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MITF, a basic Helix-Loop-Helix Zipper (bHLHZip) transcription factor, plays vital roles in melanocyte development and functions as an oncogene. We perform a genetic screen for suppressors of the Mitf-associated pigmentation phenotype in mice and identify an intragenic Mitf mutation that terminates MITF at the K316 SUMOylation site, leading to loss of the C-end intrinsically disordered region (IDR). The resulting protein is more nuclear but less stable than wild-type MITF and retains DNA-binding ability. As a dimer, it can translocate wild-type and mutant MITF partners into the nucleus, improving its own stability thus ensuring nuclear MITF supply. smFRET analysis shows interactions between K316 SUMOylation and S409 phosphorylation sites across monomers; these interactions largely explain the observed effects. The recurrent melanoma-associated E318K mutation in MITF, which affects K316 SUMOylation, also alters protein regulation in concert with S409. This suggests that residues K316 and S409 of MITF are impacted by SUMOylation and phosphorylation, respectively, mediating effects on nuclear localization and stability through conformational changes. Our work provides a novel mechanism of genetic suppression, and an example of how apparently deleterious mutations lead to normal phenotypes.
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Background and Objectives: We aimed to investigate the carriage of colistin-resistant genes among both patients with a history of antibiotic exposure and apparently healthy adults with no recent healthcare contact. Materials and Methods: Stool swabs were collected from healthy people, and specimens were collected at the infection foci from the patients. Eleven primer/probe sets were used to perform the Multiplex Real-Time PCR assay with the QuantiNova Multiplex Probe PCR kit for screening the carriage of colistin-resistant genes (mcr-1 to mcr-10) and 16S rRNA gene as internal control. Results: In total, 86 patients and 96 healthy residents were included. Twenty two patients (25.9%) were positive with at least one colistin-resistance encoding gene. The mcr-1 gene was the most frequent (16.5%), followed by mcr-9, mcr-6, and mcr-4 genes, where the prevalence was 11.8%, 10.6%, and 9.4%, respectively. No patient was positive with mcr-3, mcr-7, and mcr-8 genes. Eight patients (9.4%) were positive with multiple colistin-encoding genes. Twenty-three healthy people (24.0%) were positive with at least one colistin-resistance encoding gene, and the mcr-10 gene was the most frequent (27.0%), followed by the mcr-1, mcr-8, and mcr-9 genes, where the prevalence was 24.3%, 21.6%, and 13.5%, respectively. No person was positive with the mcr-2 and mcr-5 genes. Conclusions: Our findings underscore the urgent need for enhanced surveillance, infection control measures, and stewardship interventions to mitigate the spread of colistin resistance in Vietnam.
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Antibacterianos , Colistina , Farmacorresistencia Bacteriana , Humanos , Colistina/farmacología , Colistina/uso terapéutico , Vietnam/epidemiología , Masculino , Femenino , Adulto , Antibacterianos/uso terapéutico , Antibacterianos/farmacología , Farmacorresistencia Bacteriana/genética , Prevalencia , Persona de Mediana Edad , Heces/microbiología , Anciano , Pruebas de Sensibilidad MicrobianaRESUMEN
BACKGROUND: This report describes the U.S. Food and Drug Administration (FDA) experience in establishing a dedicated mailbox, and in publishing related guidance, to address concerns among interested parties regarding the conduct of clinical trials during the COVID-19 public health emergency (PHE). METHODS: Six hundred and thirty-four mailbox inquiries were received from March 2020 through February 2022. Qualitative methods were used to provide a structured description of, and identify common themes among, these inquiries. RESULTS: Most inquiries came from U.S.-based interested parties, including sponsors, industry trade associations, academic institutions, hospitals, clinics, research sites, trial participants, and individual persons. Approximately one-fifth of questions were related directly to COVID-19 (e.g., proposals for treatment); other inquiries were related to conduct of routine trial-related activities, and concerns were often focused on maintaining compliance with good clinical practice. In March 2020, FDA published a guidance titled Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency; the document was subsequently revised eight times based in part on issues raised in mailbox inquiries. CONCLUSIONS: The dedicated mailbox enabled expedited communication among invested parties during the COVID-19 PHE; FDA also provided updates of the aforementioned guidance. These efforts supported the continuance of ongoing trials and the initiation of new trials during the PHE in accordance with good clinical practice guidelines, thereby helping to ensure the safety of trial participants while maintaining the quality of trial data. By soliciting and responding to trial-related inquiries and addressing corresponding needs and concerns, FDA improved transparency and communication.
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COVID-19 , Ensayos Clínicos como Asunto , Salud Pública , United States Food and Drug Administration , Estados Unidos , Humanos , SARS-CoV-2RESUMEN
Cordyceps militaris is a well-known medicinal mushroom in Asian countries. This edible fungus has been widely exploited for traditional medicine and functional food production. C. militaris is a heterothallic fungus that requires both the mating-type loci, MAT1-1 and MAT1-2, for fruiting body formation. However, recent studies also indicated two groups of C. militaris, including monokaryotic strains carrying only MAT1-1 in their genomes and heterokaryotic strains harboring both MAT1-1 and MAT1-2. These strain groups are able to produce fruiting bodies under suitable cultivating conditions. In previous work, we showed that monokaryotic strains are more stable than heterokaryotic strains in fruiting body formation through successive culturing generations. In this study, we report a high cordycepin-producing monokaryotic C. militaris strain (HL8) collected in Vietnam. This strain could form normal fruiting bodies with high biological efficiency and contain a cordycepin content of 14.43 mg/g lyophilized fruiting body biomass. The ethanol extraction of the HL8 fruiting bodies resulted in a crude extract with a cordycepin content of 69.15 mg/g. Assays of cytotoxic activity on six human cancer cell lines showed that the extract inhibited the growth of all these cell lines with the IC50 values of 6.41-11.51 µg/mL. Notably, the extract significantly reduced cell proliferation and promoted apoptosis of breast cancer cells. Furthermore, the extract also exhibited strong antifungal activity against Malassezia skin yeasts and the citrus postharvest pathogen Penicillium digitatum. Our work provides a promising monokaryotic C. militaris strain as a bioresource for medicine, cosmetics, and fruit preservation.
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Antineoplásicos , Cordyceps , Neoplasias , Penicillium , Humanos , Penicillium/genética , Cuerpos Fructíferos de los HongosRESUMEN
The present study focuses on the problem of vehicle routing with limited capacity, with the objective of minimizing the transportation distance required to serve h clients with predetermined locations and needs. The aim is to create k trips that cover the shortest possible distance. To achieve this goal, a hybrid whale optimization algorithm (hGWOA) is proposed, which combines the whale optimization algorithm (WOA) with the grey wolf optimizer (GWO). The proposed hybrid model is comprised of two main steps. First step, the GWO's hunting mechanism is integrated transitioning to the utilization phase of WOA, and a newly devised state is introduced that is linked to GWO. In the second step, a novel technique is incorporated into the exploration mission phase to enhance the resolve after per iteration. The algorithm's performance is assessed and compared with other modern algorithms, including the GWO, WOA, ant lion optimizer (ALO), and dragonfly algorithm (DA) using 23 benchmark test functions and CEC2017 benchmark test function. The results indicate that the hybrid hGWOA method outperforms other algorithms in terms of delivery distance optimization for scenarios involving scale and complexity. These findings are corroborated through case studies related to cement delivery and a real-world scenario in Viet Nam.
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Vietnam, classified as a developing nation, encounters numerous challenges within its construction sector, including the scarcity of comprehensive and documented historical data regarding risks and a deficiency in embracing contemporary methodologies to mitigate the impact of risk factors on construction project objectives. This paper outlines initial findings from an ongoing research endeavor that centers on implementing Lean Construction (LC) techniques to enhance construction management practices specifically for marble floor finishing work within Vietnam. Therefore, this study aims to apply the construction lean principle combined with discrete-event simulation (DES) by using EZStrobe to simulate the marble floor finishing process in reality, from observing and collecting data of each activity in the actual process on the site. By building, running simulations, and resulting from real-world simulations, we'll understand the sources of waste, and then apply lean construction principles through methods such as just in time, reduce the batch size and resources priorities, and multi-skilled teams for the initial construction process. The study's lean modeling results has led to a 13% reduction in construction cycle time, a 141% improvement in process efficiency, a 268% enhancement in average productivity, and a 96% reduction in labor cost. The result has become the reference document resource for the managers and construction engineers to improve the performance of not only general finishing work but also marble floor finishing work.
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Meta-heuristic algorithms distinguish themselves from conventional optimization methods owing to their intrinsic adaptability and straightforward implementation. Among them, the sine cosine algorithm (SCA) is lauded for its ability to transition seamlessly between exploration and exploitation phases throughout the optimization process. However, there exists potential for enhancing the balance that SCA maintains between exploration and exploitation. To augment the proficiency in global optimization of SCA, an innovative strategy-nSCA-that integrates the roulette wheel selection (RWS) with opposition-based learning was formulated. The robustness of nSCA was rigorously evaluated against leading-edge methods such as the genetic algorithm (GA), particle swarm optimization, moth-flame optimization, ant lion optimization, and multi-verse optimizer, as well as the foundational SCA. This evaluation included benchmarks set by both CEC 2019 and CEC 2021 test functions. Additionally, the performance of nSCA was confirmed through numerous practical optimization problems, emphasizing its effectiveness in applied settings. In all evaluations, nSCA consistently showcased superior performance compared to its evolutionary algorithm counterparts, delivering top-tier solutions for both benchmark functions and real-world optimization challenges. Given this compelling evidence, one can posit that nSCA serves as a strong candidate for addressing intricate optimization challenges found in real-world contexts, regardless of whether they are of a discrete or continuous nature.
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Background: Simultaneous repair of the extensor tendons and soft tissues in hand injuries remains challenging. The free chimeric anterolateral thigh (ALT) flap with fascia lata (FL) flap represents an alternative for hand reconstruction. This report describes the reconstruction of the extensor tendon and skin defects using free chimeric ALT flaps with FL. Methods: Eight patients (one female and seven male) underwent reconstruction of complex hand defects with free chimeric ALT and FL flaps. The defects were caused by crushing injuries, burns, snakebite scars, and animal bite wounds. The average skin defect was 116 cm2. Perforators were selected for the skin paddle and the FL flap. The thinning procedure was performed microsurgically. Results: The skin paddle size ranged from 12 to 23 cm in length and 6 to 11 cm in width, and the FL flaps ranged from 3 × 5 to 12 × 5 cm. The mean pedicle length was 7.88 cm. Nine extensor tendons were repaired with FL flaps. The flap thickness after thinning was only 3-6 mm. The donor site was closed primarily in six patients, and skin grafts were used in two cases. All flaps survived without complications. The follow-up period lasted from 17 to 80 months. Range of motion was achieved with satisfaction. Conclusion: The chimeric-thinned ALT and FL flap is a valuable material, and it should be considered a reconstructive option for hand soft tissue and extensor tendon reconstruction. This technique allows us to achieve a good appearance and extensor function without donor-site morbidity.
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Filoviruses comprise a family of single-stranded, negative-sense RNA viruses with a significant impact on human health. Given the risk for disease outbreaks, as highlighted by the recent outbreaks across Africa, there is an unmet need for flexible diagnostic technologies that can be deployed in resource-limited settings. Herein, we highlight the use of plasmonic-fluor lateral flow assays (PF-LFA) for the rapid, quantitative detection of an Ebolavirus-secreted glycoprotein, a marker for infection. Plasmonic fluors are a class of ultrabright reporter molecules that combine engineered nanorods with conventional fluorophores, resulting in improved analytical sensitivity. We have developed a PF-LFA for Orthoebolavirus zairense (EBOV) and Orthoebolavirus sudanense (SUDV) that provides estimated limits of detection as low as 0.446 and 0.641 ng/mL, respectively. Furthermore, our assay highlights a high degree of specificity between the two viral species while also maintaining a turnaround time as short as 30 min. To highlight the utility of our PF-LFA, we demonstrate the detection of EBOV infection in non-human primates. Our PF-LFA represents an enormous step forward in the development of a robust, field-deployable assay for filoviruses.
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Ebolavirus , Fiebre Hemorrágica Ebola , Animales , Fiebre Hemorrágica Ebola/diagnóstico , Ebolavirus/genética , Glicoproteínas , Brotes de EnfermedadesRESUMEN
One of the biggest environmental alterations we have made to our species is the change in the exposure to light. During the day, we typically sit behind glass windows illuminated by artificial light that is >400 times dimmer and has a very different spectrum than natural daylight. On the opposite end are the nights that are now lit up by several orders of magnitude. This review aims to provide food for thought as to why this matters for humans and other animals. Evidence from behavioral neuroscience, physiology, chronobiology, and molecular biology is increasingly converging on the conclusions that the biological nonvisual functions of light and photosensory molecules are highly complex. The initial work of von Frisch on extraocular photoreceptors in fish, the identification of rhodopsins as the molecular light receptors in animal eyes and eye-like structures and cryptochromes as light sensors in nonmammalian chronobiology, still allowed for the impression that light reception would be a relatively restricted, localized sense in most animals. However, light-sensitive processes and/or sensory proteins have now been localized to many different cell types and tissues. It might be necessary to consider nonlight-responding cells as the exception, rather than the rule.
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Criptocromos , Células Fotorreceptoras de Invertebrados , Humanos , Animales , Células Fotorreceptoras de Invertebrados/fisiologíaRESUMEN
This study introduces an optimized design approach for west-facing room façades to improve daylighting while adhering to LEED v4.1 sustainability criteria. Employing parametric modeling, metaheuristic optimization, and validated daylight simulations, the research highlights the African Vulture Optimization Algorithm's success in achieving 100% LEED compliance and superior performance over random models in daylight sufficiency and glare reduction. Light-colored materials and transparent glazing emerged as beneficial for LEED points. Despite computational limitations and the need for empirical validation, this method offers architects versatile and sustainable design solutions. Comparative analysis reveals the algorithm's strong performance, although opportunities exist for refinement. Future research directions include contrasting this algorithm with other optimization methods, focusing on empirical backing, assessing environmental and human-centric impacts, adapting to varied building types and conditions, and examining diverse geographical and material factors. This work advances daylight-integrated façade design, suggesting a more comprehensive framework for building performance optimization.
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The global construction industry plays a pivotal role, yet its unique characteristics pose distinctive challenges. Each construction project, marked by its individuality, substantial value, intricate scale, and constrained adaptability, confronts crucial limitations concerning time and cost. Despite contributing significantly to environmental concerns throughout construction activities and infrastructure operations, environmental considerations remain insufficiently addressed by project managers. This research introduces an improved rendition of the muti-objective grasshopper optimization algorithm (MOGOA), termed eMOGOA, as a novel methodology to tackle time, cost, and carbon dioxide emission trade-off problems (TCCP) in construction project management. To gauge its efficacy, a case study involving 29 activities is employed. eMOGOA amalgamates MOGOA, tournament selection (TS), and opposition-based learning (OBL) techniques to enhance the performance of the original MOGOA. The outcomes demonstrate that eMOGOA surpasses other optimization algorithms, such as MODA, MOSMA, MOALO and MOGOA when applied to TCCP. These findings underscore the efficiency and relevance of the eMOGOA algorithm within the realm of construction project management.
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Cryptochromes (CRYs) are a structurally conserved but functionally diverse family of proteins that can confer unique sensory properties to organisms. In the marine bristle worm Platynereis dumerilii, its light receptive cryptochrome L-CRY (PdLCry) allows the animal to discriminate between sunlight and moonlight, an important requirement for synchronizing its lunar cycle-dependent mass spawning. Using cryo-electron microscopy, we show that in the dark, PdLCry adopts a dimer arrangement observed neither in plant nor insect CRYs. Intense illumination disassembles the dimer into monomers. Structural and functional data suggest a mechanistic coupling between the light-sensing flavin adenine dinucleotide chromophore, the dimer interface, and the C-terminal tail helix, with a likely involvement of the phosphate binding loop. Taken together, our work establishes PdLCry as a CRY protein with inverse photo-oligomerization with respect to plant CRYs, and provides molecular insights into how this protein might help discriminating the different light intensities associated with sunlight and moonlight.
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Criptocromos , Luz , Animales , Criptocromos/metabolismo , Microscopía por CrioelectrónRESUMEN
MITF, a basic-Helix-Loop-Helix Zipper (bHLHZip) transcription factor, plays vital roles in melanocyte development and functions as an oncogene. To explore MITF regulation and its role in melanoma, we conducted a genetic screen for suppressors of the Mitf-associated pigmentation phenotype. An intragenic Mitf mutation was identified, leading to termination of MITF at the K316 SUMOylation site and loss of the C-end intrinsically disordered region (IDR). The resulting protein is more nuclear but less stable than wild-type MITF and retains DNA-binding ability. Interestingly, as a dimer, it can translocate wild-type and mutant MITF partners into the nucleus, improving its own stability and ensuring an active nuclear MITF supply. Interactions between K316 SUMOylation and S409 phosphorylation sites across monomers largely explain the observed effects. Notably, the recurrent melanoma-associated E318K mutation in MITF, which affects K316 SUMOylation, also alters protein regulation in concert with S409, unraveling a novel regulatory mechanism with unexpected disease insights.
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Venomous snakebites can cause severe injury. The loss of tendon and skin of the hand is incredibly challenging for the surgeon. A single-staged reconstruction with the free composite anterolateral thigh flap is an acceptable option for a complex thumb injury. In this case, reconstruction for a 23-year-old patient with a complex cobra-induced thumb injury had failed to cover the defect with a skin graft. There was a limitation in choice, and the patient was treated with the free composite anterolateral thigh (ALT) flap and fascia lata flap in one stage to reconstruct both the extensor tendon and the soft tissue coverage. The flap was well-vascularized, and no complications were reported. A single-stage reconstruction with a composite ALT flap with vascularized fascia was chosen as a suitable alternative. The result is satisfying both aesthetically and functionally. This technique can help shorten treatment time and restore function quickly, allowing patients to return to work in less time. The disadvantages of this technique are flap thickness, which can affect finger movement and aesthetics. The composite ALT flap with vascularized fascia lata shows that it is a reliable procedure for single-staged reconstruction, especially combined with the tendon preparation in the hand.
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Marburg virus (MARV) causes a hemorrhagic fever disease in human and nonhuman primates with high levels of morbidity and mortality. Concerns about weaponization of aerosolized MARV have spurred the development of nonhuman primate (NHP) models of aerosol exposure. To address the potential threat of aerosol exposure, a monoclonal antibody that binds MARV glycoprotein was tested, MR186YTE, for its efficacy as a prophylactic. MR186YTE was administered intramuscularly to NHPs at 15 or 5 mg/kg 1 month prior to MARV aerosol challenge. Seventy-five percent (3/4) of the 15 mg/kg dose group and 50% (2/4) of the 5 mg/kg dose group survived. Serum analyses showed that the NHP dosed with 15 mg/kg that succumbed to infection developed an antidrug antibody response and therefore had no detectable MR186YTE at the time of challenge. These results suggest that intramuscular dosing of mAbs may be a clinically useful prophylaxis for MARV aerosol exposure.
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Enfermedad del Virus de Marburg , Marburgvirus , Animales , Humanos , Anticuerpos Monoclonales , Primates , AerosolesRESUMEN
This experimental study investigates the effects of several heuristic cues and systematic factors on users' misinformation susceptibility in the context of health news. Specifically, it examines whether author credentials, writing style, and verification check flagging influence participants' intent to follow article behavioral recommendations provided by the article, perceived article credibility, and sharing intent. Findings suggest that users rely only on verification checks (passing/failing) in assessing information credibility. Of the two antecedents to systematic processing, social media self-efficacy moderates the links between verification and participants' susceptibility. Theoretical and practical implications are discussed.
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The analysis of the relationship between time and cost is a crucial aspect of construction project management. Various optimization techniques have been developed to solve time-cost trade-off problems. A hybrid multi-verse optimizer model (hDMVO) is introduced in this study, which combines the multi-verse optimizer (MVO) and the sine cosine algorithm (SCA) to address the discrete time-cost trade-off problem (DTCTP). The algorithm's optimality is evaluated by using 23 well-known benchmark test functions. The results demonstrate that hDMVO is competitive with MVO, SCA, the dragonfly algorithm and ant lion optimization. The performance of hDMVO is evaluated using four benchmark test problems of DTCTP, including two medium-scale instances (63 activities) and two large-scale instances (630 activities). The results indicate that hDMVO can provide superior solutions in the time-cost optimization of large-scale and complex projects compared to previous algorithms.
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Traumatic rupture of the thoracic aorta is a rare condition, with a high mortality rate. Over the last 2 decades, strategies for managing aortic injury caused by blunt chest trauma have changed substantially, resulting in significantly improved outcomes. The recent development of endovascular repair offers a less invasive alternative to conventional open repair, particularly in patients with multiple injuries. Here, we report the case of a 31-year-old man who was referred to our emergency department with blunt chest trauma following a motorcycle-truck collision. Computed tomography confirmed acute traumatic rupture of the thoracic aorta, and the patient was successfully treated with endovascular repair.