Interneuron-Targeted Disruption of SYNGAP1 Alters Sensory Representations in the Neocortex and Impairs Sensory Learning.

SYNGAP1 haploinsufficiency in humans leads to severe neurodevelopmental disorders characterized by intellectual disability, autism, epilepsy, and sensory processing deficits. However, the circuit mechanisms underlying these disorders are not well understood. In mice, a decrease of SynGAP levels results in cognitive deficits by interfering with the development of excitatory glutamatergic connections. Recent evidence suggests that SynGAP also plays a crucial role in the development and function of GABAergic inhibitory interneurons. Nevertheless, it remains uncertain whether and to what extent the expression of SYNGAP1 in inhibitory interneurons contributes to cortical circuit function and related behaviors. The activity of cortical neurons has not been measured simultaneously with behavior. To address these gaps, we recorded from layer 2/3 neurons in the primary whisker somatosensory cortex (wS1) of mice while they learned to perform a whisker tactile detection task. Our results demonstrate that mice with interneuron-specific SYNGAP1 haploinsufficiency exhibit learning deficits characterized by heightened behavioral responses in the absence of relevant sensory input and premature responses to unrelated sensory stimuli not associated with reward acquisition. These behavioral deficits are accompanied by specific circuit abnormalities within wS1. Interneuron-specific SYNGAP1 haploinsufficiency increases detrimental neuronal correlations directly related to task performance and enhances responses to irrelevant sensory stimuli unrelated to the reward acquisition. In summary, our findings indicate that a reduction of SynGAP in inhibitory interneurons impairs sensory representation in the primary sensory cortex by disrupting neuronal correlations, which likely contributes to the observed cognitive deficits in mice with pan-neuronal SYNGAP1 haploinsufficiency.SIGNIFICANCE STATEMENT SYNGAP1 haploinsufficiency leads to severe neurodevelopmental disorders. The exact nature of neural circuit dysfunction caused by SYNGAP1 haploinsufficiency remains poorly understood. SynGAP plays a critical role in the function of GABAergic inhibitory interneurons as well as glutamatergic pyramidal neurons in the neocortex. Whether and how decreasing SYNGAP1 level in inhibitory interneurons disrupts a behaviorally relevant circuit remains unclear. We measure neural activity and behavior in mice learning a perceptual task. Mice with interneuron-targeted disruption of SYNGAP1 display increased detrimental neuronal correlations and elevated responses to irrelevant sensory inputs, which are related to impaired task performance. These results show that cortical interneuron dysfunction contributes to sensory deficits in SYNGAP1 haploinsufficiency with important implications for identifying therapeutic targets.

Coagulation abnormalities associated with CAR-T-cell therapy in haematological malignancies: A review.

Chimeric antigen receptor (CAR)-T-cell therapy has demonstrated considerable efficacy and safety in the treatment of patients with relapsed/refractory haematological malignancies. Owing to significant advances, CAR-T-cell therapeutic modality has undergone substantial shifts in its clinical application. Coagulation abnormalities, which are prevalent complications in CAR-T-cell therapy, can range in severity from simple abnormalities in coagulation parameters to serious haemorrhage or disseminated intravascular coagulation associated with life-threatening multiorgan dysfunction. Nonetheless, there is a lack of a comprehensive overview concerning the coagulation abnormalities associated with CAR-T-cell therapy. With an aim to attract heightened clinical focus and to enhance the safety of CAR-T-cell therapy, this review presents the characteristics of the coagulation abnormalities associated with CAR-T-cell therapy, including clinical manifestations, coagulation parameters, pathogenesis, risk factors and their influence on treatment efficacy in patients receiving CAR-T-cell infusion. Due to limited data, these conclusions may undergo changes as more experience accumulates.

Nanoconfined Silver Nanoclusters Combined with X-Shaped DNA Recognizer-Triggered Cascade Amplification for Electrochemiluminescence Detection of APE1.

Apurinic/apyrimidinic endonuclease 1 (APE1), as a vital base excision repair enzyme, is essential for maintaining genomic integrity and stability, and its abnormal expression is closely associated with malignant tumors. Herein, we constructed an electrochemiluminescence (ECL) biosensor for detecting APE1 activity by combining nanoconfined ECL silver nanoclusters (Ag NCs) with X-shaped DNA recognizer-triggered cascade amplification. Specifically, the Ag NCs were prepared and confined in the glutaraldehyde-cross-linked chitosan hydrogel network using the one-pot method, resulting in a strong ECL response and exceptional stability in comparison with discrete Ag NCs. Furthermore, the self-assembled X-shaped DNA recognizers were designed for APE1 detection, which not only improved reaction kinetics due to the ordered arrangement of recognition sites but also achieved high sensitivity by utilizing the recognizer-triggered cascade amplification of strand displacement amplification (SDA) and DNAzyme catalysis. As expected, this biosensor achieved sensitive ECL detection of APE1 in the range of 1.0 × 10-3 U·µL-1 to 1.0 × 10-10 U·µL-1 with the detection limit of 2.21 × 10-11 U·µL-1, rendering it a desirable approach for biomarker detection.

A Cortico-Cortical Pathway Targets Inhibitory Interneurons and Modulates Paw Movement during Locomotion in Mice.

The primary somatosensory cortex (S1) is important for the control of movement as it encodes sensory input from the body periphery and external environment during ongoing movement. Mouse S1 consists of several distinct sensorimotor subnetworks that receive topographically organized corticocortical inputs from distant sensorimotor areas, including the secondary somatosensory cortex (S2) and primary motor cortex (M1). The role of the vibrissal S1 area and associated cortical connections during active sensing is well documented, but whether (and if so, how) non-whisker S1 areas are involved in movement control remains relatively unexplored. Here, we demonstrate that unilateral silencing of the non-whisker S1 area in both male and female mice disrupts hind paw movement during locomotion on a rotarod and a runway. S2 and M1 provide major long-range inputs to this S1 area. Silencing S2→non-whisker S1 projections alters the hind paw orientation during locomotion, whereas manipulation of the M1 projection has little effect. Using patch-clamp recordings in brain slices from male and female mice, we show that S2 projection preferentially innervates inhibitory interneuron subtypes. We conclude that interneuron-mediated S2-S1 corticocortical interactions are critical for efficient locomotion.SIGNIFICANCE STATEMENT Somatosensory cortex participates in controlling rhythmic movements, such as whisking and walking, but the neural circuitry underlying movement control by somatosensory cortex remains relatively unexplored. We uncover a corticocortical circuit in primary somatosensory cortex that regulates paw orientation during locomotion in mice. We identify neuronal elements that comprise these cortical pathways using pharmacology, behavioral assays, and circuit-mapping methods.

Target-Driven Annular DNA Walker Coupled with Electrochemiluminescent Silicon Quantum Dots for APE1 Bioanalysis.

Functional DNA walkers with substantial nanostructures have been extensively investigated; however, their stability still faces challenges when exposed to diverse nuclease in clinical biological samples, resulting in the unreliability of actual assessment. This work proposed a target-driven annular DNA walker with enhanced stability enabling the sensitive and reliable response to different concentrations of apurinic/apyrimidinic endonuclease 1 (APE1), by preparing silicon quantum dots (SiQDs) as electrochemiluminescence (ECL) emitters. Specifically, the SiQDs showed significant strong and stable ECL signals by purifying the microenvironment of SiQDs through the dialysis removal of the gel-like layers surrounding the SiQDs. The relative standard deviation (RSD) of their ECL signal had been improved 16.59 times under consecutive scanning compared to that of SiQDs without dialysis, demonstrating a significant improvement in ECL stability. Subsequently, in the presence of APE1, the designed annular DNA walker was activated to move along the numerous quenching probes within the continuous cross-based DNA orbits, which were immobilized to the SiQD-modified electrode, providing ECL readout signals. The linear range of this ECL biosensor was 1.0 × 10-13 U·µL-1 to 1.0 × 10-7 U·µL-1, and the limit of detection (LOD) was as low as 1.766 × 10-14 U·µL-1. This work provides a novel structure of a DNA walker with nuclease resistance for clinical sample detection and designs a new strategy for synthesizing SiQDs with favorable ECL performance, tremendously expanding the ECL application of SiQDs.

Strategy for reducing the effect of surface fluctuation in the classification of aluminum alloy via data transfer and laser-induced breakdown spectroscopy.

Laser-induced breakdown spectroscopy (LIBS) plays an increasingly important role in the classification and recycling of aluminum alloys owing to its outstanding elemental analysis performance. For LIBS measurements with sample surface fluctuations, consistently and exactly maintaining the laser and fiber focus points on the sample surface is difficult, and fluctuations in the focus severely affect the stability of the spectrum. In this study, a data transfer method is introduced to reduce the effect of spectral fluctuations on the model performance. During the experiment, a focal point is placed on the sample surface. Then, keeping experimental conditions unchanged, the three-dimensional platform is only moved up and down along the z-axis by 0.5 mm, 1 mm, 1.5 mm, 2 mm and 2.5 mm, respectively. Eleven spectral datasets at different heights are collected for analysis. The KNN model is used as the base classifier, and the accuracies of the 11 datasets, from the lowest to the highest, are 11.48%, 19.71%, 30.57%, 45.71%, 53.57%, 88.28%, 52.57%, 21.42%, 14.42%, 14.42%, and 14.42%. To improve predictive performance, the difference in data distribution between the spectra collected at the sample surface and those collected at other heights is reduced by data transfer. Feature selection is introduced and combined with data transfer, and the final accuracies are 78.14%, 82.28%, 80.14%, 89.71%, 91.85%, 98.42%, 94.28%, 92.42%, 82.14%, 78.57%, and 73.71%. It can be seen that the proposed method provides a new feasible and effective way for the classification of aluminum alloys in a real detection environment.

Accuracy of Mean Value of Central Venous Pressure from Monitor Digital Display: Influence of Amplitude of Central Venous Pressure during Respiration.

Background A simple measurement of central venous pressure (CVP)-mean by the digital monitor display has become increasingly popular. However, the agreement between CVP-mean and CVP-end (a standard method of CVP measurement by analyzing the waveform at end-expiration) is not well determined. This study was designed to identify the relationship between CVP-mean and CVP-end in critically ill patients and to introduce a new parameter of CVP amplitude (ΔCVP= CVPmax - CVPmin) during the respiratory period to identify the agreement/disagreement between CVP-mean and CVP-end.Methods In total, 291 patients were included in the study. CVP-mean and CVP-end were obtained simultaneously from each patient. CVP measurement difference (|CVP-mean - CVP-end|) was defined as the difference between CVP-mean and CVP-end. The ΔCVP was calculated as the difference between the peak (CVPmax) and the nadir value (CVPmin) during the respiratory cycle, which was automatically recorded on the monitor screen. Subjects with |CVP-mean - CVP-end|≥ 2 mmHg were divided into the inconsistent group, while subjects with |CVP-mean - CVP-end| < 2 mmHg were divided into the consistent group.Results ΔCVP was significantly higher in the inconsistent group [7.17(2.77) vs.5.24(2.18), P<0.001] than that in the consistent group. There was a significantly positive relationship between ΔCVP and |CVP-mean - CVP-end| (r=0.283, P <0.0001). Bland-Altman plot showed the bias was -0.61 mmHg with a wide 95% limit of agreement (-3.34, 2.10) of CVP-end and CVP-mean. The area under the receiver operating characteristic curves (AUC) of ΔCVP for predicting |CVP-mean - CVP-end| ≥ 2 mmHg was 0.709. With a high diagnostic specificity, using ΔCVP<3 to detect |CVP-mean - CVP-end| lower than 2mmHg (consistent measurement) resulted in a sensitivity of 22.37% and a specificity of 93.06%. Using ΔCVP>8 to detect |CVP-mean - CVP-end| >8 mmHg (inconsistent measurement) resulted in a sensitivity of 31.94% and a specificity of 91.32%.Conclusions CVP-end and CVP-mean have statistical discrepancies in specific clinical scenarios. ΔCVP during the respiratory period is related to the variation of the two CVP methods. A high ΔCVP indicates a poor agreement between these two methods, whereas a low ΔCVP indicates a good agreement between these two methods.

ER-associated degradation preserves hematopoietic stem cell quiescence and self-renewal by restricting mTOR activity.

Hematopoietic stem cells (HSC) self-renew to sustain stem cell pools and differentiate to generate all types of blood cells. HSCs remain in quiescence to sustain their long-term self-renewal potential. It remains unclear whether protein quality control is required for stem cells in quiescence when RNA content, protein synthesis, and metabolic activities are profoundly reduced. Here, we report that protein quality control via endoplasmic reticulum-associated degradation (ERAD) governs the function of quiescent HSCs. The Sel1L/Hrd1 ERAD genes are enriched in the quiescent and inactive HSCs, and conditional knockout of Sel1L in hematopoietic tissues drives HSCs to hyperproliferation, which leads to complete loss of HSC self-renewal and HSC depletion. Mechanistically, ERAD deficiency via Sel1L knockout leads to activation of mammalian target of rapamycin (mTOR) signaling. Furthermore, we identify Ras homolog enriched in brain (Rheb), an activator of mTOR, as a novel protein substrate of Sel1L/Hrd1 ERAD, which accumulates upon Sel1L deletion and HSC activation. Importantly, inhibition of mTOR, or Rheb, rescues HSC defects in Sel1L knockout mice. Protein quality control via ERAD is, therefore, a critical checkpoint that governs HSC quiescence and self-renewal by Rheb-mediated restriction of mTOR activity.

Respiratory fabric sensor based on the side luminescence and photosensitivity mechanism of polymer optical fibers.

It is significant to monitor respiration conveniently and in real time for people suffering from respiratory diseases. Polymer optical fibers (POFs) have the advantages of flexibility and light weight, which is highly desirable for wearable respiratory monitoring. However, in most current applications, the POFs are stitched on the textile substrates in the form of macro-bending. This method is complex to fix the bending with certain curvatures and uncomfortable compared with the POF sensors woven into the textile. In this paper, a respiratory fabric sensor based on the side luminescence and photosensitivity mechanism of POF is proposed and demonstrated. The 750µm-diameter POFs were woven into a fabric as warp and laser marking was performed at their designed positions to make them release or couple light. The spacing change between the POFs caused by the respiratory movement accordingly makes the light intensity change in the photosensitive fiber. We chose four fabric widths (10cm, 8cm, 6cm and 4cm) and four fabric weaves (plain weave, honeycomb weave, 1/3 right twill weave and 8/3 warp satin weave) to implement the full-factor experiment for exploring the measurement effect of the respiratory fabric sensor. The result is that the fabric with width of 4cm and weave of 8/3 warp satin is optimal. The calm and deep respiratory tests of the human chest and abdomen in sitting and standing posture were carried out and the test performance of the fabric sensor is almost comparable to that of the medical monitor. The proposed respiratory fabric sensor is comfortable, easily woven and high in precision, which is expected to realize industrialized scale production.

Concomitant genetic alterations are associated with plasma D-dimer level in patients with non-small-cell lung cancer.

Objective: D-dimer is correlated to the poor prognosis of non-small-cell lung cancer. The study aimed to investigate the association between plasma D-dimer and concomitant mutations in non-small-cell lung cancer. Methods: A total of 517 non-small-cell lung cancer patients were recruited and tested for ALK, BRAF, EGFR, HER2/ERBB2, KRAS, MET, PIK3CA, RET and ROS1 mutation by next-generation sequencing. Multiple gene mutation information, clinical baseline data and laboratory test data were analyzed statistically. Results: All patients were divided into three groups: wild-type group, single-gene mutation group and concomitant mutation group. The analysis of D-dimer, uric acid, gender, family history, smoking history, histology and distant metastasis all showed significant differences in the three groups (p < 0.05). D-dimer was considered as a risk factor for concomitant mutations according to the unordered multiple logistic regression analysis. The receiver operating characteristic curve analysis indicated that D-dimer had an important predictive value for the occurrence of concomitant mutations (area under the curve [AUC]: 0.94; sensitivity: 88.71%; specificity: 86.46). There was significantly shorter median progression-free survival in the concomitant mutation group compared with the single mutation group (7.70 months vs 14.00 months; p = 0.0133). Conclusion: Plasma D-dimer is significantly associated with concomitant mutations and may be regarded as a potent predictor of concomitant mutations for non-small-cell lung cancer patients.

Plain language summary Non-small-cell lung cancer (NSCLC) is a common type of lung cancer. Gene mutation is an important cause of NSCLC. The authors are eager to predict the occurrence of gene mutations through some non-specific indicators. These non-specific indicators need to meet the conditions of simple acquisition and low detection cost. In this study, patients are divided into wild-type, single-gene mutation and concomitant mutation groups based on next-generation sequencing results. The authors have observed that the levels of D-dimer are significantly increased in some NSCLC patients. And D-dimer is considered to be a risk factor for concomitant mutations and had important predictive value for concomitant mutations. This study provides a new predictive and prognostic indicator (D-dimer) for patients with concomitant mutations. D-dimer is a new method for predicting concomitant mutations and guides further treatment in NSCLC.

Natural population re-sequencing detects the genetic basis of local adaptation to low temperature in a woody plant.

KEY MESSAGE: Total of 14 SNPs associated with overwintering-related traits and 75 selective regions were detected. Important candidate genes were identified and a possible network of cold-stress responses in woody plants was proposed. Local adaptation to low temperature is essential for woody plants to against changeable climate and safely survive the winter. To uncover the specific molecular mechanism of low temperature adaptation in woody plants, we sequenced 134 core individuals selected from 494 paper mulberry (Broussonetia papyrifera), which naturally distributed in different climate zones and latitudes. The population structure analysis, PCA analysis and neighbor-joining tree analysis indicated that the individuals were classified into three clusters, which showed forceful geographic distribution patterns because of the adaptation to local climate. Using two overwintering phenotypic data collected at high latitudes of 40°N and one bioclimatic variable, genome-phenotype and genome-environment associations, and genome-wide scans were performed. We detected 75 selective regions which possibly undergone temperature selection and identified 14 trait-associated SNPs that corresponded to 16 candidate genes (including LRR-RLK, PP2A, BCS1, etc.). Meanwhile, low temperature adaptation was also supported by other three trait-associated SNPs which exhibiting significant differences in overwintering traits between alleles within three geographic groups. To sum up, a possible network of cold signal perception and responses in woody plants were proposed, including important genes that have been confirmed in previous studies while others could be key potential candidates of woody plants. Overall, our results highlighted the specific and complex molecular mechanism of low temperature adaptation and overwintering of woody plants.

MicroRNA-Triggered Deconstruction of Field-Free Spherical Nucleic Acid as an Electrochemiluminescence Biosensing Switch.

Herein, a new field-free and highly ordered spherical nucleic acid (SNA) nanostructure was self-assembled directly by ferrocene (Fc)-labeled DNA tweezers and DNA linkers based on the Watson-Crick base pairing rule, which was employed as an electrochemiluminescence (ECL) quenching switch with improved recognition efficiency due to the high local concentration of the ordered nanostructure. Moreover, with a collaborative strategy combined with the advantages of both self-accelerated approach and pore confinement-enhanced ECL effect, the mesoporous silica nanospheres (mSiO2 NSs) were prepared to be filled with rubrene (Rub) as ECL emitters and Pt nanoparticles (PtNPs) as coreaction accelerators (Rub-Pt@mSiO2 NSs), which demonstrated high ECL response in the aqueous media (dissolved O2 as coreactant). When the SNA nanostructure was immobilized on the Rub-Pt@mSiO2 NSs-modified electrode, it presented a "signal off" state owing to the quenching effect of the Fc molecules. As a proof of concept, the SNA-based ECL switch platform was applied in the detection of microRNA let-7b (let-7b). Impressively, in the presence of the target let-7b, a deconstruction of the SNA nanostructure was actuated, causing the Fc to leave the electrode surface and achieved an extremely high ECL recovery ("signal on" state). Hence, a sensitive determination for let-7b was realized with a low detection limit of 1.8 aM ranging from 10 aM to 1 nM by employing the Rub-Pt@mSiO2 NSs-based ECL platform combined with the target-triggered SNA deconstruction, which also offered an ingenious method for the further applications of biomarker analyses.

An Affinity-Enhanced DNA Intercalator with Intense ECL Embedded in DNA Hydrogel for Biosensing Applications.

Herein, an amphiphilic perylene derivative (denoted as PTC-DEDA) was explored as DNA intercalators endowed with an enhanced affinity and intense electrochemiluminescence (ECL) to construct a target-induced DNA hydrogel biosensing platform for the sensitive detection of microRNA let-7a (miRNA let-7a). Specifically, the DNA hydrogel with numerous dendritic DNA structures was in situ generated via a target-induced nonlinear hybrid chain reaction in the presence of miRNA let-7a, which possessed a large loading capacity to entrap massive DNA intercalators. Then, the PTC-DEDA with positive charges could easily intercalate into the DNA grooves due to the inherent amphipathic structure, achieving a strong ECL signal. Using the proposed PTC-DEDA as both DNA intercalators and ECL emitters, the DNA hydrogel biosensing platform exhibited a high stability and an excellent sensitivity for miRNA let-7a, with a desirable linear range (10 fM to 10 nM) and a low detection limit (1.49 fM). Significantly, the work provides a potential alternative to develop simple and high-efficiency ECL platforms for biochemical analysis applications.

Cooperation between Broussonetia papyrifera and Its Symbiotic Fungal Community To Improve Local Adaptation of the Host.

The genetic basis of plant local adaptation has been extensively studied, yet the interplay between local adaptation, plant genetic divergence, and the microbial community remains unclear. Our study used the restriction-site associated DNA sequencing (RAD-seq) approach to explore genetic divergence in Broussonetia papyrifera and used internal transcribed spacers (ITS) to characterize fungal community. RAD-seq results show that B. papyrifera individuals could be divided into three genotypes; this genotyping result was consistent with the classification of climate type at the sample site. Most of the 101 highly differentiated genes were related to stress resistance and the microbiome. Moreover, ß-diversity results indicated that genetic divergence had a significant effect on fungal community across all compartments (P < 0.01). At genus and operational taxonomic unit (OTU) level, Mortierella, Hannaella oryzae, OTU81578 (Mortierella), and OTU1665209 (H. oryzae) were found to be the major OTUs that contribute to differences in fungal community. The properties of cooccurrence networks vary greatly among three genotypes. The results of redundancy analysis (RDA) indicated that B. papyrifera-associated fungal community was significantly related to its local adaptability. Our findings suggest that genetic divergence of B. papyrifera is closely related to local adaptation, with significant effects on the associated fungal community, which in turn would enhance host local adaptability. This improves present understanding about the coevolution of microbial communities and the host plant.IMPORTANCE The coevolution of plants with the associated fungal community and its effect on plant adaptability are not clear, especially for native trees. This study focuses on the genetic basis of local adaptation in plants and the effect of genetic divergence of Broussonetia papyrifera on the associated fungal community. We identified genes related to the microbiome that are important for local adaptation of the host. Our results show that genetic divergence in B. papyrifera significantly affects the fungal community, which has a close connection with local adaptation. This helps us to understand the relationship between local adaptation, genetic divergence, and associated fungal communities. This study highlights the effect of plant genetic divergence on associated fungal community for native trees and establishes a close connection between this effect and local adaptability in the host. In addition, these observations lay a foundation for the research of coevolution of plants and their symbiotic microbiome through genome-wide association study (GWAS).

Effects of reduced platelet count on the prognosis for patients with non-small cell lung cancer treated with EGFR-TKI: a retrospective study.

BACKGROUND: Progressive lung cancer is associated with abnormal coagulation. Platelets play a vital part in evading immune surveillance and angiogenesis in the case of tumor metastasis. The study aimed to analyze the predictive and prognostic effects of platelet count on non-small cell lung cancer (NSCLC) patients treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). METHODS: This study retrospectively analyzed the prognostic effects of platelets on 52 NSCLC patients with epidermal growth factor receptor (EGFR) mutant following EGFR-TKI treatment. Related data, together with the progression-free survival (PFS) and overall survival (OS) were collected before and after 2 cycles of treatments (60 days). RESULTS: The anti-EGFR treatment markedly reduced the platelet count in 33 (63.5%) patients after 2 cycles of treatment. Multivariate Cox analysis revealed that, the decreased platelet count was closely correlated with the longer OS (HR = 0.293; 95%CI: 0.107-0.799; p = 0.017). Besides, the median OS was 326 days in the decreased platelet count group and 241 days in the increased platelet count group (HR = 0.311; 95%CI: 0.118-0.818; P = 0.018), as obtained from the independent baseline platelet levels and other clinical features. CONCLUSIONS: The platelet count may predict the prognosis for EGFR-TKI treatment without additional costs. Besides, changes in platelet count may serve as a meaningful parameter to establish the prognostic model for NSCLC patients receiving anti-EGFR targeted therapy.

Association of Ang-2, vWF, and EVLWI with risk of mortality in sepsis patients with concomitant ARDS: A retrospective study.

BACKGROUND/PURPOSE: This study aimed to determine the potential effects of angiopoietin-2 (Ang-2), von Willebrand factor (vWF), and extravascular lung water index (EVLWI) on the risk of mortality in sepsis patients with concomitant acute respiratory distress syndrome (ARDS). METHODS: This retrospective study recruited 41 sepsis patients with concomitant ARDS from January 2015 to June 2018. Data of Ang-2 and vWF levels, EVLWI, and sequential organ failure assessment scores were collected at 0, 24, and 48 h after admission to the hospital. RESULTS: The length of intensive care unit stay (P = 0.041) and Acute Physiology and Chronic Health Evaluation-2 (APACHE II) score (P = 0.003) were associated with the risk of mortality. Furthermore, increased Ang-2 levels and EVLWI at 24 h and 48 h were associated with an increased risk of mortality. Moreover, the APACHE II score at hospital admission significantly predicted the risk of mortality (area under the curve [AUC], 0.834; 95% confidence interval [CI], 0.665-0.983). Finally, the models containing a combination of Ang-2 level and EVLWI at 24 h (AUC, 0.908; 95% CI, 0.774-0.996) and Ang-2 level and EVLWI at 48 h (AUC, 0.981; 95% CI, 0.817-1.000) had high diagnostic values for predicting risk of mortality. CONCLUSION: The study findings indicate that Ang-2 levels and EVLWI at 24 h and 48 h after admission are significantly associated with the risk of mortality.

Phosphoproteomic Analysis of Paper Mulberry Reveals Phosphorylation Functions in Chilling Tolerance.

Paper mulberry is a valuable woody species with a good chilling tolerance. In this study, phosphoproteomic analysis, physiological measurement, and mRNA quantification were employed to explore the molecular mechanism of chilling (4 °C) tolerance in paper mulberry. After chilling for 6 h, 427 significantly changed phosphoproteins were detected in paper mulberry seedlings without obvious physiological injury. When obvious physiological injury occurred after chilling for 48 h, a total of 611 phosphoproteins were found to be significantly changed at the phosphorylation level. Several protein kinases, especially CKII, were possibly responsible for these changes according to conserved sequence analysis. The results of Gene Ontology analysis showed that phosphoproteins were mainly responsible for signal transduction, protein modification, and translation during chilling. Additionally, transport and cellular component organization were enriched after chilling for 6 and 48 h, respectively. On the basis of the protein-protein interaction network analysis, a protein kinase and phosphatases hub protein (P1959) were found to be involved in cross-talk between Ca2+, BR, ABA, and ethylene-mediated signaling pathways. We also highlighted the phosphorylation of BpSIZ1 and BpICE1 possibly impacted on the CBF/DREB-responsive pathway. From these results, we developed a schematic for the chilling tolerance mechanism at phosphorylation level.

Identification and Functional Divergence Analysis of WOX Gene Family in Paper Mulberry.

The WOX (WUSCHEL-related homeobox) is a plant-specific transcription factor involved in plant development and stress response. However, few studies have been reported on the WOX gene in woody plants. In this study, 10 BpWOX genes were isolated from paper mulberry by RACE-PCR and categorized into three clades through phylogenetic analysis, ancient, intermediate and WUS clade. Among them, five members had the transcriptional activity detected by yeast one-hybrid and seven were uniquely localized to the nucleus through green fluorescent protein (GFP) observation. The expression patterns of BpWOX genes in different tissues and under diverse treatments were quantified by the qRT-PCR method. Results showed that BpWUS was expressed in the apical bud, stem and root, BpWOX5 and BpWOX7 functioned only in the root tip, and three BpWOXs regulated leaf development redundantly. BpWOX9 and BpWOX10 were induced by indole-3-acetic acid (IAA) or jasmonic acid (JA), while BpWOX2 was repressed by five phytohormones. Interestingly, most BpWOX genes were responsive to the abiotic stress stimuli of drought, salt, cold, and cadmium (CdCl2). Together, our study revealed that BpWOXs were functionally divergent during paper mulberry development and environmental adaptation, which might be related to their evolutionary relationships. Our work will benefit the systematic understanding of the precise function of WOX in plant development and environmental stress responses.

The effect of variable arterial transducer level on the accuracy of pulse contour waveform-derived measurements in critically ill patients.

We know that a 10 cm departure from the reference level of pressure transducer position is equal to a 7.5 mmHg change of invasive hemodynamic pressure monitoring in a fluid-filled system. However, the relationship between the site level of a variable arterial pressure transducer and the pulse contour-derived parameters has yet to be established in critically ill patients. Moreover, the related quantitative analysis has never been investigated. Forty-two critically ill patients requiring PiCCO-Plus cardiac output monitoring were prospectively studied. The phlebostatic axis was defined as the zero reference level; the arterial pressure transducer was then vertically adjusted to different positions (+5, +10, +15, +20, -20, -15, -10, -5 cm) of departure from the zero reference site. The pulse contour waveform-derived parameters were recorded at each position. Elevation of the pressure transducer caused significantly positive changes in the continuous cardiac index (+CCI), stroke volume index (+SVI), and stroke volume variation (+SVV), and negative changes in the rate of left ventricular pressure rise during systole (-dP/dtmax), the systemic vascular resistance index (-SVRI), and vice versa. At the 5 cm position, the SVRI changes reached statistical significance with error. At the 10 cm position, the changes in CCI and dP/dtmax reached statistical significance with error, while the change in SVV reached statistical significance at 15 cm. The change rate of CCI was more than 5 % at the 15 cm position and approximately 10 % at the 20 cm position. On average, for every centimeter change of the transducer, there was a corresponding 0.014 L/min/m(2) CCI change and 0.36 % change rate, a 1.41 mmHg/s dP/dtmax change and 0.13 % change rate, and a 25 dyne/s/cm(5) SVRI change and 1.2 % change rate. The variation of arterial transducer position can result in inaccurate measurement of pulse contour waveform-derived parameters, especially when the transducer's vertical distance is more than 10 cm from the phlebostatic axis. These findings have clinical implications for continuous hemodynamic monitoring.

The cold responsive mechanism of the paper mulberry: decreased photosynthesis capacity and increased starch accumulation.

BACKGROUND: Most studies on the paper mulberry are mainly focused on the medicated and pharmacology, fiber quality, leaves feed development, little is known about its mechanism of adaptability to abiotic stress. Physiological measurement, transcriptomics and proteomic analysis were employed to understand its response to cold stress in this study. METHODS: The second to fourth fully expanded leaves from up to down were harvested at different stress time points forthe transmission electron microscope (TEM) observation. Physiological characteristics measurement included the relative electrolyte leakage (REL), SOD activity assay, soluble sugar content, and Chlorophyll fluorescence parameter measurement. For screening of differentially expressed genes, the expression level of every transcript in each sample was calculated by quantifying the number of Illumina reads. To identify the differentially expressed protein, leaves of plants under 0, 6, 12, 24, 48 and 72 h cold stress wereharvested for proteomic analysis. Finally, real time PCR was used to verify the DEG results of the RNA-seq and the proteomics data. RESULTS: Results showed that at the beginning of cold stress, respiratory metabolism was decreased and the transportation and hydrolysis of photosynthetic products was inhibited, leading to an accumulation of starch in the chloroplasts. Total of 5800 unigenes and 38 proteins were affected, including the repressed expression of photosynthesis and the enhanced expression in signal transduction, stress defense pathway as well as secondary metabolism. Although the transcriptional level of a large number of genes has been restored after 12 h, sustained cold stress brought more serious injury to the leaf cells, including the sharp rise of the relative electrolyte leakage, the declined Fv/Fm value, swelled chloroplast and the disintegrated membrane system. CONCLUSION: The starch accumulation and the photoinhibition might be the main adaptive mechanism of the paper mulberry responded to cold stress. Most of important, enhancing the transport and hydrolysis of photosynthetic products could be the potential targets for improving the cold tolerance of the paper mulberry.