Miracle-dz/UniFAR-FTUs huggingface dataset:
Improving Accuracy of Lung Nodule Classification Using Deep Learning with Focal Loss

Early detection and classification of pulmonary nodules using computer-aided diagnosis (CAD) systems is useful in reducing mortality rates of lung cancer. In this paper, we propose a new deep learning method to improve classification accuracy of pulmonary nodules in computed tomography (CT) scans. Our method uses a novel 15-layer 2D deep convolutional neural network architecture for automatic feature extraction and classification of pulmonary candidates as nodule or nonnodule. Focal loss function is then applied to the training process to boost classification accuracy of the model. We evaluated our method on the LIDC/IDRI dataset extracted by the LUNA16 challenge. The experiments showed that our deep learning method with focal loss is a high-quality classifier with an accuracy of 97.2%, sensitivity of 96.0%, and specificity of 97.3%.
Suppressor Mutations in degS Overcome the Acute Temperature-Sensitive Phenotype of ΔdegP and ΔdegP Δtol-pal Mutants of Escherichia coli

The Tol-Pal complex plays a poorly defined role in envelope biogenesis. The data presented here show that DegP’s periplasmic protease activity becomes crucial in mutants lacking the intact Tol-Pal complex, but this requirement can be circumvented by suppressor mutations that activate the basal protease activity of a regulatory protease, DegS. These observations point to a critical role for periplasmic proteases when Tol-Pal-mediated envelope structure and/or functions are perturbed. ABSTRACT In Escherichia coli, the periplasmic protease DegP plays a critical role in degrading misfolded outer membrane proteins (OMPs). Consequently, mutants lacking DegP display a temperature-sensitive growth defect, presumably due to the toxic accumulation of misfolded OMPs. The Tol-Pal complex plays a poorly defined but an important role in envelope biogenesis, since mutants defective in this complex display a classical periplasmic leakage phenotype. Double mutants lacking DegP and an intact Tol-Pal complex display exaggerated temperature-sensitive growth defects and the leaky phenotype. Two revertants that overcome the temperature-sensitive growth phenotype carry missense mutations in the degS gene, resulting in D102V and D320A substitutions. D320 and E317 of the PDZ domain of DegS make salt bridges with R178 of DegS’s protease domain to keep the protease in the inactive state. However, weakening of the tripartite interactions by D320A increases DegS’s basal protease activity. Although the D102V substitution is as effective as D320A in suppressing the temperature-sensitive growth phenotype, the molecular mechanism behind its effect on DegS’s protease activity is unclear. Our data suggest that the two DegS variants modestly activate RseA-controlled, σE-mediated envelope stress response pathway and elevate periplasmic protease activity to restore envelope homeostasis. Based on the release of a cytoplasmic enzyme in the culture supernatant, we conclude that the conditional lethal phenotype of ΔtolB ΔdegP mutants stems from a grossly destabilized envelope structure that causes excessive cell lysis. Together, the data point to a critical role for periplasmic proteases when the Tol-Pal complex-mediated envelope structure and/or functions are compromised. IMPORTANCE The Tol-Pal complex plays a poorly defined role in envelope biogenesis. The data presented here show that DegP’s periplasmic protease activity becomes crucial in mutants lacking the intact Tol-Pal complex, but this requirement can be circumvented by suppressor mutations that activate the basal protease activity of a regulatory protease, DegS. These observations point to a critical role for periplasmic proteases when Tol-Pal-mediated envelope structure and/or functions are perturbed.
Aztreonam plus Clavulanate, Tazobactam, or Avibactam for Treatment of Infections Caused by Metallo-β-Lactamase-Producing Gram-Negative Bacteria

Metallo-β-lactamase (MBL)-producing Gram-negative bacteria are often extremely resistant, leading to a real therapeutic dead end. Here, we evaluated the in vitro and in vivo efficacy of aztreonam in combination with ceftazidime-avibactam, ceftolozane-tazobactam, or amoxicillin-clavulanate for the treatment of infections caused by MBL-producing Enterobacteriaceae, MBL-producing Pseudomonas aeruginosa, and extremely drug-resistant Stenotrophomonas maltophilia. ABSTRACT Metallo-β-lactamase (MBL)-producing Gram-negative bacteria are often extremely resistant, leading to a real therapeutic dead end. Here, we evaluated the in vitro and in vivo efficacy of aztreonam in combination with ceftazidime-avibactam, ceftolozane-tazobactam, or amoxicillin-clavulanate for the treatment of infections caused by MBL-producing Enterobacteriaceae, MBL-producing Pseudomonas aeruginosa, and extremely drug-resistant Stenotrophomonas maltophilia. First, we report two clinical cases, namely, a urinary tract infection caused by an NDM-5-producing Escherichia coli isolate and a pulmonary infection caused by a S. maltophilia isolate efficiently treated with the association of aztreonam-ceftazidime-avibactam and aztreonam-amoxicillin-clavulanate, respectively. Then, a total of 50 MBL-producing Enterobacteriaceae isolates, 3 MBL-producing P. aeruginosa isolates, and 5 extremely drug-resistant S. maltophilia isolates were used to test aztreonam susceptibility in combination with ceftolozane-tazobactam, ceftazidime-avibactam, or amoxicillin-clavulanate. The Etest strip superposition method was used to determine the MICs of the aztreonam/inhibitor combinations. According to CLSI breakpoints, aztreonam susceptibility was fully restored for 86%, 20%, and 50% of the MBL-producing Enterobacteriaceae isolates when combined with ceftazidime-avibactam, ceftolozane-tazobactam, and amoxicillin-clavulanate, respectively. In P. aeruginosa, the aztreonam-ceftazidime-avibactam combination was the most potent, even though the reduction in MICs was at most 2-fold. With the 5 S. maltophilia isolates, aztreonam-ceftazidime-avibactam and aztreonam-amoxicillin-clavulanate were found to be equal (100% susceptibility). Overall, aztreonam-ceftazidime-avibactam was the most potent combination to treat infections caused by MBL producers compared with aztreonam-amoxicillin-clavulanate and aztreonam-ceftolozane-tazobactam. However, in many cases aztreonam-amoxicillin-clavulanate was found to be as efficient as aztreonam-ceftazidime-avibactam, offering the main advantage to be markedly cheaper. We also confirmed the validity of Etest superpositions as a very simple method to determine MICs of aztreonam combinations.
Functional Characterization of Target of Rapamycin Signaling in Verticillium dahliae

More than 200 plants have been suffering from Verticillium wilt caused by Verticillium dahliae (V. dahliae) across the world. The target of rapamycin (TOR) is a lethal gene and controls cell growth and development in various eukaryotes, but little is known about TOR signaling in V. dahliae. Here, we found that V. dahliae strain is hypersensitive to rapamycin in the presence of rapamycin binding protein VdFKBP12 while the deletion mutant aaavdfkbp12 is insensitive to rapamycin. Heterologous expressing VdFKBP12 in Arabidopsis conferred rapamycin sensitivity, indicating that VdFKBP12 can bridge the interaction between rapamycin and TOR across species. The key across species of TOR complex 1 (TORC1) and TORC2 have been identified in V. dahliae, suggesting that TOR signaling pathway is evolutionarily conserved in eukaryotic species. Furthermore, the RNA-seq analysis showed that ribosomal biogenesis, RNA polymerase II transcription factors and many metabolic processes were significantly suppressed in rapamycin treated cells of V. dahliae. Importantly, transcript levels of genes associated with cell wall degrading enzymes (CWEDs) were dramatically down-regulated in TOR-inhibited cells. Further infection assay showed that the pathogenicity of V. dahliae and occurrence of Verticillium wilt can be blocked in the presence of rapamycin. These observations suggested that VdTOR is a key target of V. dahliae for controlling and preventing Verticillium wilt in plants.
Analysis of the Pseudomonas aeruginosa Aminoglycoside Differential Resistomes Allows Defining Genes Simultaneously Involved in Intrinsic Antibiotic Resistance and Virulence

High-throughput screening of transposon insertion libraries is a useful strategy for unveiling bacterial genes whose inactivation results in an altered susceptibility to antibiotics. A potential drawback of these studies is they are usually based on just one model antibiotic for each structural family, under the assumption that the results can be extrapolated to all members of said family. ABSTRACT High-throughput screening of transposon insertion libraries is a useful strategy for unveiling bacterial genes whose inactivation results in an altered susceptibility to antibiotics. A potential drawback of these studies is they are usually based on just one model antibiotic for each structural family, under the assumption that the results can be extrapolated to all members of said family. To determine if this simplification is appropriate, we have analyzed the susceptibility of mutants of Pseudomonas aeruginosa to four aminoglycosides. Our results indicate that each mutation produces different effects on susceptibility to the tested aminoglycosides, with only two mutants showing similar changes in the susceptibility to all studied aminoglycosides. This indicates that the role of a particular gene in the resistome of a given antibiotic should not be generalized to other members of the same structural family. Five aminoglycoside-hypersusceptible mutants inactivating glnD, hflK, PA2798, PA3016, and hpf were chosen for further analysis in order to elucidate if lower aminoglycoside susceptibility correlates with cross-hypersusceptibility to other antibiotics and with impaired virulence. Our results indicate that glnD inactivation leads to increased cross-susceptibility to different antibiotics. The mutant in this gene is strongly impaired in virulence traits such as pyocyanin production, biofilm formation, elastase activity, and swarming motility and the ability to kill Caenorhabditis elegans. Thus, GlnD might be an interesting target for developing antibiotic coadjuvants with antiresistance and antivirulence properties against P. aeruginosa.
High dimensional mediation analysis with latent variables

We propose a model for high dimensional mediation analysis that includes latent variables. We describe our model in the context of an epidemiologic study for incident breast cancer with one exposure and a large number of biomarkers (i.e., potential mediators). We assume that the exposure directly influences a group of latent, or unmeasured, factors which are associated with both the outcome and a subset of the biomarkers. The biomarkers associated with the latent factors linking the exposure to the outcome are considered “mediators. ” We derive the likelihood for this model and develop an expectation‐maximization algorithm to maximize an L1‐penalized version of this likelihood to limit the number of factors and associated biomarkers. We show that the resulting estimates are consistent and that the estimates of the nonzero parameters have an asymptotically normal distribution. In simulations, procedures based on this new model can have significantly higher power for detecting the mediating biomarkers compared with the simpler approaches. We apply our method to a study that evaluates the relationship between body mass index, 481 metabolic measurements, and estrogen‐receptor positive breast cancer.
Reliable imaging of ATP in living budding and fission yeast

ABSTRACT Adenosine triphosphate (ATP) is a main metabolite essential for all living organisms. However, our understanding of ATP dynamics within a single living cell is very limited. Here, we optimized the ATP-biosensor QUEEN and monitored the dynamics of ATP with good spatial and temporal resolution in living yeasts. We found stable maintenance of ATP concentration in wild-type yeasts, regardless of carbon sources or cell cycle stages, suggesting that mechanism exists to maintain ATP at a specific concentration. We further found that ATP concentration is not necessarily an indicator of metabolic activity, as there is no clear correlation between ATP level and growth rates. During fission yeast meiosis, we found a reduction in ATP levels, suggesting that ATP homeostasis is controlled by differentiation. The use of QUEEN in yeasts offers an easy and reliable assay for ATP dynamicity and will answer several unaddressed questions about cellular metabolism in eukaryotes. Highlighted Article: Budding and fission yeast strains stably expressing the ATP biosensor QUEEN, allow reliable observation of ATP dynamics with high spatiotemporal resolution in living eukaryotic cells.
Physical Impairments Disrupt the Association Between Physical Activity and Loneliness: A Longitudinal Study.

This study explores the association between physical activity (PA), loneliness, and the presence of physical chronic impairments among single older adults. A longitudinal study (N = 575; mean age 76 ± 8 years) was conducted. The association between self-reported weekly minutes of moderate to vigorous PA, loneliness, and presence of physical impairments was assessed with multilevel analyses at baseline, 3 months, and 6 months. Improvements in moderate to vigorous PA were associated with decreases in loneliness (B = -0.09, SE = 0.04, p = .020); this association became nonsignificant when including the presence of physical impairments in the analyses (p = .824), which in itself was positively associated with loneliness (B = 0.51, SE = 0.10, p < .001). Findings indicate that physical impairments have a larger influence on loneliness than the level of PA. Interventions targeting PA and loneliness should tailor specifically to physical impairments.
Long-term cardiovascular risk of white-coat hypertension with normal night-time blood pressure values

Background The prognostic impact of white-coat hypertension (WCHT) is still a matter of debate and controversy. Night-time blood pressure (NBP) is related strongly to cardiovascular (CV) prognosis, but this has not been considered currently in the definition of WCHT. Patients and methods We investigated the long-term CV prognosis of 2659 patients submitted at admission to 24 h-ambulatory blood pressure (BP) monitoring divided into three groups: normotension (NT) (n=812; 59% female; ageing 49±13 years), sustained hypertension (SHT) (n=1230; 56% female; ageing 51±13 years) and WCHT (n=617; 55% female; ageing 50±3 years) defined as office BP of at least 140/90 mmHg, daytime BP less than 135/85 mmHg and NBP less than 120/70 mmHg. Results The median follow-up was 7.6 years (range: 0.4–24.4), during which a total of 257 CV events (36 fatal) occurred (46% strokes, 32% coronary and 22% others), 38 in NT, 31 in WCHT and 188 in SHT. The event rate per 100 patient-years was 0.60 in the WCHT group, 0.66 in the NT group and 2.09 in the SHT group. Cox’s regression analysis adjusted for covariables showed a higher risk of CV events in patients with SHT than WCHT [hazard ratio (HR)=2.230, 95% confidence interval: 1.339–3.716, P=0.002], whereas there was no difference between WCHT and NT groups. Event-free survival was significantly different from SH versus WCHT and NT groups. Within the group of WCHT, 29% of patients received sustained antihypertensive medication during the follow-up, but the HR of CV events between WCHT either treated or not treated did not differ: HR=0.76 (95% confidence interval: 0.37–1.51, P=0.42). Conclusion In patients with WCHT defined by normal daytime and NBP values, the risk of CV events was significantly lower than that of SHT and similar to that of NT patients, suggesting that NBP should be included in the WCHT definition and in its prognostic stratification.
Modulated electro-hyperthermia-enhanced liposomal drug uptake by cancer cells

Purpose Modulated electro-hyperthermia (mEHT) stands to be a significant technological advancement in the hyperthermia field, utilizing autofocusing electromagnetic power on the cell membrane to create massive apoptosis. Since mEHT possesses the unique ability to excite cell membranes, we hypothesized that mEHT could enhance the uptake of liposomal drugs by enhancing phagocytic activity. Materials and methods Water bath control and mEHT were used to compare the enhancement of liposome-encapsulated doxorubicin (Lipodox®) uptake by cancer cells. Cancer cells were made visible by doxorubicin fluorescence to investigate drug uptake. Viable cell yield was determined via the Trypan Blue exclusion method. Various substrates were used to investigate the mechanism of drug-uptake enhancement. The murine colon carcinoma model, CT26, was used to confirm the tissue infiltration of Lipodox® and its therapeutic effect. Results mEHT treatment showed a significant enhancement of Lipodox® uptake of doxorubicin fluorescence compared with 37°C or 42°C water bath treatment. Tumor tissue sections also confirmed that mEHT treatment achieved the highest doxorubicin concentration in vivo (1.44±0.32 µg/g in mEHT group and 0.79±0.32 µg/g in 42°C water bath). Wortmannin was used to inhibit the macropinocytosis effect and 70 kDa dextran-FITC served as uptake substance. The uptake of dextran-FITC by cancer cells significantly increased after mEHT treatment whereas such enhancement was significantly inhibited by wortmannin. Conclusion The result showed mEHT-induced particle-uptake through macropinocytosis. mEHT-enhanced uptake of Lipodox® may amplify the therapeutic effect of liposomal drugs. This novel finding warrants further clinical investigation.
First Report of Leaf and Stem Rust Caused by Puccinia sherardiana on Sphaeralcea grossulariaefolia in North America and S. munroana in Wyoming.

Diseased samples of globe mallow, Sphaeralcea grossulariaefolia and S. munroana, were submitted by an ornamental seed producer in Wyoming to our Extension Plant Pathology Laboratory in July 1997. Dark brown, amphigenous telia surrounded by chlorotic halos were present on both foliage and stems. Mean teliospore dimensions observed were 30.8 × 44.8 μm. The teliospores germinated readily on water agar at 20°C and formed basidiospores within 24 h. Aecia and uredinia were not found. Based on characteristics mentioned above, this fungus was identified as Puccinia sherardiana Körn (1). This microcyclic rust was previously described on 12 other Sphaeralcea spp. plus other plant species in the Malvaceae family (1,2). Stem and foliar symptoms were reproduced in a greenhouse on 8-week-old plants of S. grossulariaefolia and S. munroana. These plants were inoculated with teliospores removed from the original diseased plant material. Immediately after inoculation, plants were misted and placed in plastic bags and incubated for 36 h at 100% relative humidity and 20°C. Plants continued growth with natural lighting and with day and night temperatures of 20 and 15°C, respectively. Symptoms developed within 12 days with initial telia rupturing the host epidermis 13 days after inoculation. Telia were examined microscopically to complete Koch's postulates. References: (1) J. C. Arthur. Manual of Plant Rusts in United States and Canada. Hafner Pub. , 1962. (2) D. F. Farr et al. Fungi on Plants and Plant Products in the United States. American Phytopatholical Society, St. Paul, MN, 1989.
A randomized, controlled, clinical study on a new titanium oxide abutment surface for improved healing and soft tissue health.

BACKGROUND A newly developed, anodized titanium oxide surface containing anatase has been reported to have antimicrobial properties that could reduce bacterial adherence to abutments. PURPOSE To investigate if abutments with the anodized surface improve healing and soft tissue health in a randomized controlled study. MATERIALS AND METHODS Test abutments with a nanostructured anodized surface were compared with control machined titanium abutments. In total, 35 subjects each received a pair of test and control abutments. The primary endpoint was reduction of biofilm formation at test abutments at the 6-week follow-up. Secondary endpoints included several soft tissue assessments. qPCR for gene markers was used to indirectly evaluate healing and soft tissue health. RESULTS No significant differences in biofilm formation were observed between test and control abutments, but soft tissue bleeding upon abutment removal was significantly lower for test abutments compared with control abutments (P = 0.006) at 6 weeks. Keratinized mucosa height was significantly greater at test abutments compared with control abutments at the 6-week, 6-month, and 2-year follow-ups. Significant gene expression differences indicated differences in healing and tissue remodeling. CONCLUSIONS Abutments with an anodized and nanostructured surface compared with a conventional, machined titanium surface had no significant effect on bacterial colonization and proteolytic activity but were associated with better soft tissue outcomes such as a lower bleeding index at abutment removal and consistently greater height of keratinized mucosa throughout the 2-year follow-up, suggesting improved surface-dependent peri-implant healing and soft tissue health.
Replication Study: The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44

As part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Li et al., 2015), that described how we intended to replicate selected experiments from the paper ‘The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44’ (Liu et al., 2011). Here we report the results. We found the microRNA, miR-34a, was expressed at twice the level in CD44+ prostate cancer cells purified from xenograft tumors (LAPC4 cells) compared to CD44- LAPC4 cells, whereas the original study reported miR-34a was underexpressed in CD44+ LAPC4 cells (Figure 1B; Liu et al., 2011). When LAPC4 cells engineered to express miR-34a were injected into mice, we did not observe changes in tumor growth or CD44 expression; however, unexpectedly miR-34a expression was lost in vivo. In the original study, LAPC4 cells expressing miR-34a had a statistically significant reduction in tumor regeneration and reduced CD44 expression compared to control (Figure 4A and Supplemental Figures 4A,B and 5C; Liu et al., 2011). Furthermore, when we tested if miR-34a regulated CD44 through binding sites in the 3’UTR we did not find a statistically significant difference, whereas the original study reported miR-34a decreased CD44 expression that was partially abrogated by mutation of the binding sites in the CD44 3’UTR (Figure 4D; Liu et al., 2011). Finally, where possible, we report meta-analyses for each result.