problem either fail to output optimal solutions or take too long time even executed on a PC cluster. RESULTS: We develop an approach to finding optimal solutions for the haplotype assembly problem under the minimum-error-correction (MEC) model. Most of the previous approaches assume that the columns in the input matrix correspond to (putative) heterozygous sites. This all-heterozygous assumption is correct for most columns, but it may be incorrect for a small number of columns. In this article, we consider the MEC model with or without the all-heterozygous assumption. In our approach, we first use new methods to decompose the input read matrix into small independent blocks and then model the problem for each block as an integer linear programming problem, which is then solved by an integer linear programming solver. We have tested our program on a single PC [a Linux (x64) desktop PC with i7-3960X CPU], using the filtered HuRef and the NA 12878 datasets (after applying some variant calling methods). With the all-heterozygous assumption, our approach can optimally solve the whole HuRef data set within a total time of 31 h (26 h for the most difficult block of the 15th chromosome and only 5 h for the other blocks). To our knowledge, this is the first time that MEC optimal solutions are completely obtained for the filtered HuRef dataset. Moreover, in the general case (without the all-heterozygous assumption), for the HuRef dataset our approach can optimally solve all the chromosomes except the most difficult block in chromosome 15 within a total time of 12 days. For both of the HuRef and NA12878 datasets, the optimal costs in the general case are sometimes much smaller than those in the all-heterozygous case. This implies that some columns in the input matrix (after applying certain variant calling methods) still correspond to false-heterozygous sites. AVAILABILITY: Our program, the optimal solutions found for the HuRef dataset available at http://rnc.r.dendai.ac.jp/hapAssembly.html.

An ultrafast tool for minimum reticulate networks.

Due to hybridization events in evolution, studying different genes of a set of species may yield two or more related but different phylogenetic trees for the set of species. In this case, we want to combine the trees into a reticulate network with the fewest hybridization events. In this article, we develop a software tool (named UltraNet) for several fundamental problems related to the construction of minimum reticulate networks from two or more phylogenetic trees. Our experimental results show that UltraNet is much faster than all previous tools for these problems.