Deep Learning Nomogram for the Identification of Deep Stromal Invasion in Patients With Early-Stage Cervical Adenocarcinoma and Adenosquamous Carcinoma: A Multicenter Study.

BACKGROUND: Deep stromal invasion (DSI) is one of the predominant risk factors that determined the types of radical hysterectomy (RH). Thus, the accurate assessment of DSI in cervical adenocarcinoma (AC)/adenosquamous carcinoma (ASC) can facilitate optimal therapy decision. PURPOSE: To develop a nomogram to identify DSI in cervical AC/ASC. STUDY TYPE: Retrospective. POPULATION: Six hundred and fifty patients (mean age of 48.2 years) were collected from center 1 (primary cohort, 536), centers 2 and 3 (external validation cohorts 1 and 2, 62 and 52). FIELD STRENGTH/SEQUENCE: 5-T, T2-weighted imaging (T2WI, SE/FSE), diffusion-weighted imaging (DWI, EPI), and contrast-enhanced T1-weighted imaging (CE-T1WI, VIBE/LAVA). ASSESSMENT: The DSI was defined as the outer 1/3 stromal invasion on pathology. The region of interest (ROI) contained the tumor and 3 mm peritumoral area. The ROIs of T2WI, DWI, and CE-T1WI were separately imported into Resnet18 to calculate the DL scores (TDS, DDS, and CDS). The clinical characteristics were retrieved from medical records or MRI data assessment. The clinical model and nomogram were constructed by integrating clinical independent risk factors only and further combining DL scores based on primary cohort and were validated in two external validation cohorts. STATISTICAL TESTS: Student's t-test, Mann-Whitney U test, or Chi-squared test were used to compare differences in continuous or categorical variables between DSI-positive and DSI-negative groups. DeLong test was used to compare AU-ROC values of DL scores, clinical model, and nomogram. RESULTS: The nomogram integrating menopause, disruption of cervical stromal ring (DCSRMR), DDS, and TDS achieved AU-ROCs of 0.933, 0.807, and 0.817 in evaluating DSI in primary and external validation cohorts. The nomogram had superior diagnostic ability to clinical model and DL scores in primary cohort (all P < 0.0125 [0.05/4]) and CDS (P = 0.009) in external validation cohort 2. DATA CONCLUSION: The nomogram achieved good performance for evaluating DSI in cervical AC/ASC. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

GPR84 regulates pulmonary inflammation by modulating neutrophil functions.

Acute lung injury (ALI) is an acute, progressive hypoxic respiratory failure that could develop into acute respiratory distress syndrome (ARDS) with very high mortality rate. ALI is believed to be caused by uncontrolled inflammation, and multiple types of immune cells, especially neutrophils, are critically involved in the development of ALI. The treatment for ALI/ARDS is very limited, a better understanding of the pathogenesis and new therapies are urgently needed. Here we discover that GPR84, a medium chain fatty acid receptor, plays critical roles in ALI development by regulating neutrophil functions. GPR84 is highly upregulated in the cells isolated from the bronchoalveolar lavage fluid of LPS-induced ALI mice. GPR84 deficiency or blockage significantly ameliorated ALI mice lung inflammation by reducing neutrophils infiltration and oxidative stress. Further studies reveal that activation of GPR84 strongly induced reactive oxygen species production from neutrophils by stimulating Lyn, AKT and ERK1/2 activation and the assembly of the NADPH oxidase. These results reveal an important role of GPR84 in neutrophil functions and lung inflammation and strongly suggest that GPR84 is a potential drug target for ALI.

Mechanism of Salt Tolerance and Plant Growth Promotion in Priestia megaterium ZS-3 Revealed by Cellular Metabolism and Whole-Genome Studies.

Approximately one-third of agricultural land worldwide is affected by salinity, which limits the productivity and sustainability of crop ecosystems. Plant-growth-promoting rhizobacteria (PGPR) are a potential solution to this problem, as PGPR increases crop yield through improving soil fertility and stress resistance. Previous studies have shown that Priestia megaterium ZS-3(ZS-3) can effectively help plants tolerate salinity stress. However, how ZS-3 regulates its metabolic adaptations in saline environments remains unclear. In this study, we monitored the metabolic rearrangement of compatibilisers in ZS-3 and combined the findings with genomic data to reveal how ZS-3 survives in stressful environments, induces plant growth, and tolerates stress. The results showed that ZS-3 tolerated salinity levels up to 9%. In addition, glutamate and trehalose help ZS-3 adapt to osmotic stress under low NaCl stress, whereas proline, K+, and extracellular polysaccharides regulate the osmotic responses of ZS-3 exposed to high salt stress. Potting experiments showed that applying the ZS-3 strain in saline and neutral soils could effectively increase the activities of soil acid phosphatase, urease, and invertase in both soils, thus improving soil fertility and promoting plant growth. In addition, strain ZS-3-GFP colonised the rhizosphere and leaves of Cinnamomum camphora well, as confirmed by confocal microscopy and resistance plate count analysis. Genomic studies and in vitro experiments have shown that ZS-3 exhibits a variety of beneficial traits, including plant-promoting, antagonistic, and other related traits (such as resistance to saline and heavy metal stress/tolerance, amino acid synthesis and transport, volatile compound synthesis, micronutrient utilisation, and phytohormone biosynthesis/regulatory potential). The results support that ZS-3 can induce plant tolerance to abiotic stresses. These data provide important clues to further reveal the interactions between plants and microbiomes, as well as the mechanisms by which micro-organisms control plant health.

[Echinacoside hampers malignant progression of breast cancer MCF-7 cells by modulating AKR1B10/ERK signal transduction].

This study analyzes the impact of echinacoside(ECH) in the proliferation, metastasis and adriamycin(ADR) resistance of breast cancer(BC) MCF-7 cells via the modulation of aldo-keto reductase family 1 member 10(AKR1B10)/extracellular signal-regulated kinase(ERK) pathway. The chemical structure of ECH was firstly confirmed. MCF-7 cells were treated with different concentration(0, 10, 20, 40 µg·mL~(-1)) of ECH for 48 h. Western blot was used to analyze expression of AKR1B10/ERK pathway-associated proteins and cell counting kit-8(CCK-8) assay to determine cell viability. MCF-7 cells were collected and classified into control group, ECH group, ECH + Ov-NC group, and ECH + Ov-AKR1B10 group. Then Western blot was employed to analyze the expression of AKR1B10/ERK pathway-associated proteins. CCK-8 and 5-ethynyl-2'-deoxyuridine(EdU) assay were used to examine cell proliferation. Cell migration was appraised with scratch assay, Transwell assay, and Western blot. Eventually, MCF-7 cells were treated with ADR for 48 h to induce ADR resistance. Cell viability was tested by CCK-8 assay and cell apoptosis was estimated based on terminal-deoxynucleoitidyl transferase mediated nick end labeling(TUNEL) assay and Western blot. Based on Protein Data Bank(PDB) and molecular docking, the binding affinity of ECH to AKR1B10 was assessed. Various doses of ECH decreased the expression of AKR1B10/ERK pathway-associated proteins in a dose-dependent manner and declined cell viability compared with the control group. Compared with the control group, 40 µg·mL~(-1) ECH blocked the AKR1B10/ERK pathway in MCF-7 cells and inhibited the proliferation, metastasis and ADR resistance of the cells. Compared with the ECH + Ov-NC group, ECH + Ov-AKR1B10 group showed the recovery of some biological behaviors of MCF-7 cells. ECH also targeted AKR1B10. ECH can inhibit the proliferation, metastasis, and ADR resistance of BC cells by blocking AKR1B10/ERK pathway.

NaGa3Se5: An Infrared Nonlinear Optical Material with Balanced Performance Contributed by Complex {[Ga3Se5]-}∞ Anionic Network.

Second-order nonlinear optical (NLO) materials are extensively applied in laser-related techniques. For developing IR NLO materials, chalcogenides are the main candidates. Here, NaGa3Se5 was explored as inspired by its unique anionic structure. It crystallizes with the orthorhombic chiral P212121 structure, featuring 12 types of GaSe4 tetrahedra built into a three-dimensional {[Ga3Se5]-}∞ anionic network, representing a new NLO-functional motif. NaGa3Se5 exhibits large and phase-matchable NLO response 1.37 × AgGaS2. It has the largest band gap among the noncentrosymmetric A-MIII-Se (A = alkali metal; M = Ga, In) compounds. The NLO properties' origin is explored via theoretical analysis. The success of NaGa3Se5 contributes a practical case for exploring new NLO materials.

Characterizations and Nonlinear-Optical Properties of Pentanary Transition-Metal Oxysulfide Sr2CoGe2OS6.

As one type of material containing multiple anions, oxysulfides can combine the advantages of oxides and sulfides and are deeply studied as nonlinear-optical (NLO) materials. Herein, a new melilite-type pentanary oxysulfide Sr2CoGe2OS6 is studied. It crystallizes in the noncentrosymmetric tetragonal space group P4̅21m, and its structure features GeOS3 and CoS4 tetrahedra-built {[CoGe2OS6]4-}∞ layers. Its powder sample exhibits a moderate phase-matchable NLO response and a high laser-induced damage threshold. The NLO response is mainly determined by CoS4 tetrahedra according to the theoretical calculation results. This work indicates that transition-metal oxysulfides can also be considered as potential infrared NLO materials.

Structural Chemistry and Excellent Nonlinear Optical Properties of a Series of Ternary Selenides GaxIn2-xSe3.

Novel nonlinear optical (NLO) materials possessing simple chemical compositions and facile syntheses are competitive when considering their practical application. Here, a series of ternary selenides GaxIn2-xSe3 (x = 0.07, 0.38, 0.45, and 0.81) that crystallize in a chiral P65 structure are obtained by melting Ga, In, and Se elements. Their three-dimensional structures are built by (Ga/In)Se4 tetrahedra and InSe5 trigonal bipyramids. The hexagonal modification's phase stability is analyzed by energy calculation, and their optical band gaps are determined to be 1.72-1.99 eV. They exhibit large NLO responses that are 1.41-1.64 times that of the benchmark AgGaS2. The results of density functional theory calculations suggest that introduction of Ga onto the In site in (InSe4)5- units can form a deformed tetrahedron with more distortion in the structure, and the (InSe5)7- units contribute a large amount of birefringence to the structure. This work is the first to investigate the ternary chalcogenides M2Q3 (M = Ga or In; Q = S or Se) as new types of infrared NLO crystals with excellent performances, which will stimulate more interest in those possessing simple compositions and outstanding performances.

GPR84 signaling promotes intestinal mucosal inflammation via enhancing NLRP3 inflammasome activation in macrophages.

The putative medium-chain free fatty acid receptor GPR84 is a G protein-coupled receptor primarily expressed in myeloid cells that constitute the innate immune system, including neutrophils, monocytes, and macrophages in the periphery and microglia in the brain. The fact that GPR84 expression in leukocytes is remarkably increased under acute inflammatory stimuli such as lipopolysaccharide (LPS) and TNFα suggests that it may play a role in the development of inflammatory and fibrotic diseases. Here we demonstrate that GPR84 is highly upregulated in inflamed colon tissues of active ulcerative colitis (UC) patients and dextran sulfate sodium (DSS)-induced colitis mice. Infiltrating GPR84+ macrophages are significantly increased in the colonic mucosa of both the UC patients and the mice with colitis. Consistently, GPR84-/- mice are resistant to the development of colitis induced by DSS. GPR84 activation imposes pro-inflammatory properties in colonic macrophages through enhancing NLRP3 inflammasome activation, while the loss of GPR84 prevents the M1 polarization and properties of proinflammatory macrophages. CLH536, a novel GPR84 antagonist discovered by us, suppresses colitis by reducing the polarization and function of pro-inflammatory macrophages. These results define a unique role of GPR84 in innate immune cells and intestinal inflammation, and suggest that GPR84 may serve as a potential drug target for the treatment of UC.

Prediction of Patient Survival with Psoas Muscle Density Following Transjugular Intrahepatic Portosystemic Shunts: A Retrospective Cohort Study.

BACKGROUND Psoas muscle density (PMD) as a nutritional indicator is a tool to evaluate sarcopenia, which is commonly diagnosed in patients with liver cirrhosis. However, there are limited data on its role in patients who have received a transjugular intrahepatic portosystemic shunt (TIPS). We aimed to determine the utility of PMD in predicting mortality of patients with TIPS implantation and to compare the clinical value of PMD, Child-Pugh score, model for end-stage liver disease (MELD) score, and MELD paired with serum sodium measurement (MELD-Na) score in predicting post-TIPS survival in 1 year. MATERIAL AND METHODS This retrospective study included 273 patients who met the criteria for study inclusion. All participants underwent computed tomography (CT) scans, Child-Pugh score evaluation, MELD-Na scoring, and MELD scoring. Post-TIPS survival time was estimated using the Kaplan-Meier survival curve. The prognostic values of scoring models such as the Child-Pugh score, MELD, MELD-Na, and PMD were evaluated using receiver operating characteristic curves. RESULTS During the 1-year follow-up period, 31 of 273 (11.36%) post-TIPS patients died. Multivariate analysis identified PMD as an independent protective factor. PMD showed a good ability to predict the occurrence of an endpoint within 1 year after TIPS. The area under the receiver operating characteristic curves for PMD, Child-Pugh score, MELD score, and MELD-Na for predicting mortality were, respectively, 0.72 (95% confidence interval [CI]: 0.663-0.773), 0.59 (95% CI: 0.531-0.651), 0.60 (95% CI: 0.535-0.655), and 0.58 (95% CI: 0.487-0.608). CONCLUSIONS PMD has appreciable clinical value for predicting the mortality of patients with TIPS implantation. In addition, PMD is superior to established scoring systems for identifying high-risk patients with a poor prognosis.

The diagnostic efficiency of the perfusion-related parameters in assessing the vascular disrupting agent (CA4P) response in a rabbit VX2 liver tumor model.

BACKGROUND: There are inconsistencies when concomitantly using dynamic contrast enhancement (DCE) and intravoxel incoherent motion (IVIM) to evaluate diagnostic efficiency. PURPOSE: To evaluate the diagnostic efficiency of perfusion-related parameters in assessing the effect of Combretastatin-A4-phosphate (CA4P) in a rabbit VX2 liver tumor model using DCE and IVIM. MATERIAL AND METHODS: Twenty rabbits implanted with VX2 tumors were included in the study. The perfusion-parameters of DCE (Ktrans and iAUC60) and IVIM (f and D*) were measured at baseline and 4 h after administration of CA4P. Subsequently, the rabbits were euthanized. Pre- and post-treatment perfusion parameters were analyzed using paired t-test. Correlation between the various perfusion parameters and correlation of perfusion parameters with microvascular density (MVD) were assessed using Pearson correlation analysis. The diagnostic efficiency was evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS: All perfusion parameters (Ktrans, iAUC60, f and D*) showed significant decrease after 4 h of CA4P administration (all P < 0.001). Post-treatment perfusion parameters showed a moderate correlation with MVD (r = 0.663, r = 0.567, r = 0.685, r = 0.618, respectively; all P < 0.05). At baseline and after treatment, Ktrans values and iAUC60 showed correlation with f and D* (all P < 0.05). Concomitant use of perfusion parameters of DCE and IVIM showed the best diagnostic performance, which was slightly greater than that observed with individual application of DCE or IVIM (AUC = 0.915, 0.880, and 0.895, respectively). CONCLUSION: Although concomitant application of DCE and IVIM can slightly improve the diagnostic value in assessing the effect of CA4P, the values were relatively small.

Hypermethylation of heparanase 2 promotes colorectal cancer proliferation and is associated with poor prognosis.

BACKGROUND: The epigenetic abnormality of tumor-associated genes contributes to the pathogenesis of colorectal carcinoma (CRC). However, methylation in colorectal cancer is still poorly characterized. METHOD: By integration of DNA methylation data from the GEO database and gene expression data from The Cancer Genome Atlas database, the aberrantly methylated genes involved in CRC tumorigenesis were identified. Subsequent in vitro experiments further validated their role in CRC. RESULTS: We performed integrative genomic analysis and identified HPSE2, a novel tumor suppressor gene that is frequently inactivated through promoter methylation in CRC. K-M survival analysis showed that hypermethylation-low expression of heparanase 2 (HPSE2) was related to poor patient prognosis. Overexpression of HPSE2 reduced cell proliferation in vivo and in vitro. HPSE2 could regulate the p53 signaling pathway to block the cell cycle in G1 phase. CONCLUSION: HPSE2, a novel tumor suppressor gene that is frequently inactivated through promoter methylation in CRC. HPSE2 performs a tumor suppressive function by activating the p53/ p21 signaling cascade. The promoter hypermethylation of HPSE2 is a potential therapeutic target in patients with CRC, especially those with late-stage CRC.

Decreased mortality seen in rifampicin/multidrug-resistant tuberculous meningitis treated with linezolid in Shenzhen, China.

BACKGROUND: The morbidity of rifampicin/multidrug-resistant tuberculous meningitis (RR/MDR-TBM) has shown an increasing trend globally. Its mortality rate is significantly higher than that of non-rifampicin/multidrug-resistant tuberculous meningitis (NRR/MDR-TBM). This article aimed to explore risk factors related to RR/MDR-TBM, and compare therapeutic effects of linezolid (LZD)- and non-linezolid-containing regimen for RR/MDR-TB patients in Shenzhen city. Furthermore, we aimed to find a better therapy for pathogen-negative TBM with RR/MDR-TBM related risk factors. METHODS: We conducted a retrospective study enrolling 137 hospitalized cases with confirmed TBM from June 2014 to March 2020. All patients were divided into RR/MDR-TBM group (12 cases) and NRR/MDR-TBM group (125 cases) based on GeneXpert MTB/RIF and (or) phenotypic drug susceptibility test results using cerebral spinal fluid (CSF). The risk factors related to RR/MDR-TBM were investigated through comparing clinical and examination features between the two groups. The mortality rate of RR/MDR-TBM patients treated with different regimens was analyzed to compare their respective therapeutic effects. A difference of P < 0.05 was considered statistically significant. RESULTS: Most patients (111/137, 81%) were from southern or southwestern China, and a large proportion (72/137, 52.55%) belonged to migrant workers. 12 cases were RR/MDR-TBM (12/137, 8.8%) while 125 cases were NRR/MDR-TBM (125/137, 91.2%). The proportion of patients having prior TB treatment history in the RR/MDR-TBM group was significantly higher than that of the NRR/MDR-TBM group (6/12 vs. 12/125, 50% vs. 10.5%, P < 0.01). No significant difference was observed on other clinical and examination features between the two groups. Mortality was significantly lower in RR/MDR-TBM patients on linezolid-containing treatment regimen than those who were not (0/7 versus 3/5, 0% versus 60%, P = 0.045). CONCLUSIONS: The main related risk factor of RR/MDR-TBM is the history of anti-tuberculosis treatment. Linezolid-containing regimen appears to lower mortality rate of RR/MDR-TBM significantly in our study. We think Linezolid should be evaluated prospectively in the treatment of RR/MDR-TBM.

The Feature Description of Formal Context Based on the Relationships among Concept Lattices.

Three-way concept analysis (3WCA) is extended research of formal concept analysis (FCA) by combining three-way decision. The three-way object oriented concept lattice (OEOL) is one of the important data structures which integrates rough set, concept lattice and three-way decision in 3WCA. In the paper, we investigate the characteristics of formal context based on the isomorphic relationship among the kinds of concept lattices with OEOL. Firstly, II-dual intersectable attributes and II-dual intersectable context are proposed and the relationship between the type I-dual intersectable context(dual intersectable context) and the type II-dual intersectable context are studied. In addition, the relationship among the kinds of concept lattices with OEOL are studied when the formal context is both I-dual intersectable context and II-dual intersectable context. Finally, the inverse problems of the above conclusions are discussed and the following two conclusions are obtained: (1) the formal context is the type II-dual intersectable context, when the object oriented concept lattice and OEOL are isomorphic. (2) In addition, the formal context is the type I-dual intersectable context, when the concept lattice and OEOL are anti-isomorphic.

Tumor-associated antigen-based personalized dendritic cell vaccine in solid tumor patients.

Tumor-associated antigens (TAAs) have been tested in various clinical trials in cancer treatment but the patterns of specific T cell response to personalized TAA immunization remains to be fully understood. We report antigen-specific T cell responses in patients immunized with dendritic cell vaccines pulsed with personalized TAA panels. Tumor samples from patients were first analyzed to identify overexpressed TAAs. Autologous DCs were then transfected with pre-manufactured mRNAs encoding the full-length TAAs, overexpressed in the patients' tumors. Patients with glioblastoma multiforme (GBM) or advanced lung cancer received DC vaccines transfected with personalized TAA panels, in combination with low-dose cyclophosphamide, poly I:C, imiquimod and anti-PD-1 antibody. Antigen-specific T cell responses were measured. Safety and efficacy were evaluated. A total of ten patients were treated with DC vaccines transfected with personalized TAA panels containing 3-13 different TAAs. Among the seven patients tested for anti-TAA T cell responses, most of the TAAs induced antigen-specific CD4+ and/or CD8+ T cell responses, regardless of their expression levels in the tumor tissues. No Grade III/IV adverse events were observed among these patients. Furthermore, the treated patients were associated with favorable overall survival when compared to patients who received standard treatment in the same institution. Personalized TAA immunization-induced-specific CD4+ and CD8+ T cell responses without obvious autoimmune adverse events and was associated with favorable overall survival. These results support further studies on DC immunization with personalized TAA panels for combined immunotherapeutic regimens in solid tumor patients.Trial registration ClinicalTrials.gov, NCT02709616 (March, 2016), NCT02808364 (June 2016), NCT02808416 (June, 2016).

Identification of temporal condition patterns associated with pediatric obesity incidence using sequence mining and big data.

BACKGROUND: Electronic health records (EHRs) are potentially important components in addressing pediatric obesity in clinical settings and at the population level. This work aims to identify temporal condition patterns surrounding obesity incidence in a large pediatric population that may inform clinical care and childhood obesity policy and prevention efforts. METHODS: EHR data from healthcare visits with an initial record of obesity incidence (index visit) from 2009 through 2016 at the Children's Hospital of Philadelphia, and visits immediately before (pre-index) and after (post-index), were compared with a matched control population of patients with a healthy weight to characterize the prevalence of common diagnoses and condition trajectories. The study population consisted of 49,694 patients with pediatric obesity and their corresponding matched controls. The SPADE algorithm was used to identify common temporal condition patterns in the case population. McNemar's test was used to assess the statistical significance of pattern prevalence differences between the case and control populations. RESULTS: SPADE identified 163 condition patterns that were present in at least 1% of cases; 80 were significantly more common among cases and 45 were significantly more common among controls (p < 0.05). Asthma and allergic rhinitis were strongly associated with childhood obesity incidence, particularly during the pre-index and index visits. Seven conditions were commonly diagnosed for cases exclusively during pre-index visits, including ear, nose, and throat disorders and gastroenteritis. CONCLUSIONS: The novel application of SPADE on a large retrospective dataset revealed temporally dependent condition associations with obesity incidence. Allergic rhinitis and asthma had a particularly high prevalence during pre-index visits. These conditions, along with those exclusively observed during pre-index visits, may represent signals of future obesity. While causation cannot be inferred from these associations, the temporal condition patterns identified here represent hypotheses that can be investigated to determine causal relationships in future obesity research.

Whole-body physiology-based pharmacokinetics of caspofungin for general patients, intensive care unit patients and hepatic insufficiency patients.

Caspofungin is an echinocandin antifungal agent licensed as a first-line therapy for invasive candidiasis in patients with moderate to severe illness or recent exposure to azoles. In this study we developed a whole-body physiology-based pharmacokinetics (WB-PBPK) model to predict the pharmacokinetics (PK) of caspofungin, and combined with Monte Carlo simulation (MCS) to optimize clinical dosage regimens of caspofungin in different kinds of patients. A WB-PBPK model of caspofungin was built and validated with raw data from 4 previous trials of general patients, intensive care unit (ICU) patients with Child-Pugh B, ICU patients on continuous renal replacement therapy, mild and moderate hepatic insuffciency (HI) patients. MCS was used to optimize clinical dosage regimens of caspofungin in these patients. A cumulative fraction of response (CFR) value of ≥90% was considered to be the minimum for achieving optimal empirical therapy. The simulated results of the WB-PBPK model were in good agreement with observed values of all trials. For general and ICU patients with caspofungin 70/50 mg, AUC and Cmax were decreased with the increase of body weight (BW) and showed great variation. MCS showed all general patients achieved CFR≥90% regardless of BW. But not all ICU patients with higher BW (≥70 kg) could achieve CFR≥90%. Compared with standard dosage regimens in general patients, caspofungin 70/35 mg in ICU patients with Child-Pugh B achieved significantly decreased AUC and Cmax, but obtained similar AUC and Cmax in moderate HI patients with Child-Pugh B. The WB-PBPK model of caspofungin is able to predict PK of all populations correctly. The combined WB-PBPK model with MCS can successfully optimize clinical dosage regimens of caspofungin in all patient populations.

Subcellular Relocalization and Positive Selection Play Key Roles in the Retention of Duplicate Genes of Populus Class III Peroxidase Family.

Gene duplication is the primary source of new genes and novel functions. Over the course of evolution, many duplicate genes lose their function and are eventually removed by deletion. However, some duplicates have persisted and evolved diverse functions. A particular challenge is to understand how this diversity arises and whether positive selection plays a role. In this study, we reconstructed the evolutionary history of the class III peroxidase (PRX) genes from the Populus trichocarpa genome. PRXs are plant-specific enzymes that play important roles in cell wall metabolism and in response to biotic and abiotic stresses. We found that two large tandem-arrayed clusters of PRXs evolved from an ancestral cell wall type PRX to vacuole type, followed by tandem duplications and subsequent functional specification. Substitution models identified seven positively selected sites in the vacuole PRXs. These positively selected sites showed significant effects on the biochemical functions of the enzymes. We also found that positive selection acts more frequently on residues adjacent to, rather than directly at, a critical active site of the enzyme, and on flexible regions rather than on rigid structural elements of the protein. Our study provides new insights into the adaptive molecular evolution of plant enzyme families.

Crowd control: Effectively utilizing unscreened crowd workers for biomedical data annotation.

Annotating unstructured texts in Electronic Health Records data is usually a necessary step for conducting machine learning research on such datasets. Manual annotation by domain experts provides data of the best quality, but has become increasingly impractical given the rapid increase in the volume of EHR data. In this article, we examine the effectiveness of crowdsourcing with unscreened online workers as an alternative for transforming unstructured texts in EHRs into annotated data that are directly usable in supervised learning models. We find the crowdsourced annotation data to be just as effective as expert data in training a sentence classification model to detect the mentioning of abnormal ear anatomy in radiology reports of audiology. Furthermore, we have discovered that enabling workers to self-report a confidence level associated with each annotation can help researchers pinpoint less-accurate annotations requiring expert scrutiny. Our findings suggest that even crowd workers without specific domain knowledge can contribute effectively to the task of annotating unstructured EHR datasets.