Engineering a lipase B from Candida antactica with efficient perhydrolysis performance by eliminating its hydrolase activity

A Ser105Ala mutant of the lipase B from Candida antarctica enables 'perhydrolase-only' reactions. At the example of the chemoenzymatic Baeyer-Villiger oxidation of cyclohexanone, we demonstrate that with this mutant selective oxidation can be achieved in deep eutectic solvent while essentially eliminating the undesired hydrolysis reaction of the product.BT/Biocatalysi

Transcriptional Factors Smad1 and Smad9 Act Redundantly to Mediate Zebrafish Ventral Specification Downstream of Smad5

Background: Ventral specification is regulated by Smad1-, Smad5-, and/or Smad9-mediated bone morphogenetic protein (BMP) signaling. Results: Double knockdown instead of single knockdown of smad1 and smad9 induces dorsalization, which cannot be rescued by smad5 overexpression. Conclusion:smad1 and smad9 act redundantly and downstream of smad5 to mediate ventral specification. Significance: The regulation network and cooperative roles of BMP R-Smads in early development are clarified. Bone morphogenetic proteins (BMPs) are multifunctional growth factors that play crucial roles during embryonic development and cell fate determination. Nuclear transduction of BMP signals requires the receptor type Smad proteins, Smad1, Smad5, and Smad9. However, how these Smad proteins cooperate in vivo to regulate various developmental processes is largely unknown. In zebrafish, it was widely believed that the maternally expressed smad5 is essential for dorso-ventral (DV) patterning, and the zygotically transcribed smad1 is not required for normal DV axis establishment. In the present study, we have identified zygotically expressed smad9, which cooperates with smad1 downstream of smad5, to mediate zebrafish early DV patterning in a functional redundant manner. Although knockdown of smad1 or smad9 alone does not lead to visible dorsalization, double knockdown strongly dorsalizes zebrafish embryos, which cannot be efficiently rescued by smad5 overexpression, whereas the dorsalization induced by smad5 knockdown can be fully rescued by overexpression of smad1 or smad9. We have further revealed that the transcription initiations of smad1 and smad9 are repressed by each other, that they are direct transcriptional targets of Smad5, and that smad9, like smad1, is required for myelopoiesis. In conclusion, our study uncovers that smad1 and smad9 act redundantly to each other downstream of smad5 to mediate ventral specification and to regulate embryonic myelopoiesis.Background: Ventral specification is regulated by Smad1-, Smad5-, and/or Smad9-mediated bone morphogenetic protein (BMP) signaling. Results: Double knockdown instead of single knockdown of smad1 and smad9 induces dorsalization, which cannot be rescued by smad5 overexpression. Conclusion:smad1 and smad9 act redundantly and downstream of smad5 to mediate ventral specification. Significance: The regulation network and cooperative roles of BMP R-Smads in early development are clarified

Interannual variability and correlation of vegetation cover and precipitation in Eastern China

Based on the SPOT/VEGETATION Normalized Difference Vegetation Index (NDVI) data and daily precipitation data of 357 meteorological stations, the spatial and temporal variability of vegetation cover, measured by NDVI, and precipitation as well as their relationships are investigated in Eastern China, which is portioned into three subregions (regions I, II, and III), for the period 1998-2010. The results show that high NDVI values appear mainly in Northeastern China and in August while high precipitation (PRETOT) occurs in Southeastern China and in July (June for Southern China). Extreme precipitation days (RD95p) and amount (EPRETOT) coincide well with PRETOT. Extreme precipitation intensity (RINTEN) has a similar spatial variability to PRETOT but with a smaller seasonal variation than PRETOT. Growing season NDVI is positively correlated with PRETOT in 11.7 % of the study area (mostly in arid to subhumid regions of Northern China), where precipitation is a limiting factor for vegetation growth. In contrast, a negative correlation between growing season NDVI and PRETOT is found in 4.8 % of the study area, mostly in areas around the Yangtze River and deep Northeastern China. No significant correlations between these two variables are found for the other regions because vegetation response to precipitation is affected by other factors such as temperature, radiation, and human disturbance. On a monthly scale, there is a positive correlation between NDVI and PRETOT in May (for region II) and September (all subregions except region I). NDVI variations lag 1 month behind PRETOT in June (for region I) and October. Correlations between NDVI and RD95p, EPRETOT are similar to that with PRETOT, but the relationships between NDVI and RINTEN are relatively weaker than with PRETOT. This study provides the technical basis for agriculture development and ecological construction in Eastern China.Based on the SPOT/VEGETATION Normalized Difference Vegetation Index (NDVI) data and daily precipitation data of 357 meteorological stations, the spatial and temporal variability of vegetation cover, measured by NDVI, and precipitation as well as their relationships are investigated in Eastern China, which is portioned into three subregions (regions I, II, and III), for the period 1998-2010. The results show that high NDVI values appear mainly in Northeastern China and in August while high precipitation (PRETOT) occurs in Southeastern China and in July (June for Southern China). Extreme precipitation days (RD95p) and amount (EPRETOT) coincide well with PRETOT. Extreme precipitation intensity (RINTEN) has a similar spatial variability to PRETOT but with a smaller seasonal variation than PRETOT. Growing season NDVI is positively correlated with PRETOT in 11.7 % of the study area (mostly in arid to subhumid regions of Northern China), where precipitation is a limiting factor for vegetation growth. In contrast, a negative correlation between growing season NDVI and PRETOT is found in 4.8 % of the study area, mostly in areas around the Yangtze River and deep Northeastern China. No significant correlations between these two variables are found for the other regions because vegetation response to precipitation is affected by other factors such as temperature, radiation, and human disturbance. On a monthly scale, there is a positive correlation between NDVI and PRETOT in May (for region II) and September (all subregions except region I). NDVI variations lag 1 month behind PRETOT in June (for region I) and October. Correlations between NDVI and RD95p, EPRETOT are similar to that with PRETOT, but the relationships between NDVI and RINTEN are relatively weaker than with PRETOT. This study provides the technical basis for agriculture development and ecological construction in Eastern China

Facial perception bias in patients with major depression

This study used a morphed categorical perception facial expression task to evaluate whether patients with depression demonstrated deficits in distinguishing boundaries between emotions. Forty-one patients with depression and 41 healthy controls took part in this study. They were administered a standardized set of morphed photographs of facial expressions with varying emotional intensities between 0% and 100% of the emotion, in 10% increments to provide a range of intensities from pleasant to unpleasant(e.g. happy to sad, happy to angry) and approach-avoidance (e.g. angry to fearful). Compared with healthy controls, the patients with depression demonstrated a rapid perception of sad expressions in happy-sad emotional continuum and demonstrated a rapid perception of angry expressions in angry-fearful emotional continuum. In addition, when facial expressions shifted from happy to angry, the depressed patients had a clear demarcation for the happy-angry continuum. Depressed patients had a perceptual bias towards unpleasant versus pleasant expressions and the hypersensitivity to angry facial signals might influence the interaction behaviors between depressed patients and others. (C) 2012 Elsevier Ireland Ltd. All rights reserved.</p

Enhanced methane emissions from oil and gas exploration areas to the atmosphere - The central Bohai Sea

The distributions of dissolved methane in the central Bohai Sea were investigated in November 2011, May 2012, July 2012, and August 2012. Methane concentration in surface seawater, determined using an underway measurement system combined with wavelength-scanned cavity ring-down spectroscopy, showed marked spatiotemporal variations with saturation ratio from 107% to 1193%. The central Bohai Sea was thus a source of atmospheric methane during the survey periods. Several episodic oil and gas spill events increased surface methane concentration by up to 4.7 times and raised the local methane out-gassing rate by up to 14.6 times. This study demonstrated a method to detect seafloor CH4 leakages at the sea surface, which may have applicability in many shallow sea areas with oil and gas exploration activities around the world. (C) 2014 Elsevier Ltd. All rights reserved.The distributions of dissolved methane in the central Bohai Sea were investigated in November 2011, May 2012, July 2012, and August 2012. Methane concentration in surface seawater, determined using an underway measurement system combined with wavelength-scanned cavity ring-down spectroscopy, showed marked spatiotemporal variations with saturation ratio from 107% to 1193%. The central Bohai Sea was thus a source of atmospheric methane during the survey periods. Several episodic oil and gas spill events increased surface methane concentration by up to 4.7 times and raised the local methane out-gassing rate by up to 14.6 times. This study demonstrated a method to detect seafloor CH4 leakages at the sea surface, which may have applicability in many shallow sea areas with oil and gas exploration activities around the world. (C) 2014 Elsevier Ltd. All rights reserved

Deficits in sustaining reward responses in subsyndromal and syndromal major depression

Preliminary findings suggest a reduction in capacity to sustain reward responses in major depression. However, relatively little is known about the stability of reward learning over time and the effect of stress on reward responses in depressed individuals. This study aimed to evaluate sustained behaviour to maximize reward in the context of known reinforcement contingencies and to evaluate the extent to which stress influences such behaviour in clinically depressed patients (n = 43), subsyndromally depressed individuals (n = 43), and healthy controls (n = 44). A probabilistic reward learning task with contingencies known to participants was used to evaluate the change of reward response over time in both &#39;stress&#39; and &#39;non-stress&#39; conditions. Stress was induced by salient negative feedback during the task performance. Questionnaires capturing subjective affect were also administered to all participants after completion of the task. Response bias to the stimulus signaling greater reward decreased significantly over time in both subsyndromally and clinically depressed participants, but not in healthy controls. Healthy controls demonstrated a trend of dysfunctional reward processing under the stress condition. Moreover, in the stress condition, the deficit in sustaining behaviour to maximize reward was associated with subjective rating of pleasure in participants with either subsyndromal depression or major depression. These findings suggest that individuals with depression have difficulty sustaining behaviour during a known reinforcement schedule. Participants with anhedonic symptoms are even less likely to sustain behaviour to maximize reward under stress. (C) 2011 Elsevier Inc. All rights reserved.</p

Graphene-Based Anticancer Nanosystem and Its Biosafety Evaluation Using a Zebrafish Model

In this paper, a facile strategy to develop graphene-based delivery nanosystems for effective drug loading and sustained drug release was proposed and validated. Specifically, biocompatible naphthalene-terminated PEG (NP) and anticancer drugs (curcumin or doxorubicin (DOX)) were simultaneously integrated onto oxidized graphene (GO), leading to self-assembled, nanosized complexes. It was found that the oxidation degree of GO had a significant impact on the drug-loading efficiency and the structural stability of nanosystems. Interestingly, the nanoassemblies resulted in more effective cellular entry of DOX in comparison with free DOX or DOX-loaded PEG-polyester micelles at equivalent DOX dose, as demonstrated by confocal microscopy studies. Moreover, the nanoassemblies not only exhibited a sustained drug release pattern without an initial burst release, but also significantly improved the stability of formulations which were resistant to drug leaking even in the presence of strong surfactants such as aromatic sodium benzenesulfonate (SBen) and aliphatic sodium dodecylsulfonate (SDS). In addition, the nanoassemblies without DOX loading showed negligible in vitro cytotoxicity, whereas DOX-loaded counterparts led to considerable toxicity against He La cells. The DOX-mediated cytotoxicity of the graphene-based formulation was around 20 folds lower than that of free DOX, most likely due to the slow DOX release from complexes. A zebrafish model was established to assess the in vivo safety profile of curcumin-loaded nanosystems. The results showed they were able to excrete from the zebrafish body rapidly and had nearly no influence on the zebrafish upgrowth. Those encouraging results may prompt the advance of graphene-based nanotherapeutics for biomedical applications.In this paper, a facile strategy to develop graphene-based delivery nanosystems for effective drug loading and sustained drug release was proposed and validated. Specifically, biocompatible naphthalene-terminated PEG (NP) and anticancer drugs (curcumin or doxorubicin (DOX)) were simultaneously integrated onto oxidized graphene (GO), leading to self-assembled, nanosized complexes. It was found that the oxidation degree of GO had a significant impact on the drug-loading efficiency and the structural stability of nanosystems. Interestingly, the nanoassemblies resulted in more effective cellular entry of DOX in comparison with free DOX or DOX-loaded PEG-polyester micelles at equivalent DOX dose, as demonstrated by confocal microscopy studies. Moreover, the nanoassemblies not only exhibited a sustained drug release pattern without an initial burst release, but also significantly improved the stability of formulations which were resistant to drug leaking even in the presence of strong surfactants such as aromatic sodium benzenesulfonate (SBen) and aliphatic sodium dodecylsulfonate (SDS). In addition, the nanoassemblies without DOX loading showed negligible in vitro cytotoxicity, whereas DOX-loaded counterparts led to considerable toxicity against He La cells. The DOX-mediated cytotoxicity of the graphene-based formulation was around 20 folds lower than that of free DOX, most likely due to the slow DOX release from complexes. A zebrafish model was established to assess the in vivo safety profile of curcumin-loaded nanosystems. The results showed they were able to excrete from the zebrafish body rapidly and had nearly no influence on the zebrafish upgrowth. Those encouraging results may prompt the advance of graphene-based nanotherapeutics for biomedical applications

Brain structural plasticity in survivors of a major earthquake

Background: Stress responses have been studied extensively in animal models, but effects of major life stress on the human brain remain poorly understood. The aim of this study was to determine whether survivors of a major earthquake, who were presumed to have experienced extreme emotional stress during the disaster, demonstrate differences in brain anatomy relative to individuals who have not experienced such stressors. Methods: Healthy survivors living in an area devastated by a major earthquake and matched healthy controls underwent 3-dimentional high-resolution magnetic resonance imaging (MRI). Survivors were scanned 13-25 days after the earthquake; controls had undergone MRI for other studies not long before the earthquake. We used optimized voxel-based morphometry analysis to identify regional differences of grey matter volume between the survivors and controls. Results: We included 44 survivors (17 female, mean age 37 [standard deviation (SD) 10.6] yr) and 38 controls (14 female, mean age 35.3 [SD 11.2] yr) in our analysis. Compared with controls, the survivors showed significantly lower grey matter volume in the bilateral insula, hippocampus, left caudate and putamen, and greater grey matter volume in the bilateral orbitofrontal cortex and the parietal lobe (all p < 0.05, corrected for multiple comparison). Limitations: Differences in the variance of survivor and control data could impact study findings. Conclusion: Acute anatomic alterations could be observed in earthquake survivors in brain regions where functional alterations after stress have been described. Anatomic changes in the present study were observed earlier than previously reported and were seen in prefrontal-limbic, parietal and striatal brain systems. Together with the results of previous functional imaging studies, our observations suggest a complex pattern of human brain response to major life stress affecting brain systems that modulate and respond to heightened affective arousal

Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial

Background: Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist being examined in an ongoing phase 3 trial in adults with IgA nephropathy. We report the prespecified interim analysis of the primary proteinuria efficacy endpoint, and safety. Methods: PROTECT is an international, randomised, double-blind, active-controlled study, being conducted in 134 clinical practice sites in 18 countries. The study examines sparsentan versus irbesartan in adults (aged ≥18 years) with biopsy-proven IgA nephropathy and proteinuria of 1·0 g/day or higher despite maximised renin-angiotensin system inhibitor treatment for at least 12 weeks. Participants were randomly assigned in a 1:1 ratio to receive sparsentan 400 mg once daily or irbesartan 300 mg once daily, stratified by estimated glomerular filtration rate at screening (30 to 1·75 g/day). The primary efficacy endpoint was change from baseline to week 36 in urine protein-creatinine ratio based on a 24-h urine sample, assessed using mixed model repeated measures. Treatment-emergent adverse events (TEAEs) were safety endpoints. All endpoints were examined in all participants who received at least one dose of randomised treatment. The study is ongoing and is registered with ClinicalTrials.gov, NCT03762850. Findings: Between Dec 20, 2018, and May 26, 2021, 404 participants were randomly assigned to sparsentan (n=202) or irbesartan (n=202) and received treatment. At week 36, the geometric least squares mean percent change from baseline in urine protein-creatinine ratio was statistically significantly greater in the sparsentan group (-49·8%) than the irbesartan group (-15·1%), resulting in a between-group relative reduction of 41% (least squares mean ratio=0·59; 95% CI 0·51-0·69; p<0·0001). TEAEs with sparsentan were similar to irbesartan. There were no cases of severe oedema, heart failure, hepatotoxicity, or oedema-related discontinuations. Bodyweight changes from baseline were not different between the sparsentan and irbesartan groups. Interpretation: Once-daily treatment with sparsentan produced meaningful reduction in proteinuria compared with irbesartan in adults with IgA nephropathy. Safety of sparsentan was similar to irbesartan. Future analyses after completion of the 2-year double-blind period will show whether these beneficial effects translate into a long-term nephroprotective potential of sparsentan. Funding: Travere Therapeutics