Novel structure of the anti-CRISPR protein AcrIE3 and its implication on the CRISPR-Cas inhibition.

As a response to viral infections, bacteria have evolved the CRISPR-Cas system as an adaptive immune mechanism, enabling them to target and eliminate viral genetic material introduced during infection. However, viruses have also evolved mechanisms to counteract this bacterial defense, including anti-CRISPR proteins, which can inactivate the CRISPR-Cas adaptive immune system, thus aiding the viruses in their survival and replication within bacterial hosts. In this study, we establish the high-resolution crystal structure of the Type IE anti-CRISPR protein, AcrIE3. Our structural examination showed that AcrIE3 adopts a helical bundle fold comprising four α-helices, with a notably extended loop at the N-terminus. Additionally, surface analysis of AcrIE3 revealed the presence of three acidic regions, which potentially play a crucial role in the inhibitory function of this protein. The structural information we have elucidated for AcrIE3 will provide crucial insights into fully understanding its inhibitory mechanism. Furthermore, this information is anticipated to be important for the application of the AcrIE family in genetic editing, paving the way for advancements in gene editing technologies.

TRAF1 from a Structural Perspective.

Tumor necrosis factor receptor-associated factor (TRAF) proteins play pivotal roles in a multitude of cellular signaling pathways, encompassing immune response, cell fate determination, development, and thrombosis. Their involvement in these processes hinges largely on their ability to interact directly with diverse receptors via the TRAF domain. Given the limited binding interface, understanding how specific TRAF domains engage with various receptors and how structurally similar binding interfaces of TRAF family members adapt their distinct binding partners has been the subject of extensive structural investigations over several decades. This review presents an in-depth exploration of the current insights into the structural and molecular diversity exhibited by the TRAF domain and TRAF-binding motifs across a range of receptors, with a specific focus on TRAF1.

High-performance piezoelectric energy harvesting in amorphous perovskite thin films deposited directly on a plastic substrate.

Most reported thin-film piezoelectric energy harvesters have been based on cantilever-type crystalline ferroelectric oxide thin films deposited on rigid substrates, which utilize vibrational input sources. Herein, we introduce flexible amorphous thin-film energy harvesters based on perovskite CaCu3Ti4O12 (CCTO) thin films on a plastic substrate for highly competitive electromechanical energy harvesting. The room-temperature sputtering of CCTO thin films enable the use of plastic substrates to secure reliable flexibility, which has not been available thus far. Surprisingly, the resultant amorphous nature of the films results in an output voltage and power density of ~38.7 V and ~2.8 × 106 µW cm-3, respectively, which break the previously reported record for typical polycrystalline ferroelectric oxide thin-film cantilevers. The origin of this excellent electromechanical energy conversion is systematically explored as being related to the localized permanent dipoles of TiO6 octahedra and lowered dielectric constant in the amorphous state, depending on the stoichiometry and defect states. This is the leading example of a high-performance flexible piezoelectric energy harvester based on perovskite oxides not requiring a complex process for transferring films onto a plastic substrate.

Deep Learning Method for Precise Landmark Identification and Structural Assessment of Whole-Spine Radiographs.

This study measured parameters automatically by marking the point for measuring each parameter on whole-spine radiographs. Between January 2020 and December 2021, 1017 sequential lateral whole-spine radiographs were retrospectively obtained. Of these, 819 and 198 were used for training and testing the performance of the landmark detection model, respectively. To objectively evaluate the program's performance, 690 whole-spine radiographs from four other institutions were used for external validation. The combined dataset comprised radiographs from 857 female and 850 male patients (average age 42.2 ± 27.3 years; range 20-85 years). The landmark localizer showed the highest accuracy in identifying cervical landmarks (median error 1.5-2.4 mm), followed by lumbosacral landmarks (median error 2.1-3.0 mm). However, thoracic landmarks displayed larger localization errors (median 2.4-4.3 mm), indicating slightly reduced precision compared with the cervical and lumbosacral regions. The agreement between the deep learning model and two experts was good to excellent, with intraclass correlation coefficient values >0.88. The deep learning model also performed well on the external validation set. There were no statistical differences between datasets in all parameters, suggesting that the performance of the artificial intelligence model created was excellent. The proposed automatic alignment analysis system identified anatomical landmarks and positions of the spine with high precision and generated various radiograph imaging parameters that had a good correlation with manual measurements.

Novel structure of secreted small molecular weight antigen Mtb12 from Mycobacterium tuberculosis.

Mtb12, a small protein secreted by Mycobacterium tuberculosis, is known to elicit immune responses in individuals infected with the pathogen. It serves as an antigen recognized by the host's immune system. Due to its immunogenic properties and pivotal role in tuberculosis (TB) pathogenesis, Mtb12 is considered a promising candidate for TB diagnosis and vaccine development. However, the structural and functional properties of Mtb12 are largely unexplored, representing a significant gap in our understanding of M. tuberculosis biology. In this study, we present the first structure of Mtb12, which features a unique tertiary configuration consisting of four beta strands and four alpha helices. Structural analysis reveals that Mtb12 has a surface adorned with a negatively charged pocket adjacent to a central cavity. The features of these structural elements and their potential effects on the function of Mtb12 warrant further exploration. These findings offer valuable insights for vaccine design and the development of diagnostic tools.

Skin Deep: The Potential of Microbiome Cosmetics.

The interplay between the skin microbiome and its host is a complex facet of dermatological health and has become a critical focus in the development of microbiome cosmetics. The skin microbiome, comprising various microorganisms, is essential from birth, develops over the lifespan, and performs vital roles in protecting our body against pathogens, training the immune system, and facilitating the breakdown of organic matter. Dysbiosis, an imbalance of these microorganisms, has been implicated in a number of skin conditions such as acne, atopic dermatitis, and skin cancer. Recent scientific findings have spurred cosmetic companies to develop products that preserve and enhance the skin's microbial diversity balance. These products may incorporate elements like prebiotics, probiotics, and postbiotics, which are beneficial for the skin microbiome. Beyond topical products, there's increasing interest in ingestible beauty supplements (i.e. oral probiotics), highlighting the connection between the gut and skin. This review examines the influence of the microbiome on skin health and the emerging trends of microbiome skincare products.

Efficacy and Safety of Tirofiban Before Stenting for Symptomatic Intracranial Atherosclerotic Stenosis: A Randomized Clinical Trial.

BACKGROUND AND OBJECTIVES: Acute stent thrombosis (AST) is not uncommon and even catastrophic during intracranial stenting angioplasty in patients with symptomatic high-grade intracranial atherosclerotic stenosis (ICAS). The purpose of this study was to investigate whether adjuvant intravenous tirofiban before stenting could reduce the risk of AST and periprocedural ischemic stroke in patients receiving stent angioplasty for symptomatic ICAS. METHODS: A prospective, multicenter, open-label, randomized clinical trial was conducted from September 9, 2020, to February 18, 2022, at 10 medical centers in China. Patients intended to receive stent angioplasty for symptomatic high-grade ICAS were enrolled and randomly assigned to receive intravenous tirofiban or not before stenting in a 1:1 ratio. The primary outcomes included the incidence of AST within 30 minutes after stenting, periprocedural new-onset ischemic stroke, and symptomatic intracranial hemorrhage. The outcomes were analyzed using logistic regression analysis to obtain an odds ratio and 95% confidence interval. RESULTS: A total of 200 participants (122 men [61.0%]; median [interquartile ranges] age, 57 [52-66] years) were included in the analysis, with 100 participants randomly assigned to the tirofiban group and 100 participants to the control (no tirofiban) group. The AST incidence was lower in the tirofiban group than that in the control group (4.0% vs 14.0%; adjusted odds ratio, 0.25; 95% CI 0.08-0.82; p = 0.02). No significant difference was observed in the incidence of periprocedural ischemic stroke (7.0% vs 8.0%; p = 0.98) or symptomatic intracranial hemorrhage between the 2 groups. DISCUSSION: This study suggests that adjuvant intravenous tirofiban before stenting could lower the risk of AST during stent angioplasty in patients with symptomatic high-grade ICAS. TRIAL REGISTRATION INFORMATION: URL: chictr.org.cn; Unique identifier: ChiCTR2000031935. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with symptomatic high-grade ICAS, pretreatment with tirofiban decreases the incidence of acute stent thrombosis. This study is Class II due to the unequal distribution of involved arteries between the 2 groups.

When selection pays: Structured public goods game with a generalized interaction mode.

The public goods game is a broadly used paradigm for studying the evolution of cooperation in structured populations. According to the basic assumption, the interaction graph determines the connections of a player where the focal actor forms a common venture with the nearest neighbors. In reality, however, not all of our partners are involved in every game. To elaborate this observation, we propose a model where individuals choose just some selected neighbors from the complete set to form a group for public goods. We explore the potential consequences by using a pair-approximation approach in a weak selection limit. We theoretically analyze how the number of total neighbors and the actual size of the restricted group influence the critical enhancement factor where cooperation becomes dominant over defection. Furthermore, we systematically compare our model with the traditional setup and show that the critical enhancement factor is lower than in the case when all players are present in the social dilemma. Hence, the suggested restricted interaction mode offers a better condition for the evolution of cooperation. Our theoretical findings are supported by numerical calculations.

Biosynthesis of Chryseno[2,1,c]oxepin-12-Carboxylic Acid from Glycyrrhizic Acid in Aspergillus terreus TMZ05-2, and Analysis of Its Anti-inflammatory Activity.

Glycyrrhizic acid, glycyrrhetinic acid, and their oxo, ester, lactone, and other derivatives, are known for their anti-inflammatory, anti-oxidant, and hypoglycemic pharmacological activities. In this study, chryseno[2,1-c]oxepin-12-carboxylic acid (MG) was first biosynthesized from glycyrrhizic acid through sequential hydrolysis, oxidation, and esterification using Aspergillus terreus TMZ05-2, providing a novel in vitro biosynthetic pathway for glycyrrhizic acid derivatives. Assessing the influence of fermentation conditions and variation of strains during culture under stress-induction strategies enhanced the final molar yield to 88.3% (5 g/L glycyrrhizic acid). CCK8 assays showed no cytotoxicity and good cell proliferation, and anti-inflammatory experiments demonstrated strong inhibition of NO release (36.3%, low-dose MG vs. model), transcriptional downregulation of classical effective cellular factors tumor necrosis factor-α (TNF-α; 72.2%, low-dose MG vs. model), interleukin-6 (IL-6; 58.3%, low-dose MG vs. model) and interleukin-1ß (IL-1ß; 76.4%, low-dose MG vs. model), and decreased abundance of P-IKK-α, P-IKB-α, and P-P65 proteins, thereby alleviating inflammatory responses through the NF-κB pathway in LPS-induced RAW264.7 cells. The findings provide a reference for the biosynthesis of lactone compounds from medicinal plants.

Risk of Subsequent Vitiligo in Transplant Recipients With Comorbid Graft-vs-Host Disease.

Importance: Vitiligo is a multifactorial, depigmenting skin disorder characterized by selective loss of melanocytes. Large-scale studies are lacking to determine the risk of vitiligo in transplant recipients with graft-vs-host disease (GVHD). Objective: To investigate the incidence rates and risk of vitiligo in patients who had received solid organ transplant (SOT) or hematopoietic stem cell transplant (HSCT) overall and by HSCT graft type and concomitant GVHD. Design, Setting, and Participants: This population-based cohort study included data from the National Health Insurance Service database of Korea for patients aged 20 years or older who had received a transplant (SOT or HSCT) between January 2010 and December 2017, with follow-up until December 2019. A cohort of age- and sex-matched (1:5) control individuals who did not receive a transplant was included for comparison. Data were analyzed from July 2021 to December 2021. Exposure: Transplant (SOT or HSCT) and GVHD. Main Outcomes and Measures: The main outcome was risk of vitiligo, assessed using multivariable Cox proportional hazards regression analyses adjusting for potential confounding factors. Results: The study included 23 829 patients who had undergone SOT or HSCT (62.78% male; mean [SD] age, 49.58 [11.59] years) and 119 145 age- and sex-matched controls. Patients who had undergone transplant had a significantly higher risk of vitiligo compared with controls (adjusted hazard ratio [AHR], 1.73; 95% CI, 1.35-2.22). Risk of vitiligo was also slightly higher in kidney transplant recipients and liver transplant recipients compared with the controls but was highest in HSCT recipients (AHR, 12.69; 95% CI, 5.11-31.50). Patients who had received allogeneic grafts (AHR, 14.43; 95% CI, 5.61-37.15), those who had received autologous grafts (AHR, 5.71; 95% CI, 1.20-3.18), those with comorbid GVHD (AHR, 24.09; 95% CI, 9.16-63.35), and those without GVHD (AHR, 8.21; 95% CI, 3.08-21.87) had a higher risk of vitiligo compared with controls. Conclusion and Relevance: In this study, risk of vitiligo was significantly higher in transplant recipients, especially in HSCT recipients and those with allogeneic grafts or comorbid GVHD. These findings provide new insights into the association between the risk of vitiligo and transplant and GVHD. Clinicians should be aware of these risks, implementing a multidisciplinary approach for monitoring.

All-Cause and Cause-Specific Mortality among Patients with Vitiligo: A Nationwide Population-Based Study in Korea.

Vitiligo is a common autoimmune skin disorder; however, there is limited information about risks of mortality among patients with vitiligo. Therefore, we aimed to investigate the mortality in patients with vitiligo. A population-based cohort study was conducted using the data linkage of the National Health Insurance Service database and the National Death Registry. Patients with incident vitiligo were matched with sociodemographic factors-matched controls without vitiligo in a 1:5 ratio. All-cause and cause-specific mortalities were compared between patients with vitiligo and controls. In total, 107,424 patients with incident vitiligo and 537,120 matched controls were included. The mortality rates were 34.8 and 45.3 per 10,000 person-years in patients and controls, respectively. Patients with vitiligo showed a significantly lower risk of mortality (adjusted hazard ratio = 0.75, 95% confidence interval = 0.72-0.78). The cause-specific mortality from infectious diseases, oncologic diseases, hematologic diseases, endocrine diseases, neurologic diseases, cardiovascular diseases, respiratory diseases, and renal/urogenital disease was significantly lower in patients with vitiligo. Patients with vitiligo were associated with a lower risk of mortality, suggesting that vitiligo-associated autoimmunity might contribute to reduced morbidity and mortality.

Plaque features of the middle cerebral artery are associated with periprocedural complications of intracranial angioplasty and stenting.

PURPOSE: The identification of plaque features in the middle cerebral artery (MCA) may help minimize periprocedural complications and select patients suitable for percutaneous transluminal angioplasty and stenting (PTAS). However, relevant research is lacking. METHODS: We retrospectively included patients with symptomatic MCA stenosis who received PTAS. All patients underwent intracranial vessel wall MRI (VWMRI) before surgery. Periprocedural complications (PC) included ischemic and hemorrhagic stroke within 30 days. Stenosis location, MCA shape, plaque eccentricity and distribution, plaque thickness and length, and enhancement ratio were compared between patients with and without PC. RESULTS: Sixty-six patients were included in the study, of which 12.1% (8/66) had PC. Of the eight patients with PC, seven (87.5%) had superior wall plaques. In the non-PC group (n = 58), nine (17%) patients had superior wall plaques. Compared with patients without PC, those with PC had more frequent superior wall plaques (17% vs 87.5%, p < 0.001) and s-shaped MCAs (19% vs 50%, p = 0.071), different stenosis locations (p = 0.012), thicker plaques (1.58 [1.35, 2.00] vs 1.98 [1.73, 2.43], p = 0.038), and less frequent inferior wall plaques (79.2% vs 12.5%, p < 0.001). Multivariate analysis showed that only the presence of superior wall plaques (OR = 41.54 [2.31, 747.54]) was independently associated with PC. CONCLUSION: MCA plaque features were highly correlated with PC in patients with symptomatic MCA stenosis who underwent PTAS.

Robust 2D layered MXene matrix-boron carbide hybrid films for neutron radiation shielding.

Large-scale fabrication of neutron-shielding films with flexible or complex shapes is challenging. Uniform and high boron carbide (B4C) filler loads with sufficient workability are needed to achieve good neutron-absorption capacity. Here, we show that a two-dimensional (2D) Ti3C2Tx MXene hybrid film with homogeneously distributed B4C particles exhibits high mechanical flexibility and anomalous neutron-shielding properties. Layered and solution-processable 2D Ti3C2Tx MXene flakes serve as an ideal robust and flexible matrix for high-content B4C fillers (60 wt.%). In addition, the preparation of a scalable neutron shielding MXene/B4C hybrid paint is demonstrated. This composite can be directly integrated with various large-scale surfaces (e.g., stainless steel, glass, and nylon). Because of their low thickness, simple and scalable preparation method, and an absorption capacity of 39.8% for neutrons emitted from a 241Am-9Be source, the 2D Ti3C2Tx MXene hybrid films are promising candidates for use in wearable and lightweight applications.

Exploration on Electronic Properties of Self-Assembled Indium Nitrogen Nanosheets and Nanowires by a Density Functional Method.

Equilibrium geometries and properties of self-assembled (InN)12n (n = 1-9) nanoclusters (nanowires and nanosheets) are studied using the GGA-PBE (general gradient approximation with Perdew-Burke-Ernzerh) method. The relative stabilities and growth patterns of semiconductor (InN)12n nanoclusters are investigated. The odd-numbered nano-size (InN)12n (n is odd) have weaker stabilities compared with the neighboring even-numbered (InN)12n (n is even) ones. The most stable (InN)48 nanosheet is selected as a building unit for self-assembled nano-size film materials. In particular, the energy gaps of InN nanoclusters show an even-odd oscillation and reflect that (InN)12n (n = 1-9) nanoclusters are good optoelectronic materials and nanodevices due to their energy gaps in the visible region. Interestingly, the calculated energy gaps for (InN)12n nanowires varies slightly compared with that of individual (InN)12 units. Additionally, the predicted natural atomic populations of In atoms in (InN)12n nanoclusters show that the stabilities of (InN)12n nanoclusters is enhanced through the ionic bonding and covalent bonding of (InN)12n (n = 1-9) nanoclusters.

The ways to avoid abusive supervision: the moderating effects of the characteristics of supervisors and subordinates on abusive supervision.

Following the recent emphasis on supervisory interactions in abusive supervision, this study explains why and how supervisors' job insecurity and authoritarianism are related to abusive supervision and how subordinates' characteristics, agreeableness and negotiating resistance interact with the effects of supervisors' characteristics. We conducted a field study with 261 supervisor and subordinate dyads in South Korea, and the study findings confirmed that supervisors' authoritarianism is positively related to abusive supervision and that the effect is enhanced when subordinates are highly agreeable and display resistant behaviors. The study contributes to the leadership literature, particularly on abusive supervision and personality. Moreover, our findings have practical implications for employees to manage their work relationships with their supervisors or subordinates.

Autoimmune and Autoinflammatory Connective Tissue Disorders Following COVID-19.

Importance: Multiple cases of autoimmune and autoinflammatory diseases after COVID-19 have been reported. However, their incidences and risks have rarely been quantified. Objective: To investigate the incidences and risks of autoimmune and autoinflammatory connective tissue disorders after COVID-19. Design, Setting, and Participants: This was a retrospective population-based study conducted between October 8, 2020, and December 31, 2021, that used nationwide data from the Korea Disease Control and Prevention Agency COVID-19 National Health Insurance Service cohort and included individuals who received a diagnosis of COVID-19 via polymerase chain reaction testing and a control group with no evidence of COVID-19 identified from National Health Insurance Service of Korea cohort. Data analysis was conducted from September 2022 to August 2023. Exposures: Receipt of diagnosis of COVID-19. Main Outcomes and Measures: The primary outcomes were the incidence and risk of autoimmune and autoinflammatory connective tissue disorders following COVID-19. A total of 32 covariates, including demographics, socioeconomic statuses, lifestyle factors, and comorbidity profiles, were balanced through inverse probability weighting. The incidences and risks of autoimmune and autoinflammatory connective tissue disorders were compared between the groups using multivariable Cox proportional hazard analyses. Results: A total of 354 527 individuals with COVID-19 (mean [SD] age, 52.24 [15.55] years; 179 041 women [50.50%]) and 6 134 940 controls (mean [SD] age, 52.05 [15.63] years; 3 074 573 women [50.12%]) were included. The risks of alopecia areata (adjusted hazard ratio [aHR], 1.12; 95% CI, 1.05-1.19), alopecia totalis (aHR, 1.74; 95% CI, 1.39-2.17), antineutrophil cytoplasmic antibody-associated vasculitis (aHR, 2.76; 95% CI, 1.64-4.65), Crohn disease (aHR, 1.68; 95% CI, 1.31-2.15), and sarcoidosis (aHR, 1.59; 95% CI, 1.00-2.52) were higher in the COVID-19 group. The risks of alopecia totalis, psoriasis, vitiligo, vasculitis, Crohn disease, ulcerative colitis, rheumatoid arthritis, adult-onset Still disease, Sjögren syndrome, ankylosing spondylitis, and sarcoidosis were associated with the severity of COVID-19. Conclusions and Relevance: In this retrospective cohort study, COVID-19 was associated with a substantial risk for autoimmune and autoinflammatory connective tissue disorders, indicating that long-term management of patients with COVID-19 should include evaluation for such disorders.

Exon Junction Complex Mediates the Cap-Independent Translation of Circular RNA.

Evidence that circular RNAs (circRNA) serve as protein template is accumulating. However, how the cap-independent translation is controlled remains largely uncharacterized. Here, we show that the presence of intron and thus splicing promote cap-independent translation. By acquiring the exon junction complex (EJC) after splicing, the interaction between circRNA and ribosomes was promoted, thereby facilitating translation. Prevention of splicing by treatment with spliceosome inhibitor or mutating splicing signal hindered cap-independent translation of circRNA. Moreover, EJC-tethering using Cas13 technology reconstituted EJC-dependent circRNA translation. Finally, the level of a coding circRNA from succinate dehydrogenase assembly factor 2 (circSDHAF2) was found to be elevated in the tumorous tissues from patients with colorectal cancer, and shown to be critical in tumorigenesis of colorectal cancer in both cell and murine models. These findings reveal that EJC-dependent control of circSDHAF2 translation is involved in the regulation of oncogenic pathways. IMPLICATIONS: EJC-mediated cap-independent translation of circRNA is implicated in the tumorigenesis of colorectal cancer.