Characterization of myoinhibitory peptide signaling system and its implication in larval metamorphosis and spawning behavior in Pacific abalone.

Myoinhibitory peptides (MIPs) affect various physiological functions, including juvenile hormone signaling, muscle contraction, larval development, and reproduction in invertebrates. Although MIPs are ligands for MIP and/or sex peptide receptors (MIP/SPRs) in diverse arthropods and model organisms belonging to Lophotrochozoa, the MIP signaling system has not yet been fully investigated in mollusks. In this study, we identified the MIP signaling system in the Pacific abalone Haliotis discus hannai (Hdh). Similar to the invertebrate MIPs, a total of eight paracopies of MIPs (named Hdh-MIP1 to Hdh-MIP8), harboring a WX5-7Wamide motif, except for Hdh-MIP2, were found in the Hdh-MIP precursor. Furthermore, we characterized a functional Hdh-MIPR, which responded to the Hdh-MIPs, except for Hdh-MIP2, possibly linked with the PKC/Ca2+ and PKA/cAMP signaling pathways. Hdh-MIPs delayed larval metamorphosis but increased the spawning behavior. These results suggest that the Hdh-MIP signaling system provides insights into the unique function of MIP in invertebrates.

Prognostic impact of pretreatment skeletal muscle index and CONUT score in diffuse large B-cell Lymphoma.

BACKGROUND: Although the prognostic value of the Controlling Nutritional Status (CONUT) score in diffuse large B-cell lymphoma (DLBCL) has been reported in several previous studies, its clinical relevance for the presence of sarcopenia has not been assessed. METHODS: In this study, 305 DLBCL patients were reviewed. They were categorized into normal/mild (n = 219) and moderate/severe (n = 86) CONUT groups. Sarcopenia was assessed using the L3-skeletal muscle index measured by baseline computed tomography imaging. Based on CONUT score and sarcopenia, patients were grouped: A (normal/mild CONUT and no sarcopenia), B (either moderate/severe CONUT or sarcopenia, but not both), and C (both moderate/severe CONUT and sarcopenia). RESULTS: The moderate/severe CONUT group showed higher rates of ≥ grade 3 febrile neutropenia, thrombocytopenia, non-hematologic toxicities, and early treatment discontinuation not related to disease progression, compared to the normal/mild CONUT group. The moderate/severe CONUT group had a lower complete response rate (58.1% vs. 80.8%) and shorter median overall survival (18.5 vs. 162.6 months) than the normal/mild group. Group C had the poorest prognosis with a median survival of 8.6 months, while groups A and B showed better outcomes (not reached and 60.1 months, respectively). Combining CONUT score and sarcopenia improved the predictive accuracy of the Cox regression model (C-index: 0.763), compared to the performance of using either CONUT score (C-index: 0.754) or sarcopenia alone (C-index: 0.755). CONCLUSIONS: In conclusion, the moderate/severe CONUT group exhibited treatment intolerance, lower response, and poor prognosis. Additionally, combining CONUT score and sarcopenia enhanced predictive accuracy for survival outcomes compared to individual variables.

COVID-19 Vaccine-Associated Pneumonitis in the Republic of Korea: A Nationwide Multicenter Survey.

BACKGROUND: Recent reports have suggested that pneumonitis is a rare complication following vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, its clinical features and outcomes are not well known. The aim of this study was to identify the clinical characteristics and outcomes of patients with vaccine-associated pneumonitis following vaccination against SARS-CoV-2. METHODS: In this nationwide multicenter survey study, questionnaires were distributed to pulmonary physicians in referral hospitals. They were asked to report cases of development or exacerbation of interstitial lung disease (ILD) associated with the coronavirus disease 2019 vaccine. Vaccine-associated pneumonitis was defined as new pulmonary infiltrates documented on chest computed tomography within 4 weeks of vaccination and exclusion of other possible etiologies. RESULTS: From the survey, 49 cases of vaccine-associated pneumonitis were identified between February 27 and October 30, 2021. After multidisciplinary discussion, 46 cases were analyzed. The median age was 66 years and 28 (61%) were male. The median interval between vaccination and respiratory symptoms was 5 days. There were 20 (43%), 17 (37%), and nine (19%) patients with newly identified pneumonitis, exacerbation of pre-diagnosed ILD, and undetermined pre-existing ILD, respectively. The administered vaccines were BNT162b2 and ChAdOx1 nCov-19/AZD1222 each in 21 patients followed by mRNA-1273 in three, and Ad26.COV2.S in one patient. Except for five patients with mild disease, 41 (89%) patients were treated with corticosteroid. Significant improvement was observed in 26 (57%) patients including four patients who did not receive treatment. However, ILD aggravated in 9 (20%) patients despite treatment. Mortality was observed in eight (17%) patients. CONCLUSION: These results suggest pneumonitis as a potentially significant safety concern for vaccines against SARS-CoV-2. Clinical awareness and patient education are necessary for early recognition and prompt management. Additional research is warranted to identify the epidemiology and characterize the pathophysiology of vaccine-associated pneumonitis.

Ankle-targeted exosuit resistance increases paretic propulsion in people post-stroke.

BACKGROUND: Individualized, targeted, and intense training is the hallmark of successful gait rehabilitation in people post-stroke. Specifically, increasing use of the impaired ankle to increase propulsion during the stance phase of gait has been linked to higher walking speeds and symmetry. Conventional progressive resistance training is one method used for individualized and intense rehabilitation, but often fails to target paretic ankle plantarflexion during walking. Wearable assistive robots have successfully assisted ankle-specific mechanisms to increase paretic propulsion in people post-stroke, suggesting their potential to provide targeted resistance to increase propulsion, but this application remains underexamined in this population. This work investigates the effects of targeted stance-phase plantarflexion resistance training with a soft ankle exosuit on propulsion mechanics in people post-stroke. METHODS: We conducted this study in nine individuals with chronic stroke and tested the effects of three resistive force magnitudes on peak paretic propulsion, ankle torque, and ankle power while participants walked on a treadmill at their comfortable walking speeds. For each force magnitude, participants walked for 1 min while the exosuit was inactive, 2 min with active resistance, and 1 min with the exosuit inactive, in sequence. We evaluated changes in gait biomechanics during the active resistance and post-resistance sections relative to the initial inactive section. RESULTS: Walking with active resistance increased paretic propulsion by more than the minimal detectable change of 0.8 %body weight at all tested force magnitudes, with an average increase of 1.29 ± 0.37 %body weight at the highest force magnitude. This improvement corresponded to changes of 0.13 ± 0.03 N m kg- 1 in peak biological ankle torque and 0.26 ± 0.04 W kg- 1 in peak biological ankle power. Upon removal of resistance, propulsion changes persisted for 30 seconds with an improvement of 1.49 ± 0.58 %body weight after the highest resistance level and without compensatory involvement of the unresisted joints or limb. CONCLUSIONS: Targeted exosuit-applied functional resistance of paretic ankle plantarflexors can elicit the latent propulsion reserve in people post-stroke. After-effects observed in propulsion highlight the potential for learning and restoration of propulsion mechanics. Thus, this exosuit-based resistive approach may offer new opportunities for individualized and progressive gait rehabilitation.

Manual stabilization reveals a transient role for balance control during locomotor adaptation.

A fundamental feature of human locomotor control is the need to adapt walking patterns in response to changes in the environment. For example, when people walk on a split-belt treadmill, which has belts that move at different speeds, they adapt to the asymmetric speed constraints by reducing spatiotemporal asymmetry. Here, we aim to understand the role of balance control as a potential factor driving this adaptation process. We recruited 24 healthy, young adults to adapt to walking on a split-belt treadmill while either holding on to a handrail or walking with free arm swing. We measured whole body angular momentum and step length asymmetry as measures of dynamic balance and spatiotemporal asymmetry, respectively. To understand how changes in intersegmental coordination influenced whole body angular momentum, we also measured segmental angular momenta and the coefficient of cancellation. When participants were initially exposed to the asymmetry in belt speeds, we observed an increase in whole body angular momentum that was due to both an increase in the momentum of individual segments and a reduction in the coefficient of cancellation. Holding on to a handrail reduced the perturbation to asymmetry during the early phase of adaptation and resulted in a smaller aftereffect during early postadaptation. In addition, the stabilization provided by holding on to a handrail led to reductions in the coupling between angular momentum and asymmetry. These results suggest that regulation of dynamic balance is most important during the initial, transient phase of adaptation to walking on a split-belt treadmill.NEW & NOTEWORTHY We investigated the role of dynamic balance during adaptation to a split-belt treadmill by measuring whole body angular momentum with or without holding on to a handrail. The initial step length asymmetry and associations between balance and asymmetry reduced when holding on to a handrail during early adaptation. These findings indicate that dynamic balance mostly contributes to the initial phase of adaptation when people are exposed to an asymmetric walking constraint.

The Endothelial Activation and Stress Index (EASIX) score is an independent prognostic factor in patients with diffuse large B-cell lymphoma.

BACKGROUND: The endothelial activation and stress index (EASIX) score has been reported to predict overall survival (OS) in hematological cancers. However, it has not been validated as a prognostic marker for diffuse large B-cell lymphoma (DLBCL) to date. METHODS: The records of 265 patients who presented with DLBCL in the Republic of Korea between January 07, 2004, and March 05, 2020 were retrospectively reviewed. For all included patients, EASIX scores were calculated using serum lactate dehydrogenase (LDH) and creatinine levels and the platelet count measured at diagnosis as follows: LDH (U/L) × creatinine (mg/dL)/platelet count (109/L). RESULTS: The median age of the patients was 64 years. The optimal cutoff value of EASIX according to the receiver operating characteristic analysis for OS was 1.33. All the patients were treated with cyclophosphamide, doxorubicin, vincristine, and prednisone combined with rituximab. The 1-year OS and progression-free survival (PFS) rates were lower in the high-EASIX group than in the low EASIX group (63.8% vs. 84.4%, p < 0.001 and 54.0% vs. 79.6%, p < 0.001, respectively). A high EASIX was an independent poor prognostic factor for OS and PFS (hazard ratio, 1.606; 95% CI, 1.077-2.395; p = 0.020 and hazard ratio, 1.621; 95% CI, 1.066-2.464; p = 0.024, respectively). CONCLUSIONS: EASIX is a readily available and cheaply obtainable parameter in clinical studies and shows considerable potential as a new prognostic marker for patients with newly diagnosed DLBCL.

Pion-Nucleon Sigma Term from Lattice QCD.

We present an analysis of the pion-nucleon σ-term σ_{πN} using six ensembles with 2+1+1-flavor highly improved staggered quark action generated by the MILC Collaboration. The most serious systematic effect in lattice calculations of nucleon correlation functions is the contribution of excited states. We estimate these using chiral perturbation theory (χPT) and show that the leading contribution to the isoscalar scalar charge comes from Nπ and Nππ states. Therefore, we carry out two analyses of lattice data to remove excited-state contamination, the standard one and a new one including Nπ and Nππ states. We find that the standard analysis gives σ_{πN}=41.9(4.9) MeV, consistent with previous lattice calculations, while our preferred χPT-motivated analysis gives σ_{πN}=59.6(7.4) MeV, which is consistent with phenomenological values obtained using πN scattering data. Our data on one physical pion mass ensemble were crucial for exposing this difference, therefore, calculations on additional physical mass ensembles are needed to confirm our result and resolve the tension between lattice QCD and phenomenology.

Impact of capsaicin concentration evoking coughs on clinical variables in patients with asthma.

BACKGROUND: Inhaled capsaicin (8-methyl-N-vanillyl-6-nonenamide) has been used to induce cough in a safe and dose-dependent manner. Chronic cough is associated with an increased sensitivity to inhaled capsaicin in patients with asthma. The aim of this study was to evaluate clinical impact of capsaicin provocation test for chronic cough, and to find relationship between capsaicin concentration producing coughs and clinical variables in patients with asthma. Methods: 385 patients with chronic cough [capsaicin provocation test (+, n = 152)] vs. [capsaicin provocation test (-, n = 233)] who has done with capsaicin provocation test recruited and evaluated by asthma diagnosis and clinical variables. Asthma diagnoses were based on the Global Initiative for Asthma guidelines. Results: Capsaicin positivity was more prevalent in patient with asthma diagnosis than in patients without asthma diagnosis (129/304 vs. 24/81, p = 0.037). Capsaicin positivity was more prevalent in female patients than in male patients (123/271 = 45.4% vs. 30/114 = 26.3%, p = 0.001). Capsaicin concentration producing coughs correlated with smoke amount (r = 0.126, p = 0.014). Capsaicin positivity was more prevalent in nonsmoker patients than in smoker patients (133/295 = 45.1% vs. 20/90 = 22.2%, p = 0.001). Capsaicin concentration producing coughs negatively correlated with methacholine PC20 (4 mg mL-1, p = 0.037), (16 mg mL-1, p = 0.069) and (20 mg mL-1, p = 0.045). Capsaicin concentration producing coughs correlated with BMI (r = 0.120, p = 0.019). Capsaicin concentration producing coughs negatively correlated with FEV1/FVC % pred. (r = -0.137, p = 0.007). There was no relationship between capsaicin concentration producing coughs and age, IgE, and atopy. Conclusions: Capsaicin test for asthma diagnosis should be considered for variable clinical factors. Key message Cough in asthmatic patients is not only common and troublesome but also predicts disease severity and poor prognosis. The capsaicin cough challenge test is a simple and reproducible provocation method for assessing cough susceptibility in patients with cough. Capsaicin test for asthma diagnosis should be considered for variable clinical factors.

Effect of pre-operative internal obturator muscle mass index in MRI on biochemical recurrence of prostate cancer patients after radical prostatectomy: a multi-center study.

BACKGROUND: Recent reports show that the pre-operative or post-operative skeletal mass index (sarcopenia) affects survival rates for various cancers; however, the link between prostate cancer survival and sarcopenia is unclear. Therefore, this study examined the effect of the pre-operative internal obturator muscle (IOM) mass index on biochemical recurrence (BCR) of prostate cancer (PCa) patients who underwent radical prostatectomy. METHODS: In total, 222 patients, who underwent open, laparoscopic, or robot-assisted radical prostatectomy at seven centers in 2011 and were followed up for 5 years, were enrolled. BCR was examined in the context of pre-operative IOM mass index and BMI. RESULTS: The mean age of the patients was 67.82 ± 6.23 years, and the mean pre-operative prostate-specific antigen (PSA) level was 11.61 ± 13.22 ng/ml. There was no significant difference in baseline characteristics between the low and high IOM mass index groups (p > 0.05). Age, pre-op PSA level, ECE, and T-stage were associated with BCR (p = 0.049, p < 0.001, p = 0.001, p = 0.004, respectively). BMI, prostate volume, Gleason score, resection margin, N-stage, M-stage and IOM mass index was not associated with BCR (p > 0.05). CONCLUSIONS: Pre-operative IOM mass index was not associated with BCR; however, long-term follow-up is necessary to evaluate cancer-specific and overall survival of PCa patients.

Ankle resistance with a unilateral soft exosuit increases plantarflexor effort during pushoff in unimpaired individuals.

BACKGROUND: Ankle-targeting resistance training for improving plantarflexion function during walking increases rehabilitation intensity, an important factor for motor recovery after stroke. However, understanding of the effects of resisting plantarflexion during stance on joint kinetics and muscle activity-key outcomes in evaluating its potential value in rehabilitation-remains limited. This initial study uses a unilateral exosuit that resists plantarflexion during mid-late stance in unimpaired individuals to test the hypotheses that when plantarflexion is resisted, individuals would (1) increase plantarflexor ankle torque and muscle activity locally at the resisted ipsilateral ankle, but (2) at higher forces, exhibit a generalized response that also uses the unresisted joints and limb. Further, we expected (3) short-term retention into gait immediately after removal of resistance. METHODS: Ten healthy young adults walked at 1.25 m s-1 for four 10-min discrete bouts, each comprising baseline, exposure to active exosuit-applied resistance, and post-active sections. In each bout, a different force magnitude was applied based on individual baseline ankle torques. The peak resistance torque applied by the exosuit was 0.13 ± 0.01, 0.19 ± 0.01, 0.26 ± 0.02, and 0.32 ± 0.02 N m kg-1, in the LOW, MED, HIGH, and MAX bouts, respectively. RESULTS: (1) Across all bouts, participants increased peak ipsilateral biological ankle torque by 0.13-0.25 N m kg-1 (p < 0.001) during exosuit-applied resistance compared to corresponding baselines. Additionally, ipsilateral soleus activity during stance increased by 5.4-11.3% (p < 0.05) in all but the LOW bout. (2) In the HIGH and MAX bouts, vertical ground reaction force decreased on the ipsilateral limb while increasing on the contralateral limb (p < 0.01). Secondary analysis found that the force magnitude that maximized increases in biological ankle torque without significant changes in limb loading varied by subject. (3) Finally, peak ipsilateral plantarflexion angle increased significantly during post-exposure in the intermediate HIGH resistance bout (p < 0.05), which corresponded to the greatest average increase in soleus activity (p > 0.10). CONCLUSIONS: Targeted resistance of ankle plantarflexion during stance by an exosuit consistently increased local ipsilateral plantarflexor effort during active resistance, but force magnitude will be an important parameter to tune for minimizing the involvement of the unresisted joints and limb during training.

An Attention-Based Multilayer GRU Model for Multistep-Ahead Short-Term Load Forecasting†.

Recently, multistep-ahead prediction has attracted much attention in electric load forecasting because it can deal with sudden changes in power consumption caused by various events such as fire and heat wave for a day from the present time. On the other hand, recurrent neural networks (RNNs), including long short-term memory and gated recurrent unit (GRU) networks, can reflect the previous point well to predict the current point. Due to this property, they have been widely used for multistep-ahead prediction. The GRU model is simple and easy to implement; however, its prediction performance is limited because it considers all input variables equally. In this paper, we propose a short-term load forecasting model using an attention based GRU to focus more on the crucial variables and demonstrate that this can achieve significant performance improvements, especially when the input sequence of RNN is long. Through extensive experiments, we show that the proposed model outperforms other recent multistep-ahead prediction models in the building-level power consumption forecasting.

Parenteral immunization of Salmonella Typhimurium ghosts with surface-displayed Escherichia coli flagellin enhancesTLR-5 mediated activation of immune responses that protect the chicken against Salmonella infection.

The present study investigates the enhancement of immunogenicity and protection efficacy of Salmonella Typhimurium ghosts surface-displayed with FliC against chicken salmonellosis. The membrane-anchored FliC is a potential TLR-5 agonist, delivers an essential adjuvant effect for the ghost vaccine candidate. The present ghost plasmid pJHL184 construct carries a convergent dual promoter system that has the temperature-dependent induction of the phage lysis gene E and the target antigen FliC at the same time. Under permissible conditions of temperatures, less than 30 °C at the presence of 20 mM l-arabinose effectively suppresses expression of the lysis gene. Once the temperature is up-lifted to 42 °C without arabinose, cause the generation of ST ghosts expelling the cytoplasmic content. The addition of FliC adjuvant significantly enhanced the IgY response, cell-mediated immune responses, regulatory cytokine induction and subsequently enhanced protection against Salmonella challenge. Further, intramuscular immunization with ST ghosts displaying FliC induced particularly high CD8+ response demarcating its proficiency to elicit Type I immune responses. Further, ST ghosts displaying FliC caused an increase in both CD4+ and CD8+ response compared to the PBS control suggesting its capability to engage both cell-mediated and humoral immune responses essential for the elimination of Salmonella. Upon the virulent challenge, we could observe a significant reduction in challenged bacterial load on spleen, liver and cecum tissues in the ST ghosts surface-displaying FliC adjuvant. Our study suggests the biological incorporation of FliC on ST ghosts enhances vaccine immunogenic potency and acts as a safe and effective prevention strategy against chicken salmonellosis.

Prognostic model based on the geriatric nutritional risk index and sarcopenia in patients with diffuse large B-cell lymphoma.

BACKGROUND: Systemic inflammation and cachexia are associated with adverse clinical outcomes in diffuse large B-cell lymphoma (DLBCL). The Geriatric Nutritional Risk Index (GNRI) is one of the main parameters used to assess these conditions, but its efficacy in DLBCL is inconclusive. METHODS: We retrospectively reviewed 228 DLBCL patients who were treated with R-CHOP immunochemotherapy (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). The patients were stratified according to GNRI score (> 98, 92 to 98, 82 to < 92, and < 82) as defined in previous studies. Additionally, the extent of sarcopenia was categorized as sarcopenia-both, sarcopenia-L3/PM alone, and non-sarcopenia-both according to skeletal muscle index. RESULTS: Survival curves plotted against a combination of GNRI and sarcopenia scores revealed two clear groups as follows: high cachexia risk (HCR) group (GNRI < 82, sarcopenia-both, or GNRI 82-92 with sarcopenia-L3/PM alone) and low cachexia risk (LCR) group (others). The HCR group had a lower complete response rate (46.5% vs. 86.6%) and higher frequency of treatment-related mortality (19.7% vs. 3.8%) and early treatment discontinuation (43.7% vs. 8.3%) compared with the LCR group. The median progression-free survival (PFS) (not reached vs. 10.3 months, p <  0.001) and overall survival (OS) (not reached vs. 12.9 months, p <  0.001) were much shorter in the HCR group than in the LCR group. On multivariable analyses, the HCR group was shown to be an independent negative prognostic factor for PFS and OS after adjusting the National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI). CONCLUSIONS: A combined model of GNRI and sarcopenia may provide prognostic information independently of the NCCN-IPI in DLBCL.

Oral immunization with an attenuated Salmonella Gallinarum encoding the H9N2 haemagglutinin and M2 ectodomain induces protective immune responses against H9N2 infection in chickens.

H9N2, a low pathogenic avian influenza virus, causes significant economic losses in the poultry industry worldwide. Herein, we describe the construction of an attenuated Salmonella Gallinarum (SG) strain for expression and delivery of H9N2 haemagglutinin (HA) 1 (SG-HA1), HA2 (SG-HA2) and/or the conserved matrix protein 2 ectodomain (SG-M2e). We demonstrated that recombinant SG strains expressing HA1, HA2 and M2e antigens were immunogenic and safe in a chicken model. Chickens (n = 8) were vaccinated once orally with SG alone, SG-HA1, SG-HA2, SG-M2e, or mixture of SG-HA1, SG-HA2 and SG-M2e, or vaccinated once intramuscularly with an oil-adjuvant inactivated H9N2 vaccine. Our results demonstrated that vaccination with SG mutants encoding influenza antigens, administered individually or as a mixture, elicited significantly (P < 0.05) greater antigen-specific humoral and cell-mediated immune responses in chickens compared with those vaccinated with SG alone. A conventional H9N2 vaccine induced significantly (P < 0.05) greater HA1 and HA2 antibody responses than SG-based H9N2 vaccine strains, but significantly (P < 0.05) less robust M2e-specific responses. Upon challenge with the virulent H9N2 virus on day 28 post-vaccination, chickens vaccinated with either the SG-based H9N2 or conventional H9N2 vaccines exhibited comparable lung inflammation and viral loads, although both were significantly lower (P < 0.05) than in the group vaccinated with SG alone. In conclusion, our results showed that SG-based vaccination stimulated efficient immune responses against virulent H9N2. Further studies are needed to fully develop this approach as a preventive strategy for low pathogenic avian influenza viruses affecting poultry. RESEARCH HIGHLIGHTS S. gallinarum expressing HA1, HA2 and M2e antigens are immunogenic and safe. Salmonella has dual function of acting as a delivery system and as a natural adjuvant. Vaccine constructs elicit specific humoral and cell-mediated immune responses.

Bagging Ensemble of Multilayer Perceptrons for Missing Electricity Consumption Data Imputation.

For efficient and effective energy management, accurate energy consumption forecasting is required in energy management systems (EMSs). Recently, several artificial intelligence-based techniques have been proposed for accurate electric load forecasting; moreover, perfect energy consumption data are critical for the prediction. However, owing to diverse reasons, such as device malfunctions and signal transmission errors, missing data are frequently observed in the actual data. Previously, many imputation methods have been proposed to compensate for missing values; however, these methods have achieved limited success in imputing electric energy consumption data because the period of data missing is long and the dependency on historical data is high. In this study, we propose a novel missing-value imputation scheme for electricity consumption data. The proposed scheme uses a bagging ensemble of multilayer perceptrons (MLPs), called softmax ensemble network, wherein the ensemble weight of each MLP is determined by a softmax function. This ensemble network learns electric energy consumption data with explanatory variables and imputes missing values in this data. To evaluate the performance of our scheme, we performed diverse experiments on real electric energy consumption data and confirmed that the proposed scheme can deliver superior performance compared to other imputation methods.

Transcriptional Profiling of the Probiotic Escherichia coli Nissle 1917 Strain under Simulated Microgravity.

Long-term space missions affect the gut microbiome of astronauts, especially the viability of some pathogens. Probiotics may be an effective solution for the management of gut microbiomes, but there is a lack of studies regarding the physiology of probiotics in microgravity. Here, we investigated the effects of microgravity on the probiotic Escherichia coli Nissle 1917 (EcN) by comparing transcriptomic data during exponential and stationary growth phases under simulated microgravity and normal gravity. Microgravity conditions affected several physiological features of EcN, including its growth profile, biofilm formation, stress responses, metal ion transport/utilization, and response to carbon starvation. We found that some changes, such as decreased adhesion ability and acid resistance, may be disadvantageous to EcN relative to gut pathogens under microgravity, indicating the need to develop probiotics optimized for space flight.

Generation of N-Centered Radicals via a Photocatalytic Energy Transfer: Remote Double Functionalization of Arenes Facilitated by Singlet Oxygen.

An unprecedented approach to the generation of an N-centered radical via a photocatalytic energy-transfer process from readily available heterocyclic precursors is reported, which is distinctive of the previous electron transfer approaches. In combination with singlet oxygen, the in-situ-generated nitrogen radical from the oxadiazoline substrate in the presence of fac-Ir(ppy)3 undergoes a selective ipso addition to arenes to furnish remotely double-functionalized spiro-azalactam products. The mechanistic studies provide compelling evidence that the catalytic cycle selects the energy-transfer pathway. A concurrent activation of molecular oxygen to generate singlet oxygen by energy transfer is also rationalized. Furthermore, the occurrence of the electron transfer phenomenon is excluded on the basis of the negative driving forces for one-electron transfer between oxadiazoline and the excited state of fac-Ir(ppy)3 with a consideration of their redox potentials. The necessity of singlet oxygen as well as the photoactivated oxadiazoline substrate is clearly supported by a series of controlled experiments. Density functional studies have also been carried out to support these observations. The scope of substrates is explored by synthesizing diversely functionalized cyclohexadienone moieties in view of their utility in complex organic syntheses and as potential targets in pharmacology.

CYP52A23 from Candida albicans and its Substrate Preference for Fatty Acid Hydroxylation.

The pathogenic fungus Candida albicans contains genes encoding five fatty acid hydroxylases belonging to the CYP52 family in its genome. Our previous study reported that CYP52A21 demonstrated typical omega-hydroxylation of lauric acid (Kim D, Cryle MJ, De Voss JJ, Ortiz de Montellano PR (2007) Arch Biochem Biophys 464, 213-220). Functional characterization of CYP52 fatty acid hydroxylases was studied, and their selectivity for hydroxylation was analyzed. Genes for four other CYP52 members (CYP52A22, CYP52A23, CYP52A24, and CYP52C3) from C. albicans were cloned, and their recombinant enzymes were expressed in Escherichia coli. CO-binding spectral analyses showed that the functional P450 holoenzyme was obtained only in CYP52A23, while no holoenzyme peak was observed in the other three CYP52 enzymes. Spectral change of the type II binding was observed in purified CYP52A23 when titrated with fatty acids but none was observed with alkanes. The gas chromatography-mass spectrometry (GC-MS) analysis revealed that CYP52A23 predominantly exhibited omega-hydroxylation activity during the oxidation reaction of fatty acids. Interestingly, it was found that CYP52A23 preferred longer-chain fatty acids (stearic acid and arachidic acid) for its catalytic activities while CYP52A21 preferred mid-chain fatty acids (lauric acid and mystic acid). To analyze the selectivity of fatty acids, hybrid mutagenesis of genes encoding CYP52A21 and CYP52A23 by overlap extension polymerase chain reaction was conducted. Two hybrid mutants containing the N-terminal fragments of CYP52A21 and C-terminal fragments of CYP52A23 displayed higher catalytic activity in palmitic acid and arachidic acid. These results suggested that the C-terminal part of CYP52A23 may be responsible for its preference to longer-chain fatty acids.

Clinical impact of prognostic nutritional index in diffuse large B cell lymphoma.

We evaluated the association between the prognostic nutritional index (PNI) and the clinical features of diffuse large B cell lymphoma (DLBCL) and developed a novel prognostic model using a nomogram including the PNI and other biomarkers for cancer cachexia. A total of 228 DLBCL patients treated with first-line R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) were retrospectively reviewed. PNI was calculated as 10 × serum levels of albumin (g/dL) + 0.005 × absolute lymphocyte count (/mm3). Patients were categorized into low- and high-PNI groups based on a cut-off value of 40. The nomogram for predicting overall survival (OS) was constructed using a Cox regression model. PNI was positively correlated with skeletal muscle index, body mass index, and serum levels of albumin. The low-PNI group had a lower complete response rate (60.3% vs. 87.6%), increased treatment-related toxicity, and more frequent treatment discontinuation (43.5% vs. 8.8%) than the high-PNI group. The median OS was shorter in the low-PNI group than the high-PNI group (15.6 months vs. not reached; p < 0.001). Multivariate Cox regression analyses showed that PNI, sarcopenia, and the international prognostic index (IPI) were independent prognostic factors for OS. The nomogram developed using this regression model showed excellent discriminatory ability for predicting OS (c-index, 0.80) compared to the IPI alone (c-index, 0.75). Low PNI was associated with adverse clinical features of DLBCL. The proposed nomogram supports the clinical impact of cachexia on survival and may contribute to individualized therapy in DLBCL.

Estimation of heat-related deaths during heat wave episodes in South Korea (2006-2017).

In 2016, South Korea experienced extremely high temperatures and the Korea Centre for Disease Control and Prevention (KCDC) reported 17 heat-caused deaths during these heat waves, most due to heat stroke. Because the reported number of heat-caused deaths is only part of the total deaths associated with heat waves, we aimed to estimate attributable deaths during heat wave episodes. We linked mortality to meteorological data in 16 regions in South Korea and estimated relative risk at or above threshold of maximum temperature during summer using generalized linear regression models after controlling for confounders. We computed overall, age-, sex-, and cause-specific attributable deaths from 2006 to 2017. With a 1.5% increase in all-cause mortality per 1 °C increase in concurrent days' maximum temperature during summer, this study estimates a total of 1440 all-cause deaths associated with heat waves during the 2006-2017 study period in South Korea. We estimate that 343 deaths in 2016 can be ascribed to heat waves, which is approximately 20 times more than the number reported by the KCDC (17 heat-caused deaths). This study addresses attributable heat wave deaths in South Korea and illustrates that the reports of medically classified heat-caused deaths seriously underestimate the number of deaths attributable to heat waves. Our findings may enable the implementation and reinforcement of government- and individual-level management strategies for heat waves.