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The structural diversity of biological macromolecules in different environments contributes complexity to enzymological processes vital for cellular functions. Fluorescence resonance energy transfer and electron microscopy are used to investigate the enzymatic reaction of T4 DNA ligase catalyzing the ligation of nicked DNA. The data show that both the ligase–AMP complex and the ligase–AMP–DNA complex can have four conformations. This finding suggests the parallel occurrence of four ligation reaction pathways, each characterized by specific conformations of the ligase–AMP complex that persist in the ligase–AMP–DNA complex. Notably, these complexes have DNA bending angles of ≈0°, 20°, 60°, or 100°. The mechanism of parallel reactions challenges the conventional notion of simple sequential reaction steps occurring among multiple conformations. The results provide insights into the dynamic conformational changes and the versatile attributes of T4 DNA ligase and suggest that the parallel multiple reaction pathways may correspond to diverse T4 DNA ligase functions. This mechanism may potentially have evolved as an adaptive strategy across evolutionary history to navigate complex environments. [ABSTRACT FROM AUTHOR]

Perovskite single crystals have attracted tremendous attention owing to their excellent optoelectronic properties and stability compared to typical multicrystal structures. However, the growth of high‐quality perovskite single crystals (PSCs) generally relies on temperature gradients or the introduction of additives to promote crystal growth. In this study, a vacuum evaporation crystallization technique is developed that allows PSCs to be grown under extremely stable conditions at constant temperature and without requiring additives to promote crystal growth. The new method enables the growth of PSCs of unprecedented quality, that is, MAPbBr3 single crystals that exhibit an ultranarrow full width at half maximum of 0.00701°, which surpasses that of all previously reported values. In addition, the MAPbBr3 single crystals deliver exceptional optoelectronic performance, including a long carrier lifetime of 1006 ns, an ultralow trap‐state density of 3.67 × 109 cm−3, and an ultrahigh carrier mobility of 185.86 cm2 V−1 s−1. This method is applicable to various types of PSCs, including organic–inorganic hybrids, fully inorganic structures, and low‐dimensional structures. [ABSTRACT FROM AUTHOR]

Heart failure is the final stage of several cardiovascular diseases, and the key to effectively treating heart failure is to reverse or delay ventricular remodelling. Levosimendan is a novel inotropic and vasodilator agent used in heart failure, whereas the impact of levosimendan on ventricular remodelling is still unclear. This study aims to investigate the impact of levosimendan on ventricular remodelling in patients with left ventricular systolic dysfunction. Electronic databases were searched to identify eligible studies. A total of 66 randomized controlled trials involving 7968 patients were included. Meta‐analysis results showed that levosimendan increased left ventricular ejection fraction [mean difference (MD) = 3.62, 95% confidence interval (CI) (2.88, 4.35), P < 0.00001] and stroke volume [MD = 6.59, 95% CI (3.22, 9.96), P = 0.0001] and significantly reduced left ventricular end‐systolic volume [standard mean difference (SMD) = −0.52, 95% CI (−0.67, −0.37), P < 0.00001], left ventricular end‐diastolic volume index [SMD = −1.24, 95% CI (−1.61, −0.86), P < 0.00001], and left ventricular end‐systolic volume index [SMD = −1.06, 95% CI (−1.43, −0.70), P < 0.00001]. In terms of biomarkers, levosimendan significantly reduced the level of brain natriuretic peptide [SMD = −1.08, 95% CI (−1.60, −0.56), P < 0.0001], N‐terminal pro‐brain natriuretic peptide [SMD = −0.99, 95% CI (−1.41, −0.56), P < 0.00001], and interleukin‐6 [SMD = −0.61, 95% CI (−0.86, −0.35), P < 0.00001]. Meanwhile, levosimendan may increase the incidence of hypotension [risk ratio (RR) = 1.24, 95% CI (1.12, 1.39), P < 0.0001], hypokalaemia [RR = 1.57, 95% CI (1.08, 2.28), P = 0.02], headache [RR = 1.89, 95% CI (1.50, 2.39), P < 0.00001], atrial fibrillation [RR = 1.31, 95% CI (1.12, 1.52), P = 0.0005], and premature ventricular complexes [RR = 1.86, 95% CI (1.27, 2.72), P = 0.001]. In addition, levosimendan reduced all‐cause mortality [RR = 0.83, 95% CI (0.74, 0.94), P = 0.002]. In conclusion, our study found that levosimendan might reverse ventricular remodelling when applied in patients with left ventricular systolic dysfunction, especially in patients undergoing cardiac surgery, decompensated heart failure, and septic shock. [ABSTRACT FROM AUTHOR]

Micro‐Doppler effect is a vital feature of a target that reflects its oscillatory motions apart from bulk motion and provides an important evidence for target recognition with radars. However, establishing the micro‐Doppler database poses a great challenge, since plenty of experiments are required to get the micro‐Doppler signatures of different targets for the purpose of analyses and interpretations with radars, which are dramatically limited by high cost and time‐consuming. Aiming to overcome these limits, a low‐cost and powerful simulation platform of the micro‐Doppler effects is proposed based on time‐domain digital coding metasurface (TDCM). Owing to the outstanding capabilities of TDCM in generating and manipulating nonlinear harmonics during wave‐matter interactions, it enables to supply rich and high‐precision electromagnetic signals with multiple micro‐Doppler frequencies to describe the micro‐motions of different objects, which are especially favored for the training of artificial intelligence algorithms in automatic target recognition and benefit a host of applications like imaging and biosensing. [ABSTRACT FROM AUTHOR]

Recently, blockchain has been increasingly applied to low‐carbon supply chains, enabling consumers to track production process of low‐carbon products, thereby improving brand awareness and expanding the market. However, do the operation and construction costs of blockchain come at the expense of squeezing resources originally allocated for research and development (R&D) of carbon emission reduction (CER) or reducing firms profits? Given the varying capacities of different types of firms to bear the costs of blockchain in the process of R&D of CER, this paper considers two categories of firms, superior brand firms and inferior brand firms, and studies the impact of blockchain usage on CER and profits. Research shows that the usage of blockchain is not necessarily beneficial to CER and profits enhancement. Consumers' trust and low‐carbon preference, brand awareness, blockchain operation and construction costs, and R&D difficulty of CER are key factors. Superior brand firms can improve CER level and profits through blockchain when R&D difficulty is low and consumers' trust is high or when R&D difficulty is high but consumers' low‐carbon preferences and brand awareness are high. Inferior brand firms can improve CER level and profits through blockchain when R&D difficulty is low and consumers' trust is high or when R&D difficulty is high but brand awareness is low. This study provides strategic insights for brand firms considering the usage of blockchain in their CER initiatives, highlighting the importance of aligning blockchain integration with firm‐specific characteristics and market conditions to achieve both environmental and profit objectives. [ABSTRACT FROM AUTHOR]

Postherpetic neuralgia (PHN) is a notorious neuropathic pain featuring persistent profound mechanical hyperalgesia with significant negative impact on patients' life quality. CDDO can regulate inflammatory response and programmed cell death. Its derivative also protects neurons from damages by modulating microglia activities. As a consequence of central and peripheral sensitization, applying neural blocks may benefit to minimize the risk of PHN. This study aimed to explore whether CDDO could generate analgesic action in a PHN‐rats' model. The behavioural test was determined by calibrated forceps testing. The number of apoptotic neurons and degree of glial cell reaction were assessed by immunofluorescence assay. Activation of PKC‐δ and the phosphorylation of Akt were measured by western blots. CDDO improved PHN by decreasing TRPV1‐positive nociceptive neurons, the apoptotic neurons, and reversed glial cell reaction in adult rats. It also suppressed the enhanced PKC‐δ and p‐Akt signalling in the sciatic nerve, dorsal root ganglia (DRG) and spinal dorsal horn. Our research is the promising report demonstrating the analgesic and neuroprotective action of CDDO in a PHN‐rat's model by regulating central and peripheral sensitization targeting TRPV1, PKC‐δ and p‐Akt. It also is the first study to elucidate the role of oligodendrocyte in PHN. [ABSTRACT FROM AUTHOR]

Summary: Background and Aims: We aimed to define gender‐specific, optimal alanine aminotransferase (ALT) cut‐off values for the prediction of significant liver histological changes (SLHC) in Chinese patients with grey zone (GZ) chronic hepatitis B (CHB) and normal ALT. Methods: In a retrospective study, we included 1101 consecutive patients with GZ CHB and normal ALT assigned to training or internal validation cohorts. We included an independent cohort of 842 patients for external validation. We performed receiver operating characteristic (ROC) curve, smoothed curve fitting, and threshold effect analyses to determine optimal ALT cut‐off values. Area under the curve (AUC) values were calculated to assess their predictive performance. Results: A proportion of 79.3% of patients with GZ CHB and normal ALT (≤40 U/L) had SLHC. ROC curve analysis initially identified optimal ALT cut‐off values of 29 U/L (male) and 22 U/L (female). After smoothed curve fitting and threshold effect analyses, new optimal cut‐off values were 27 U/L for males and 24 U/L for females. AUCs for these values were 0.836 (male) and 0.833 (female) in the internal validation cohort, and 0.849 (male) and 0.844 (female) in the external validation cohort. The accuracy and discriminative ability of the newly defined ALT cut‐off values were greater than those of the current recommendations. Conclusion: This study established novel optimal ALT cut‐off values for more precise prediction of SLHC among Chinese patients with GZ CHB and normal ALT levels. This may help identify individuals who will benefit from timely antiviral therapy. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) is a severe respiratory disease with a high mortality rate. The integrity of the pulmonary endothelial barrier influences the development and prognosis of ALI. Therefore, it has become an important target for ALI treatment. Extracellular vesicles (EVs) are promising nanotherapeutic agents against ALI. Herein, endothelium‐derived engineered extracellular vesicles (eEVs) that deliver microRNA‐125b‐5p (miRNA‐125b) to lung tissues exerting a protective effect on endothelial barrier integrity are reported. eEVs that are modified with lung microvascular endothelial cell‐targeting peptides (LET) exhibit a prolonged retention time in lung tissues and targeted lung microvascular endothelial cells in vivo and in vitro. To improve the efficacy of the EVs, miRNA‐125b is loaded into EVs. Finally, LET‐EVs‐miRNA‐125b is constructed. The results show that compared to the EVs, miRNA‐125b, and EVs‐miRNA‐125b, LET‐EVs‐miRNA‐125b exhibit the most significant treatment efficacy in ALI. Moreover, LET‐EVs‐miRNA‐125b is found to have an important protective effect on endothelial barrier integrity by inhibiting cell apoptosis, promoting angiogenesis, and protecting intercellular junctions. Sequencing analysis reveals that LET‐EVs‐miRNA‐125b downregulates early growth response‐1 (EGR1) levels, which may be a potential mechanism of action. Taken together, these findings suggest that LET‐EVs‐miRNA‐125b can treat ALI by protecting the endothelial barrier integrity. [ABSTRACT FROM AUTHOR]

Background: Treating postherpetic neuralgia (PHN), which is characterized with a long‐lasting lancinating mechanical allodynia or hyperalgesia, is a big challenge as it is hard to achieve complete resolution. A synthetic triterpenoid, CDDO (2‐cyano‐3,12‐dioxoolean‐1,9‐dien‐28‐oic acid) can exert pleiotropic effects including anti‐inflammation and neuroprotective activities. Nevertheless, the antinociceptive effect of CDDO and its derivatives remains unknown. Resiniferatoxin (RTX) is easily feasible, and an RTX‐treated rodent model can mimic the PHN‐like symptoms. Therefore, RTX‐treated rats were used to serve as a PHN rats' model in the study to elucidate whether a synthetic triterpenoid, CDDO, can improve mechanical allodynia in RTX‐treated rats. Methods: The antinociceptive effects of CDDO were assessed by behavioral tests, western blotting, and immunohistochemistry. Paw withdrawal mechanical threshold was determined using calibrated forceps. Results: Administration of RTX led to mechanical allodynia, neuronal cell death, and glial cell activation in the spinal cord of RTX‐treated rats. A synthetic triterpenoid, CDDO, blocked RTX‐induced mechanical allodynia, rescued neuronal cell death, and inhibited glial cell activation in the spinal cord of RTX‐treated rats. Conclusions: Our study provides a novel result that a synthetic triterpenoid, CDDO, can interfere neuronal cell death and glial cell activation in the spinal cord of RTX‐treated rats. Hence, CDDO is an alternative therapeutic choice for PHN. [ABSTRACT FROM AUTHOR]

Background: High blood pressure affects approximately 116 million adults in the United States. It is the leading risk factor for death and disability across the world. Unfortunately, over the past decade, hypertension control rates have decreased across the United States. Prediction models and clinical studies have shown that reducing clinician inertia alone is sufficient to reach the target of ≥80% blood pressure control. Digital health tools containing evidence-based algorithms that are able to reduce clinician inertia are a good fit for turning the tide in blood pressure control, but careful consideration should be taken in the design process to integrate digital health interventions into the clinical workflow., Methods: We describe the development of a provider-facing hypertension management platform. We enumerate key steps of the development process, including needs finding, clinical workflow analysis, treatment algorithm creation, platform design and electronic health record integration. We interviewed and surveyed 5 Stanford clinicians from primary care, cardiology, and their clinical care team members (including nurses, advanced practice providers, medical assistants) to identify needs and break down the steps of clinician workflow analysis. The application design and development stage were aided by a team of approximately 15 specialists in the fields of primary care, hypertension, bioinformatics, and software development., Conclusions: Digital monitoring holds immense potential for revolutionizing chronic disease management. Our team developed a hypertension management platform at an academic medical center to address some of the top barriers to adoption and achieving clinical outcomes. The frameworks and processes described in this article may be used for the development of a diverse range of digital health tools in the cardiovascular space.