A comprehensive review on ziconotide.

Managing severe chronic pain is a challenging task, given the limited effectiveness of available pharmacological and non-pharmacological treatments. This issue continues to be a significant public health concern, requiring a substantial therapeutic response. Ziconotide, a synthetic peptide initially isolated from Conus magus in 1982 and approved by the US Food and Drug Administration and the European Medicines Agency in 2004, is the first-line intrathecal method for individuals experiencing severe chronic pain refractory to other therapeutic measures. Ziconotide produces powerful analgesia by blocking N-type calcium channels in the spinal cord, which inhibits the release of pain-relevant neurotransmitters from the central terminals of primary afferent neurons. However, despite possessing many favorable qualities, including the absence of tolerance development, respiratory depression, and withdrawal symptoms (largely due to the absence of a G-protein mediation mechanism), ziconotide's application is limited due to factors such as intrathecal administration and a narrow therapeutic window resulting from significant dose-related undesired effects of the central nervous system. This review aims to provide a comprehensive and clinically relevant summary of the literatures concerning the pharmacokinetics and metabolism of intrathecal ziconotide. It will also describe strategies intended to enhance clinical efficacy while reducing the incidence of side effects. Additionally, the review will explore the current efforts to refine the structure of ziconotide for better clinical outcomes. Lastly, it will prospect potential developments in the new class of selective N-type voltage-sensitive calcium-channel blockers.

[Development and exploration of the national first-class undergraduate course in "Enzyme Engineering"].

The biotechnology industry is a strategic emerging industry in our country, holding a crucial position in the national economy. The training of innovative high-quality professionals carries immense significance. As the cornerstone course in biotechnology, "Enzyme Engineering" directly impacts the students' caliber and industry development. This course aims to address pertinent issues present in the current curriculum delivery, such as inadequately optimized content, excessive dependency on textbooks, and reliance on monotonous teaching methods. By adjusting the course outline, updating the case material repository, and engaging students' enthusiasm, we developed a three-dimensional approach to instruct. This approach included a blend of online and offline components, interactive teaching through the flipped classroom methodology, heuristic teaching using problem-based learning (PBL) mode, and topic teaching via case studies. We also improved the assessment mechanism to stimulate students' enthusiasm for learning nurture their innovation capabilities. Our objective was to foster high-quality professionals with a robust foundation and practical expertise. Through teaching exploration and practice, we have witnessed significant improvement in both teaching efficacy and students' engineering practice and innovation abilities.

Distinct gray matter abnormalities in children/adolescents and adults with history of childhood maltreatment.

Gray matter (GM) abnormalities have been reported in both adults and children/adolescents with histories of childhood maltreatment (CM). A comparison of effects in youth and adulthood may be informative regarding life-span effects of CM. Voxel-wise meta-analyses of whole-brain voxel-based morphometry studies were conducted in all datasets and age-based subgroups respectively, followed by a quantitative comparison of the subgroups. Thirty VBM studies (31 datasets) were included. The pooled meta-analysis revealed increased GM in left supplementary motor area, and reduced GM in bilateral cingulate/paracingulate gyri, left occipital lobe, and right middle frontal gyrus in maltreated individuals compared to the controls. Maltreatment-exposed youth showed less GM in the cerebellum, and greater GM in bilateral middle cingulate/paracingulate gyri and bilateral visual cortex than maltreated adults. Opposite GM alterations in bilateral middle cingulate/paracingulate gyri were found in maltreatment-exposed adults (decreased) and children/adolescents (increased). Our findings demonstrate different patterns of GM changes in youth closer to maltreatment events than those seen later in life, suggesting detrimental effects of CM on the developmental trajectory of brain structure.

Status of diagnosis and therapy of abdominal aortic aneurysms.

Abdominal aortic aneurysms (AAAs) are characterized by localized dilation of the abdominal aorta. They are associated with several serious consequences, including compression of adjacent abdominal organs, pain, treatment-related financial expenditure. The main complication of AAA is aortic rupture, which is responsible for about 200,000 deaths per year worldwide. An increasing number of researchers are dedicating their efforts to study AAA, resulting in significant progress in this field. Despite the commendable progress made thus far, there remains a lack of established methods to effectively decelerate the dilation of aneurysms. Therefore, further studies are imperative to expand our understanding and enhance our knowledge concerning AAAs. Although numerous factors are known to be associated with the occurrence and progression of AAA, the exact pathway of development remains unclear. While asymptomatic at most times, AAA features a highly unpredictable disease course, which could culminate in the highly deadly rupture of the aneurysmal aorta. Current guidelines recommend watchful waiting and lifestyle adjustment for smaller, slow-growing aneurysms, while elective/prophylactic surgical repairs including open repair and endovascular aneurysm repair are recommended for larger aneurysms that have grown beyond certain thresholds (55 mm for males and 50 mm for females). The latter is a minimally invasive procedure and is widely believed to be suited for patients with a poor general condition. However, several concerns have recently been raised regarding the postoperative complications and possible loss of associated survival benefits on it. In this review, we aimed to highlight the current status of diagnosis and treatment of AAA by an in-depth analysis of the findings from literatures.

Experimental Quantum Communication Overcomes the Rate-Loss Limit without Global Phase Tracking.

Secure key rate (SKR) of point-point quantum key distribution (QKD) is fundamentally bounded by the rate-loss limit. Recent breakthrough of twin-field (TF) QKD can overcome this limit and enables long distance quantum communication, but its implementation necessitates complex global phase tracking and requires strong phase references that not only add to noise but also reduce the duty cycle for quantum transmission. Here, we resolve these shortcomings, and importantly achieve even higher SKRs than TF-QKD, via implementing an innovative but simpler measurement-device-independent QKD that realizes repeaterlike communication through asynchronous coincidence pairing. Over 413 and 508 km optical fibers, we achieve finite-size SKRs of 590.61 and 42.64 bit/s, which are respectively 1.80 and 4.08 times of their corresponding absolute rate limits. Significantly, the SKR at 306 km exceeds 5 kbit/s and meets the bitrate requirement for live one-time-pad encryption of voice communication. Our work will bring forward economical and efficient intercity quantum-secure networks.

Spatial distribution and suitability evaluation of nighttime tourism in Kunming utilizing multi-source data.

In the post-pandemic era, nighttime tourism is vital in promoting the diversified development of tourism, enhancing the vitality of cities, and improving reemployment rates. Using Kunming City, China, as an example, this study used multi-theory and multi-source data to construct an evaluation model of the spatial distribution and suitability of nighttime tourism. The projection pursuit model and spatial analysis method were used to reveal spatial distribution and explore the suitability characteristics and spatial differences of nighttime tourism development. Our results revealed the following: (1) nighttime tourism resources showed a 'large aggregation, small dispersion' spatial distribution pattern, which is characterized by a distribution along the railway line; (2) at present, the spatial distribution of nighttime tourism in Kunming displays a pattern of 'taking a high-density large gathering area as the center and extending around; ' and (3) the most suitable nighttime tourism area accounts for 11.83% of the total land area of Kunming; highly suitable area accounts for 17.53%. The general suitable and unsuitable areas accounted for 43.29% and 27.35%, respectively. The results of this study assist in providing a scientific basis for the strategic planning and development of the nighttime tourism industry in Kunming.

Determining food tourism consumption of wild mushrooms in Yunnan Provence, China: A projection-pursuit approach.

As the first of the six elements of tourism, food is an important part of tourism activities. As an important driving force for the economic development of tourist destinations, food tourism plays an increasingly important role in tourism and has gradually become an important hub connecting tourists, local residents, and tourist destinations. This study takes Yunnan wild mushrooms as a case, obtained data through a questionnaire survey and applied a projection pursuit model (PPM) to explore the driving factors affecting food tourism consumption. Research shows that the quality and abundance of gourmet resources are the most important factors affecting tourist consumption of gourmet foods, and the needs and experiences of tourists also promote their consumption, to a certain extent. This provides a guide for Yunnan Province to expand the source market. Second, we compared PPM with structural equation modeling (SEM) and demonstrated that the former requires less data than the latter and is immune to nonlinearities, interaction effects, and the researchers' excessive prior knowledge. This makes PPM more robust, anti-interference, accurate, and objective than SEM when dealing with problems. Finally, we put forward reasonable suggestions from four aspects of government, enterprises, local residents, and tourists, which provide an effective way for Yunnan Province to develop food tourism. In addition, PPM's advantages in data selection, data processing, and result stability fill the gaps in data processing in the tourism field.

Twin-field quantum key distribution without optical frequency dissemination.

Twin-field (TF) quantum key distribution (QKD) has rapidly risen as the most viable solution to long-distance secure fibre communication thanks to its fundamentally repeater-like rate-loss scaling. However, its implementation complexity, if not successfully addressed, could impede or even prevent its advance into real-world. To satisfy its requirement for twin-field coherence, all present setups adopted essentially a gigantic, resource-inefficient interferometer structure that lacks scalability that mature QKD systems provide with simplex quantum links. Here we introduce a technique that can stabilise an open channel without using a closed interferometer and has general applicability to phase-sensitive quantum communications. Using locally generated frequency combs to establish mutual coherence, we develop a simple and versatile TF-QKD setup that does not need service fibre and can operate over links of 100 km asymmetry. We confirm the setup's repeater-like behaviour and obtain a finite-size rate of 0.32 bit/s at a distance of 615.6 km.

Neural correlates of neuroticism: A coordinate-based meta-analysis of resting-state functional brain imaging studies.

Neuroticism is one of the most robust higher-order personality traits associated with negative emotionality and risk of mental disorders. Many studies have investigated relationships between neuroticism and the brain, but the results have been inconsistent. We conducted a meta-analysis of whole-brain resting-state functional neuroimaging studies to identify the most stable neurofunctional substrates of neuroticism. We found stable significant positive correlations between neuroticism and resting-state brain activity in the left middle temporal gyrus (MTG), left striatum, and right hippocampus. In contrast, resting-state brain activity in the left superior temporal gyrus (STG) and right supramarginal gyrus (SMG) was negatively associated with neuroticism. Additionally, meta-regression analysis revealed brain regions in which sex and age moderated the link of spontaneous activity with neuroticism. This is the first study to provide a comprehensive understanding of resting-state brain activity correlates of neuroticism, and the findings may be useful for the targeting of specific brain regions for interventions to decrease the risks of mental health problems.

A voxel-based meta-analysis comparing medication-naive patients of major depression with treated longer-term ill cases.

Structural neuroimaging studies have identified brain areas implicated in the pathogenesis of major depressive disorder (MDD). However, findings have been inconsistent, potentially due to variable illness duration and effects of antidepressant treatment. Using a meta-analytic approach, we compared gray matter (GM) volumes in patients grouped by medication status (naïve and treated) and illness duration (early course and long-term ill) to identify potential treatment and illness duration effects on brain structure. A total of 70 studies were included, including 3682 patients and 3469 controls. The pooled analysis found frontal, temporal and limbic regions with decreased GM volume in MDD patients. Additional analyses indicated that larger GM volume in the right striatum and smaller GM volume in the right precuneus are likely to be associated with drug effects, while smaller GM volume in the right temporal gyrus may correlate with longer illness duration. Similar GM decreases in bilateral medial frontal cortex between patient subgroups suggest that this alteration may persist over the course of illness and drug treatment.

Changes in Public Sentiment under the Background of Major Emergencies-Taking the Shanghai Epidemic as an Example.

The occurrence of major health events can have a significant impact on public mood and mental health. In this study, we selected Shanghai during the 2019 novel coronavirus pandemic as a case study and Weibo texts as the data source. The ERNIE pre-training model was used to classify the text data into five emotional categories: gratitude, confidence, sadness, anger, and no emotion. The changes in public sentiment and potential influencing factors were analyzed with the emotional sequence diagram method. We also examined the causal relationship between the epidemic and public sentiment, as well as positive and negative emotions. The study found: (1) public sentiment during the epidemic was primarily affected by public behavior, government behavior, and the severity of the epidemic. (2) From the perspective of time series changes, the changes in public emotions during the epidemic were divided into emotional fermentation, emotional climax, and emotional chaos periods. (3) There was a clear causal relationship between the epidemic and the changes in public emotions, and the impact on negative emotions was greater than that of positive emotions. Additionally, positive emotions had a certain inhibitory effect on negative emotions.

Analysis of the Emotional Identification Mechanism of Campus Edible Landscape from the Perspective of Emotional Geography: An Empirical Study of a Chinese University Town.

Against the background of "the emotional turn" in geography, the study of emotional identification is attracting increasing attention among researchers. Edible landscape resources can satisfy the emotional needs of teachers and students by enabling them to experience pastoral landscapes that carry cultural and landscape values to campus environments. Based on a questionnaire survey of 419 students and teachers at Chenggong University Town in China, this study improved the structural equation modeling (SEM) method to construct a model to analyze the emotional identification mechanism of the campus edible landscape. The research found that emotional identification played an intermediary role between perception and behavioral intention, manifested as an association mechanism in which surface values influence perception, perception influences emotional identification, and emotional identification influences behavioral intention. The emotional identification model revealed the relationship between teachers and students' emotional identification and the value of campus edible landscape resources for the first time. It also uncovered the universality of the association mechanism in the research of emotional geography.

Spatial and Temporal Evolutionary Characteristics and Its Influencing Factors of Economic Spatial Polarization in the Yangtze River Delta Region.

Economic spatial polarization is a manifestation of unbalanced urban development. To study the unbalanced development of Chinese cities, this paper selects 41 cities in the Yangtze River Delta (YRD) region, introduces the polarization index and exploratory spatio-temporal analysis to portray their spatio-temporal evolution process, and analyzes the differences in spatial polarization patterns of economic development in three dimensions of economic quantity, quality, and structure. Finally, we use the geographic detector model to explore the driving factors and then propose corresponding policy recommendations. The results show that: (1) the degree of difference in economic development in the YRD region narrowed from 2000 to 2019, and the spatial polarization level of urban economic development showed a fluctuating downward trend, among which the spatial polarization level of the economic structure dimension has been increasing. (2) In terms of spatial distribution, the "Yangtze River Delta urban agglomeration" has economic spatial polarization in the YRD region has become the peak contiguous zone, and the spatial polarization of economic quantity and quality dimensions has formed a "polycentric" pattern, while the spatial polarization of economic structure dimensions shows a stable "one core, multiple sub-center" distribution. (3) From the evolution of spatial polarization, most cities have strong spatial locking characteristics without a transition. Spatially positive polarized are concentrated in the YRD urban agglomeration, and the inter-city neighboring relations are mainly positive synergistic growth, while the negatively polarized cities are mostly distributed in the peripheral areas of the YRD and the neighboring relations are negative synergistic growth. At the same time, the spatially positive polarization effect of the economic quantity dimension and the spatially negative polarization effect of the economic structure dimension among cities are more significant. (4) The economic spatial polarization in the YRD region is mainly dominated by market prosperity and urbanization level, while the driving effect of scientific and technological innovation development on the urban economy has also been expanding in recent years. Promoting the reasonable allocation of marketization, urbanization, and technology among cities with positive and negative spatial polarization in the future will contribute to balanced urban and regional economic development in a coordinated and orderly manner.

Identification of a novel ene reductase from Pichia angusta with potential application in (R)-levodione production.

Asymmetric reduction of electronically activated alkenes by ene reductases (ERs) is an attractive approach for the production of enantiopure chiral products. Herein, a novel FMN-binding ene reductase (PaER) from Pichia angusta was heterologously expressed in Escherichia coli BL21(DE3), and the recombinant enzyme was characterized for its biocatalytic properties. PaER displayed optimal activity at 40 °C and pH 7.5, respectively. The purified enzyme was quite stable below 30 °C over a broad pH range of 5.0-10.0. PaER was identified to have a good ability to reduce the C[double bond, length as m-dash]C bond of various α,ß-unsaturated compounds in the presence of NADPH. In addition, PaER exhibited a high reduction rate (k cat = 3.57 s-1) and an excellent stereoselectivity (>99%) for ketoisophorone. Engineered E. coli cells harboring PaER and glucose dehydrogenase (for cofactor regeneration) were employed as biocatalysts for the asymmetric reduction of ketoisophorone. As a result, up to 1000 mM ketoisophorone was completely and enantioselectively converted to (R)-levodione with a >99% ee value in a space-time yield of 460.7 g L-1 d-1. This study provides a great potential biocatalyst for practical synthesis of (R)-levodione.

Overexpression of mGDH in Gluconobacter oxydans to improve D-xylonic acid production from corn stover hydrolysate.

BACKGROUND: D-Xylonic acid is a versatile platform chemical with broad potential applications as a water reducer and disperser for cement and as a precursor for 1,4-butanediol and 1,2,4-tributantriol. Microbial production of D-xylonic acid with bacteria such as Gluconobacter oxydans from inexpensive lignocellulosic feedstock is generally regarded as one of the most promising and cost-effective methods for industrial production. However, high substrate concentrations and hydrolysate inhibitors reduce xylonic acid productivity. RESULTS: The D-xylonic acid productivity of G. oxydans DSM2003 was improved by overexpressing the mGDH gene, which encodes membrane-bound glucose dehydrogenase. Using the mutated plasmids based on pBBR1MCS-5 in our previous work, the recombinant strain G. oxydans/pBBR-R3510-mGDH was obtained with a significant improvement in D-xylonic acid production and a strengthened tolerance to hydrolysate inhibitors. The fed-batch biotransformation of D-xylose by this recombinant strain reached a high titer (588.7 g/L), yield (99.4%), and volumetric productivity (8.66 g/L/h). Moreover, up to 246.4 g/L D-xylonic acid was produced directly from corn stover hydrolysate without detoxification at a yield of 98.9% and volumetric productivity of 11.2 g/L/h. In addition, G. oxydans/pBBR-R3510-mGDH exhibited a strong tolerance to typical inhibitors, i.e., formic acid, furfural, and 5-hydroxymethylfurfural. CONCLUSION: Through overexpressing mgdh in G. oxydans, we obtained the recombinant strain G. oxydans/pBBR-R3510-mGDH, and it was capable of efficiently producing xylonic acid from corn stover hydrolysate under high inhibitor concentrations. The high D-xylonic acid productivity of G. oxydans/pBBR-R3510-mGDH made it an attractive choice for biotechnological production.

KasQ an Epimerase Primes the Biosynthesis of Aminoglycoside Antibiotic Kasugamycin and KasF/H Acetyltransferases Inactivate Its Activity.

Kasugamycin (KSM), an aminoglycoside antibiotic, is composed of three chemical moieties: D-chiro-inositol, kasugamine and glycine imine. Despite being discovered more than 50 years ago, the biosynthetic pathway of KSM remains an unresolved puzzle. Here we report a structural and functional analysis for an epimerase, KasQ, that primes KSM biosynthesis rather than the previously proposed KasF/H, which instead acts as an acetyltransferase, inactivating KSM. Our biochemical and biophysical analysis determined that KasQ converts UDP-GlcNAc to UDP-ManNAc as the initial step in the biosynthetic pathway. The isotope-feeding study further confirmed that 13C, 15N-glucosamine/UDP-GlcNH2 rather than glucose/UDP-Glc serves as the direct precursor for the formation of KSM. Both KasF and KasH were proposed, respectively, converting UDP-GlcNH2 and KSM to UDP-GlcNAc and 2-N'-acetyl KSM. Experimentally, KasF is unable to do so; both KasF and KasH are instead KSM-modifying enzymes, while the latter is more specific and reactive than the former in terms of the extent of resistance. The information gained here lays the foundation for mapping out the complete KSM biosynthetic pathway.

Design and engineering of whole-cell biocatalyst for efficient synthesis of (R)-citronellal.

Bioproduction of optical pure (R)-citronellal from (E/Z)-citral at high substrate loading remains challenging. Low catalytic efficiency of (R)-stereoselective ene reductases towards crude citral mixture is one of the major bottlenecks. Herein, a structure-based engineering strategy was adopted to enhance the catalytic efficiency and stereoselectivity of an ene reductase (OYE2p) from Saccharomyces cerevisiae YJM1341 towards (E/Z)-citral. On basis of homologous modelling, molecular docking analysis and alanine scanning at the binding pocket of OYE2p, a mutant Y84A was obtained with simultaneous increase in catalytic efficiency and stereoselectivity. Furthermore, site-saturation mutagenesis of Y84 yielded seven mutants with improved activity and stereoselectivity in the (E/Z)-citral reduction. Among them, the variant Y84V exhibited an 18.3% and 71.3% rise in catalytic efficiency (kcat /Km ) for (Z)-citral and (E)-citral respectively. Meanwhile, the stereoselectivity of Y84V was improved from 89.2% to 98.0% in the reduction in (E/Z)-citral. The docking analysis and molecular dynamics simulation of OYE2p and its variants revealed that the substitution Y84V enabled (E)-citral and (Z)-citral to bind with a smaller distance to the key hydrogen donors at a modified (R)-selective binding mode. The variant Y84V was then co-expressed with glucose dehydrogenase from Bacillus megaterium in E. coli D4, in which competing prim-alcohol dehydrogenase genes were deleted to prevent the undesired reduction in the aldehyde moiety of citral and citronellal. Employing this biocatalyst, 106 g l-1 (E/Z)-citral was completely converted into (R)-citronellal with 95.4% ee value and a high space-time yield of 121.6 g l-1  day-1 . The work highlights the synthetic potential of Y84V, which enabled the highest productivity of (R)-citronellal from (E/Z)-citral in high enantiopurity so far.

Students' motivation and continued intention with online self-regulated learning: A self-determination theory perspective.

Continued self-regulation is recognized as a critical factor for students' successful learning in an online learning environment. In the context of college students' online self-regulated learning (SRL), a research approach based on self-determination theory (SDT) is developed to explain the relations of students' basic psychological needs to their intrinsic and extrinsic motivation, as well as their continued intention to engage in online SRL. The results show that the three basic needs are associated with intrinsic motivation, while only two needs, namely perceived relatedness and competence, are related to extrinsic motivation. In addition, continued intention to engage in online SRL is related to intrinsic and extrinsic motivation. Our study provides empirical evidence for the appropriateness of the application of SDT in online SRL.

Modification of an engineered Escherichia coli by a combinatorial strategy to improve 3,4-dihydroxybutyric acid production.

OBJECTIVES: 3,4-Dihydroxybutyric acid (3,4-DHBA) is a multifunctional C4 platform compound widely used for the synthesis of various materials, including pharmaceuticals. Although, a biosynthetic pathway for 3,4-DHBA production has been developed, its low yield still precludes large-scale use. Here, a heterologous four-step biosynthetic pathway was established in recombinant Escherichia coli (E. coli) using a combinatorial strategy. RESULTS: Several aldehyde dehydrogenases (ALDHs) were screened, using in vitro enzyme assays, to identify suitable catalysts for the dehydrogenation of 3,4-dihydroxybutanal (3,4-DHB) to 3,4-DHBA. A pathway containing glucose dehydrogenase (BsGDH) from Bacillus subtilis, D-xylonate dehydratase (YagF) from E. coli, benzoylformate decarboxylase (PpMdlC) from Pseudomonas putida and ALDH was introduced into E. coli, generating 3.04 g/L 3,4-DHBA from D-xylose (0.190 g 3,4-DHBA/g D-xylose). Disruption of competing pathways by deleting xylA, ghrA, ghrB and adhP contributed to an 87% increase in 3,4-DHBA accumulation. Expression of a fusion construct containing PpMdlC and YagF enhanced the 3,4-DHBA titer, producing the highest titer and yield reported thus far (7.71 g/L; 0.482 g 3,4-DHBA/g D-xylose). CONCLUSIONS: These results showed that deleting genes from competing pathways and constructing fusion proteins significantly improved the titer and yield of 3,4-DHBA in engineered E. coli.