Development of a molecular glue-based Lin28 degrader to regulate cellular proliferation and stemness.

Let-7 microRNAs (miRNAs) regulate cellular processes including stemness and proliferation. Lin28, an RNA-binding protein, controls let-7 miRNA biogenesis and is a key factor in maintaining stem cell properties. We developed SB1349, a novel molecular glue-based degrader targeting Lin28. SB1349 induces Lin28 degradation through a proteasome-dependent pathway, enhances let-7 miRNA levels, and downregulates oncogenes c-Myc and IMP1. SB1349 also promotes the differentiation in neuroblastoma cells, highlighting its potential as a therapeutic agent for various diseases.

Broad-Spectrum Antiviral Agents against SARS-CoV-2 Variants Inhibit the Conserved Viral Protein Nsp1-RNA Interaction.

The ongoing global threats posed by COVID-19 pandemic, catalyzed by SARS-CoV-2, underscores the pressing need for effective antiviral strategies. The viral non-structural protein 1 (Nsp1) significantly influences pathogenicity by impeding host protein expression and enhancing viral RNA translation through its interaction with the stem-loop 1 (SL1) in the 5' untranslated region (UTR). We have developed a novel dual-luciferase reporter assay, designed to investigate the critical Nsp1-SL1 interaction, and identified P23E02 as a potential inhibitor. Our investigation, combining molecular docking studies and alanine mutagenesis, has unveiled that P23E02 disrupts Nsp1-40S ribosomal subunit interaction, liberating translational inhibition and empowering host antiviral responses. P23E02 exhibits antiviral efficacy against various sarbecoviruses, making it a promising candidate for combatting COVID-19 and related diseases. This study underscores the therapeutic potential of targeting the Nsp1/SL1 axis and lays the foundation for innovative antiviral interventions, ultimately fortifying global preparedness against future viral threats.

Stakeholder analysis for effective implementation of water management system: Case of groundwater charge in South Korea.

Groundwater Charge was introduced in 2005 as one of the sustainable resource management measures in South Korea. The implementation rate, however, stagnated around 37 %, indicating that most local governments chose not to adopt this 'optional' regulation. While previous Stakeholder Analysis studies mainly blamed exclusion - or limited involvement - of stakeholders in the designing and structuring stage of policy-making process for policy failures, this study focused on the interest conflicts and dynamics hindered implementation process. This is because the issue with the subject policy, i.e., Groundwater Charge in South Korea, is low 'implementation rate' not the 'collection rate' or 'tax deficit.' If it was simply design or structural issue, the Charge should suffer from tax deficit problem due to lower tax income than operational costs. Thus, in order to investigate the reasons of low Charge adoption rate at the local government level, the Stakeholder Analysis Theory was applied to examine each stakeholder of the Charge to distinguish the interaction among supportive and opposing groups. The analysis revealed that there are only strong opponents of the policy without clearly identifiable supporters. Having agricultural & fishery industry and small independent businesses in spas, hotels, and swimming pool as strong Players, the Context setters (local governments) are not motivated to enforce Groundwater charge. Furthermore, today's social norm governed by economic efficiency is preventing the environmentalists and other Subjects to counteract Players. Under these circumstances, this study recommends the Subject to transform the Crowds (general public) into policy supporters through education. Environmental education is the only viable means to encourage necessary paradigm shift to enable effective implementation of environmental policies like Groundwater charge.

Hypofractionated stereotactic radiosurgery (HSRS) as a salvage treatment for brain metastases failing prior stereotactic radiosurgery (SRS).

INTRODUCTION: Various treatment options exist to salvage stereotactic radiosurgery (SRS) failures for brain metastases, including repeat SRS and hypofractionated SRS (HSRS). Our objective was to report outcomes specific to salvage HSRS for brain metastases that failed prior HSRS/SRS. METHODS: Patients treated with HSRS to salvage local failures (LF) following initial HSRS/SRS, between July 2010 and April 2020, were retrospectively reviewed. The primary outcomes were the rates of LF, radiation necrosis (RN), and symptomatic radiation necrosis (SRN). Univariable (UVA) and multivariable (MVA) analyses using competing risk regression were performed to identify predictive factors for each endpoint. RESULTS: 120 Metastases in 91 patients were identified. The median clinical follow up was 13.4 months (range 1.1-111.1), and the median interval between SRS courses was 13.1 months (range 3.0-56.5). 115 metastases were salvaged with 20-35 Gy in 5 fractions and the remaining five with a total dose ranging from 20 to 24 Gy in 3-fractions. 67 targets (56%) were postoperative cavities. The median re-treatment target volume and biological effective dose (BED10) was 9.5 cc and 37.5 Gy, respectively. The 6- and 12- month LF rates were 18.9% and 27.7%, for RN 13% and 15.6%, and for SRN were 6.1% and 7.0%, respectively. MVA identified larger re-irradiation volume (hazard ratio [HR] 1.02, p = 0.04) and shorter interval between radiosurgery courses (HR 0.93, p < 0.001) as predictors of LF. Treatment of an intact target was associated with a higher risk of RN (HR 2.29, p = 0.04). CONCLUSION: Salvage HSRS results in high local control rates and toxicity rates that compare favorably to those single fraction SRS re-irradiation experiences reported in the literature.

Review on invasion of microplastic in our ecosystem and implications.

Today the world is going through the "Plastic Age." Nowadays, it is difficult to find a commonly used convenient item that is nonplastic. Plastic production and consumption, thus, increased exponentially and plastic emerged as one of the major concerns for waste management. Recent studies confirmed a faster rate of plastic degradation than previously believed under various conditions (e.g. saltwater, UV, soil interaction) that microplastic has become a new type of health-hazardous pollution source. Much research has been conducted since the discovery of the "Pacific Garbage Patch," and the scope has expanded from marine to soil, groundwater, air, and food chain. This article underwent a substantial amount of literature review to verify the degree of microplastic pollution progression in major pillars of the environment (aqueous, terrestrial, airborne, bio-organism, and human). Multiple kinds of literature indicated a high possibility of vigorous interaction among the pillars that microplastic is not stationary at the point of contamination but travels across the nation (transboundary) and medium (transmedium). Thus, only the waste reduction policy (i.e. production and consumption reduction) would be effective through a single national or local effort, while pollution and contamination management require more of a collective, if not global, approach. For these characteristics, this article proposes two most urgently required actions to combat microplastic pollution: (a) global acknowledgement of microplastic as transboundary and transmedium pollution source that require international collective action and (b) standardization of microplastic related research including basic definition and experimental specification to secure global comparativeness among data analysis. Without resolving these two issues, it could be very difficult to obtain an accurate global status mapping of microplastic pollution to design effective and efficient global microplastic pollution management policies.

COVID-19 Pandemic and Microplastic Pollution.

The world is suffering from aggravating, waste-generated consequences, and the contribution of microplastics to this problem is only increasing. A contributing factor to increased microplastic usage is the change in the use of personal protective equipment (PPE) from specific use in limited locations (e.g., hospitals) to general use in widespread locations to protect against the current COVID-19 pandemic. This has resulted in an overflow of microfiber waste from homes, schools, streets, and elsewhere, in every country. While various institutes have issued warnings regarding increasing PPE waste, there is no positive indication of an end to the pandemic in the near future. In this review, we examine the impact of the pandemic on microplastic production, consumption, and disposal, and suggest strategies for lessening environmental pollution. In preparation for the worst-case scenario in which PPE becomes a new normal (in the COVID-19 era), it is recommended that governments and other responsible organisations set up a structured monitoring system for the distribution and disposal of PPE to ensure the most effective waste management possible for continuous sustainable development.

Forecasting COVID-19 Cases Based on Social Distancing in Maryland, USA: A Time-Series Approach.

OBJECTIVE: Our objective is to forecast the number of coronavirus disease 2019 (COVID-19) cases in the state of Maryland, United States, using transfer function time series (TS) models based on a Social Distancing Index (SDI) and determine how their parameters relate to the pandemic mechanics. METHODS: A moving window of 2 mo was used to train the transfer function TS model that was then tested on the next week data. After accounting for a secular trend and weekly cycle of the SDI, a high correlation was documented between it and the daily caseload 9 days later. Similar patterns were also observed on the daily COVID-19 cases and incorporated in our models. RESULTS: In most cases, the proposed models provide a reasonable performance that was, on average, moderately better than that delivered by TS models based only on previous observations. The model coefficients associated with the SDI were statistically significant for most of the training/test sets. CONCLUSIONS: Our proposed models that incorporate SDI can forecast the number of COVID-19 cases in a region. Their parameters have real-life interpretations and, hence, can help understand the inner workings of the epidemic. The methods detailed here can help local health governments and other agencies adjust their response to the epidemic.

Effect of Cold Rolling on the Evolution of Shear Bands and Nanoindentation Hardness in Zr41.2Ti13.8Cu12.5Ni10Be22.5 Bulk Metallic Glass.

The effect of cold rolling on the evolution of hardness (H) and Young's modulus (E) on the rolling-width (RW), normal-rolling (NR), and normal-width (NW) planes in Zr41.2Ti13.8Cu12.5Ni10Be22.5 (Vitreloy 1) bulk metallic glass (BMG) was investigated systematically using nanoindentation at peak loads in the range of 50 mN-500 mN. The hardness at specimen surface varied with cold rolling percentage (%) and the variation is similar on RW and NR planes at all the different peak loads, whereas the same is insignificant for the core region of the specimen on the NW plane. Three-dimensional (3D) optical surface profilometry studies on the NR plane suggest that the shear band spacing decreases and shear band offset height increases with the increase of cold rolling extent. Meanwhile, the number of the pop-in events during loading for all the planes reduces with the increase of cold rolling extent pointing to more homogeneous deformation upon rolling. Calorimetric studies were performed to correlate the net free volume content and hardness in the differently cold rolled specimens.

Who Makes Your Heart Beat? What Makes You Sweat? Social Conflict in Virtual Reality for Educators.

Though educators often deal with stressful social conflicts, many face them ad hoc without much training. We studied if and how virtual agents can help University staff manage student-teacher conflicts. We explored educators' verbal, behavioral, and physiological reactions to a virtual agent that brought up a student-teacher conflict and held exit-interviews. Our qualitative analysis revealed that virtual agents for conflict training were positively received, but not for conflict mediation with cross-cultural differences. Those with non-Western backgrounds felt that an agent could help "save face," whereas Westerners preferred to resolve conflicts in person. In line with this, participants with a Western background rated the virtual agent to be less competent compared to those with non-Western backgrounds. While physiological measures only allow for limited conclusions, we found that participants who believed that the agent was controlled by a human had higher normalized hear rate variability (for the entire conversation in total) than people who thought that the agent was autonomous. We discuss implications for implementing virtual agents for training purposes, the impact of physiological signals, and the need to consider cultural and individual differences.

Public Compliance With Social Distancing Measures and SARS-CoV-2 Spread : A Quantitative Analysis of 5 States.

OBJECTIVE: We quantified the association between public compliance with social distancing measures and the spread of SARS-CoV-2 during the first wave of the epidemic (March-May 2020) in 5 states that accounted for half of the total number of COVID-19 cases in the United States. METHODS: We used data on mobility and number of COVID-19 cases to longitudinally estimate associations between public compliance, as measured by human mobility, and the daily reproduction number and daily growth rate during the first wave of the COVID-19 epidemic in California, Illinois, Massachusetts, New Jersey, and New York. RESULTS: The 5 states mandated social distancing directives during March 19-24, 2020, and public compliance with mandates started to decrease in mid-April 2020. As of May 31, 2020, the daily reproduction number decreased from 2.41-5.21 to 0.72-1.19, and the daily growth rate decreased from 0.22-0.77 to -0.04 to 0.05 in the 5 states. The level of public compliance, as measured by the social distancing index (SDI) and daily encounter-density change, was high at the early stage of implementation but decreased in the 5 states. The SDI was negatively associated with the daily reproduction number (regression coefficients range, -0.04 to -0.01) and the daily growth rate (from -0.009 to -0.01). The daily encounter-density change was positively associated with the daily reproduction number (regression coefficients range, 0.24 to 1.02) and the daily growth rate (from 0.05 to 0.26). CONCLUSIONS: Social distancing is an effective strategy to reduce the incidence of COVID-19 and illustrates the role of public compliance with social distancing measures to achieve public health benefits.