Design, synthesis, and bioevaluation of SOS1 PROTACs derived from pyrido[2,3-d]pyrimidin-7-one-based SOS1 inhibitor.

Oncogenic KRAS mutations drive an approximately 25 % of all human cancers. Son of Sevenless 1 (SOS1), a critical guanine nucleotide exchange factor, catalyzes the activation of KRAS. Targeting SOS1 degradation has engaged as a promising therapeutic strategy for KRAS-mutant cancers. Herein, we designed and synthesized a series of novel CRBN-recruiting SOS1 PROTACs using the pyrido[2,3-d]pyrimidin-7-one-based SOS1 inhibitor as the warhead. One representative compound 11o effectively induced the degradation of SOS1 in three different KRAS-mutant cancer cell lines with DC50 values ranging from 1.85 to 7.53 nM. Mechanism studies demonstrated that 11o-induced SOS1 degradation was dependent on CRBN and proteasome. Moreover, 11o inhibited the phosphorylation of ERK and displayed potent anti-proliferative activities against SW620, A549 and DLD-1 cells. Further optimization of 11o may provide us promising SOS1 degraders with favorable drug-like properties for developing new chemotherapies targeting KRAS-driven cancers.

On the approximation of bi-Lipschitz maps by invertible neural networks.

Invertible neural networks (INNs) represent an important class of deep neural network architectures that have been widely used in applications. The universal approximation properties of INNs have been established recently. However, the approximation rate of INNs is largely missing. In this work, we provide an analysis of the capacity of a class of coupling-based INNs to approximate bi-Lipschitz continuous mappings on a compact domain, and the result shows that it can well approximate both forward and inverse maps simultaneously. Furthermore, we develop an approach for approximating bi-Lipschitz maps on infinite-dimensional spaces that simultaneously approximate the forward and inverse maps, by combining model reduction with principal component analysis and INNs for approximating the reduced map, and we analyze the overall approximation error of the approach. Preliminary numerical results show the feasibility of the approach for approximating the solution operator for parameterized second-order elliptic problems.

Characterizing changes to older adults' care transition patterns from hospital to home care in the initial year of COVID-19.

BACKGROUND: Skilled home healthcare (HH) provided in-person care to older adults during the COVID-19 pandemic, yet little is known about the pandemic's impact on HH care transition patterns. We investigated pandemic impact on (1) HH service volume; (2) population characteristics; and (3) care transition patterns for older adults receiving HH services after hospital or skilled nursing facility (SNF) discharge. METHODS: Retrospective, cohort, comparative study of recently hospitalized older adults (≥ 65 years) receiving HH services after hospital or SNF discharge at two large HH agencies in Baltimore and New York City (NYC) 1-year pre- and 1-year post-pandemic onset. We used the Outcome and Assessment Information Set (OASIS) and service use records to examine HH utilization, patient characteristics, visit timeliness, medication issues, and 30-day emergency department (ED) visit and rehospitalization. RESULTS: Across sites, admissions to HH declined by 23% in the pandemic's first year. Compared to the year prior, older adults receiving HH services during the first year of the pandemic were more likely to be younger, have worse mental, respiratory, and functional status in some areas, and be assessed by HH providers as having higher risk of rehospitalization. Thirty-day rehospitalization rates were lower during the first year of the pandemic. COVID-positive HH patients had lower odds of 30-day ED visit or rehospitalization. At the NYC site, extended duration between discharge and first HH visit was associated with reduced 30-day ED visit or rehospitalization. CONCLUSIONS: HH patient characteristics and utilization were distinct in Baltimore versus NYC in the initial year of the COVID-19 pandemic. Study findings suggest some older adults who needed HH may not have received it, since the decrease in HH services occurred as SNF use decreased nationally. Findings demonstrate the importance of understanding HH agency responsiveness during public health emergencies to ensure older adults' access to care.

ARHGEF18 can promote BVDV NS5B activation of the host NF-κB signaling pathway by combining with the NS5B-palm domain.

Rho guanine nucleotide exchange factor 18 (ARHGEF18) is a member of the Rho guanine nucleotide exchange factor (RhoGEF) family. RhoGEF plays an important role in the occurrence of tumors and neurological diseases; however, its involvement in host cell resistance against pathogenic microorganisms is mostly unknown. Herein, we report that bovine viral diarrhea virus (BVDV) nonstructural protein 5B (NS5B) can activate the nuclear factor kappa B (NF-κB) signaling pathway to induce an immune response. To clarify the functional domains of NS5B that activate NF-κB signaling, the six structural domains of NS5B were expressed separately: NS5B-core, NS5B-finger, NS5B-palm, NS5B-thumb, NS5B-N and NS5B-c domain. We preliminarily determined that the functional domains of NS5B that activate NF-κB signaling are the finger and palm domains. We used a bovine kidney cell cDNA library and yeast two-hybrid technology to identify that the host protein ARHGEF18 interacts with NS5B. Co-immunoprecipitation assays showed that ARHGEF18 interacts strongly with NS5B-palm. Interestingly ARHGEF18 could promote NF-κB signaling activation by BVDV NS5B. In addition silencing ARHGEF18 significantly inhibited NS5B-palm activation of NF-κB signaling. We concluded that ARHGEF18 can bind to BVDV NS5B through the palm domain to activate the NF-κB pathway. These findings provide direct evidence that BVDV NS5B induces immune responses by activating NF-κB signaling.

For the Good of the People: an interpretive analysis of Chinese volunteerism in the critical matter of care at the start of the pandemic.

PURPOSE: China employed a unique volunteerism system where health care providers outside of Hubei Province, the epicentre, travelled to reverse the devastation wrought by coronavirus disease 2019 (COVID-19) at its global onset. The aim is to study the unique circumstances of Chinese volunteerism in the context of continuing pandemic threats, specifically exploring the experiences of 20 Chinese nurse and physician volunteers fighting COVID-19 during the outbreak. METHODS: Interviews were done through video calling. RESULTS: Using content analysis with a hermeneutic perspective, emerging patterns showed the ways in which China's particular manifestation of volunteerism teaches us how to engage global threats of this nature. The overarching lesson, For the Good of the People, was manifested in several dynamic and overlapping themes: 1) Reaching for Professional Standards Even in Crisis; 2) Constantly Caring Through Failures and Successes; and 3) Holding Fast to the Common Good. The devastation was met by the resilience of volunteers, who overcame profound challenges managing patient care. CONCLUSIONS: Volunteerism required sacrifice and tremendous support in the form of training and administrative direction, family support, and peer collaboration. Volunteers' physical and psychosocial wellbeing was a priority. Recognizing the representative themes can help societies plan for continuing and future events.

Assessing Factors Influencing Commitment to a Disparities Reduction Intervention: Social Justice Attitudes and Organizational Mission.

ABSTRACT: This mixed-methods study aims to understand what the perceptions of leaders and healthcare professionals are regarding causes of disparities, cultural competence, and motivation before launching a disparity reduction project in hypertension care, contrasting perceptions in Federally Qualified Health Centers (FQHCs), and in a non-FQHC system. We interviewed leaders of six participating primary care systems and surveyed providers and staff. FQHC respondents reported more positive cultural competence attitudes and behavior, higher motivation to implement the project, and less concern about barriers to caring for disadvantaged patients than those in the non-FQHC practices; however, egalitarian beliefs were similar among all. Qualitative analysis suggested that the organizational missions of the FQHCs reflect their critical role in serving vulnerable populations. All system leaders were aware of the challenges of provider care to underserved groups, but comprehensive initiatives to address social determinants of health and improve cultural competence were still needed in both system types. The study provides insights into the perceptions and motivations of primary care organizational leaders and providers who are interested in improving chronic care. It also offers an example for care disparity programs to understand commitment and values of the participants for tailoring interventions and setting baseline for progress.

Repair of fingertip defect with reverse digital artery island flap and repair of donor site with digital dorsal advancement flap.

Objective: The reverse digital artery island flap (RDAF) is widely used in repairing fingertip skin defects based on its good appearance and practicability. However, the donor area of the flap needs skin grafting, which can lead to complications. This retrospective study explored the clinical application of digital dorsal advance flap (DDAF) in repairing the donor site of the reverse digital artery island flap. Method: From June 2019 to February 2022, 17 patients with a soft tissue defect of the finger had been restored with the reverse digital artery island flap, and at the same time, the donor area was repaired with digital dorsal advance flap (DDAF). The sensitivity, the active range of motion (ROM) and patient satisfaction were assessed after the operation. Results: All flaps survived completely without skin grafting with only one linear scar. The sensory and motor functions of all patients recovered well. Assessment based on the Michigan Hand Outcomes Questionnaire (MHQ) showed satisfactory functional recovery for all patients. Conclusions: Reconstruction using RDAF combined with DDAF represents an effective alternative for repairing fingertip skin defects.

Discovery of a Potent, Cooperative, and Selective SOS1 PROTAC ZZ151 with In Vivo Antitumor Efficacy in KRAS-Mutant Cancers.

The linker moiety of a proteolysis-targeting chimera (PROTAC) molecule plays a critical role in modulating the degradation activity, target selectivity, and physico-chemical properties. However, the basics and underlying mechanisms of chemical modifications of the linker structure causing dramatic changes in the PROTAC degradation activity warrant further investigation. Herein, we report the design and characterization of a highly potent and selective SOS1 PROTAC ZZ151. After systematically modifying the linker length and composition, we observed that subtle modification of just one atom of the linker moiety of ZZ151 resulted in remarkable changes in the formation of the ternary complex and thus dramatically affected the degradation activities. ZZ151 quickly, specifically, and effectively induced SOS1 degradation; displayed potent antiproliferation activities against a broad panel of KRAS mutant-driven cancer cells; and showed superior anticancer activities in the KRASG12D- and G12V-mutant xenografts in mice. ZZ151 is a promising lead for developing new chemotherapies targeting KRAS mutants.

Design, Synthesis, and Bioevaluation of Pyrido[2,3-d]pyrimidin-7-ones as Potent SOS1 Inhibitors.

The use of small molecular modulators to target the guanine nucleotide exchange factor SOS1 has been demonstrated to be a promising strategy for the treatment of various KRAS-driven cancers. In the present study, we designed and synthesized a series of new SOS1 inhibitors with the pyrido[2,3-d]pyrimidin-7-one scaffold. One representative compound 8u showed comparable activities to the reported SOS1 inhibitor BI-3406 in both the biochemical assay and the 3-D cell growth inhibition assay. Compound 8u obtained good cellular activities against a panel of KRAS G12-mutated cancer cell lines and inhibited downstream ERK and AKT activation in MIA PaCa-2 and AsPC-1 cells. In addition, it displayed synergistic antiproliferative effects when used in combination with KRAS G12C or G12D inhibitors. Further modifications of the new compounds may give us a promising SOS1 inhibitor with favorable druglike properties for use in the treatment of KRAS-mutated patients.

Impact of certified infection preventionists in acute care settings: A systematic review.

BACKGROUND: Health care-associated infection (HAI) is a common adverse event affecting patient safety. This review aims to (1) establish evidence for the impact of certified infection prevention and control (CIC) specialists on infection prevention and patient safety in acute care settings and (2) summarize study design and statistical modeling used for impact assessment to inform future studies. METHODS: We searched and reviewed full-text, quantitative studies assessing the impact of CIC. The studies used empirical data published in English between January 2000 and April 2021 in PubMed, PsycINFO, and EMBASE. We identified 8 articles for data extraction and analysis. All eight studies used a cross-sectional design and had a quality rating of good to high based on the Johns Hopkins Nursing Evidence-Based Practice rating scales. RESULTS: CIC infection preventionists (IPs) may have a stronger understanding than other practitioners of the evidence for certain infection prevention practices and are more likely to recommend implementing them in the hospitals where they work, especially when the lead IP is certified. The association between CIC and HAI rates was inconsistent in our results. DISCUSSION AND CONCLUSIONS: Further studies are needed to explore the impact of CIC IPs on HAI rates.

Contributions of Structural Racism to the Food Environment: A Photovoice Study of Black Residents With Hypertension in Baltimore, MD.

BACKGROUND: Disproportionate exposure to poor food environments and food insecurity among Black Americans may partially explain critical chronic disease disparities by race and ethnicity. A complex set of structural factors and interactions between Black residents and their food environments, including store types, quantity, proximity, and quality of goods and consumer interactions within stores, may affect nutritional behaviors and contribute to higher cardiovascular and kidney disease risk. METHODS: We used the Photovoice methodology to explore the food environment in Baltimore, MD, through the perspectives of Black residents with hypertension between August and November 2019. Twenty-four participants were enrolled in the study (mean age: 65.1 years; 67% female). After a brief photography training, participants captured photos of their food environment, which they discussed in small focus groups over the course of 5 weeks. Discussions were audiotaped and analyzed for emergent themes using a line-by-line inductive approach. Themes were, then, organized into a collective narrative. RESULTS: Findings describe physical and social features of the food environment as well as participants' perceptions of its origins and holistic and generational health effects. The study illustrates the interrelationships among the broader socio-political environment, the quality and quantity of stores in the food landscape, and the ways in which they engage with the food environment as residents and consumers who have been marginalized due to their race and/or social class. The following meta-themes emerged from the data: (1) social injustice; (2) structural racism and classism; (3) interpersonal racism; (4) generational effects; (5) mistrust; (6) social programs; and (7) community asset-based approaches, including advocacy and civic engagement. CONCLUSIONS: Understanding residents' perceptions of the foundations and effects of the food environment on their health may help stakeholders to cocreate multilevel interventions alongside residents to improve access to healthy food and health outcomes among disparities affected populations.

Ultrathin and handleable nanofibrous net as a novel biomimetic basement membrane material for endothelial barrier formation.

Many strategies have been adopted to develop porous membranes to reconstitute basement membrane in vitro, which play a key role in the development of in vitro biomimetic models. However, the development of an artificial basement membrane combines cytocompatibility and nano-thickness is still challenging. Herein, a monolayer nanofibrous net patch was fabricated by combining microfabrication and electrospinning as a biomimetic basement membrane material, which was demonstrated for endothelial barrier formation. The nanofibrous net patches with different fiber densities were obtained by controlling electrospinning time. The net was with high porosity and ultrathin thickness approximate to the diameter of nanofibers, which is comparable to that of the native basement membrane. The morphology, proliferation and cell-cell/cell-substrate interactions of endothelial cells on the nanofibrous nets were studied and compared with track-etched polycarbonate membrane and traditional multilayer nanofibers membrane. In addition, the results of TEER measurement and permeability test demonstrated that the endothelial barrier formed on the nanofibrous net patch displayed stronger barrier integrity and function. Therefore, the proposed nanofibrous net patch shows great potential as a novel biomimetic basement membrane, which is promising to be applied for in vitro tissue mimetic applications.

Quantifying the influences of climate change and human activities on the grassland in the Southwest Transboundary Basin, China.

The Southwest Transboundary Basin (STB), which contains a part of the Tibetan Plateau and Southwest China, covers a large area of grassland that has been experiencing significant climate change (Cc) and human activities (Ha). However, variabilities of the grasslands and respective contributions of the drivers have not been fully understood. In this study, we quantitatively investigated the influences of Cc and Ha on the grasslands from 1982 to 2015 across the STB, using residual analysis, trend analysis, and partial correlation analysis. Particularly, vapor pressure deficit (VPD), which is increasingly paid attention to in current studies, was included in our analysis as a critical driver of alpine grasslands. Additionally, a new method, pure climate-induced grassland pixel, which combined the coefficient of variation, was proposed to significantly improve the pixel purity with higher coefficient correlation and lower error and bias. Results show that changes in the climate play an important role in the grassland coverage of STB during 1982-1999 and 2000-2015, while Ha only had a relatively weak negative impact on grassland during 2000-2015, mainly in the Lancang River Basin. Specifically, the grasslands showed an increasing trend in 1982-1999, dominated by climate change with a contribution rate of 80.87%. Temperature had the greatest contribution, followed by VPD and precipitation in this period. On the contrary, the grasslands showed a decreasing trend in 2000-2015, dominated by both Cc and Ha with the contributions of 53.16% and 46.84%, respectively. The findings of this study provide a valuable reference for future ecological restoration in other similar alpine regions.

Discovery of the First-in-Class Agonist-Based SOS1 PROTACs Effective in Human Cancer Cells Harboring Various KRAS Mutations.

Regulating SOS1 functions may result in targeted pan-KRAS therapies. Small-molecule SOS1 inhibitors showed promising anticancer potential, and the most advanced inhibitor BI 1701963 is currently under phase I clinical studies. SOS1 agonists provide new opportunities to treat cancer; however, the underlying mechanisms still warrant investigation. We here report the discovery of the first SOS1 PROTACs designed uniquely by connecting a VHL ligand to the reported SOS1 agonist, ensuring that the observed inhibitory activity results from degraders. The best compound 9d induced SOS1 degradation in various KRAS-driven cancer cells and displayed superior antiproliferation activity compared to the agonist itself. Tumor xenograft study clearly showed the promising antitumor potency of 9d against human lung cancer. This study provides good evidence of using agonists to design SOS1 PROTACs and demonstrates that targeted SOS1 degradation represents an effective therapeutic strategy for overcoming KRAS-driven cancers.

Variations in Patient Safety Climate in Chinese Hospitals.

OBJECTIVES: Patient safety climate is associated with patient outcomes in hospitals around the world. A better understanding of how safety climate varies within and across hospitals will help identify improvement opportunities. We examined variations in safety climate by work area and job category in Chinese hospitals. METHODS: We administered the Chinese Hospital Survey on Patient Safety Climate in 2011 to workers in 6 hospitals in China, with completed surveys from 1464 (86% response). We calculated the percent positive response for survey items and dimensions among hospitals and compared this across work areas and job categories using general linear models. RESULTS: Overall, 68% of responses suggested the presence of a positive safety climate. The percent positive responses were highest for organizational learning (86.1%) and unit management support for safety (84.5%) and lowest for staffing (30.6%) and error reporting (44.5%). Workers in surgical units, intensive care units, operating rooms, and emergency departments were slightly more negative regarding overall safety climate than those in medical and ancillary units. Physicians reported worse perceptions than nurses or other hospital workers on all dimensions except for unit management support for safety and communication and peer support. CONCLUSIONS: The perceived problem with staffing in Chinese hospitals was consistent with other studies. The lack of positive responses for error reporting may indicate a lack of awareness of the importance of learning from and reporting minor events and near misses. Variations within and across hospitals in safety climate suggest that improvement interventions should be tailored to individual units and professional groups.

The development of a hydrogen-helium dual-beam ion implanter.

Multiple ion beam facilities are powerful tools to simulate the irradiation effects of neutrons on relevant nuclear materials. Since hydrogen and helium are often generated in neutron irradiated materials as transmutation products and they play important roles in the defect evolution, the triple beam accelerator and transmission electron microscope link in situ facility instead of a monobeam or dual-beam facility is necessary to simulate neutron irradiation. A hydrogen-helium dual-beam ion implanter has been developed for a triple ion beam in situ facility at Xiamen University. A Penning ion source has been developed to produce H2 + and He+ simultaneously. A special system consisting of two Wien filters and an Einzel lens has been proposed to purify the species from a single Penning source and allow for the measurement of the He+/H2 + ratio, without disturbing the accelerator settings. The detail of this dual-beam ion implanter will be introduced in detail.

Screening and identification of differentially expressed genes in goose hepatocytes exposed to free fatty acid.

The overaccumulation of triglycerides in hepatocytes induces hepatic steatosis; however, little is known about the mechanism of goose hepatic steatosis. The aim of this study was to define an experimental model of hepatocellular steatosis with TG overaccumulation and minimal cytotoxicity, using a mixture of various proportions of oleate and palmitate free fatty acids (FFAs) to induce fat-overloading, then using suppressive subtractive hybridization and a quantitative PCR approach to identify genes with higher or lower expression levels after the treatment of cells with FFA mixtures. Overall, 502 differentially expressed clones, representing 21 novel genes and 87 known genes, were detected by SSH. Based on functional clustering, up- and down-regulated genes were mostly related to carbohydrate and lipid metabolism, enzyme activity and signal transduction. The expression of 20 selected clones involved with carbohydrate and lipid metabolism pathways was further studied by quantitative PCR. The data indicated that six clones similar to the genes ChREBP, FoxO1, apoB, IHPK2, KIF1B, and FSP27, which participate in de novo synthesis of fatty acid and secretion of very low density lipoproteins, had significantly lower expression levels in the hepatocytes treated with FFA mixtures. Meanwhile, 13 clones similar to the genes DGAT-1, ACSL1, DHRS7, PPARα, L-FABP, DGAT-2, PCK, ACSL3, CPT-1, A-FABP, PPARß, MAT, and ALDOB had significantly higher expression levels in the hepatocytes treated with FFA mixtures. These results suggest that several metabolic pathways are altered in goose hepatocytes, which may be useful for further research into the molecular mechanism of goose hepatic steatosis.

Identification of differentially expressed genes between hepatocytes of Landes geese (Anser anser) and Sichuan White geese (Anser cygnoides).

In this study, we examined gene expression in order to identify genes that are differentially expressed between the hepatocytes of Sichuan White geese and Landes geese. We hypothesized that such genes may be involved in the different predispositions between these two species to develop hepatic steatosis. RNA was isolated from primary hepatocytes of the two species, and suppression subtractive hybridization was employed to screen for genes that showed differences in mRNA expression. We built and characterized two reciprocal cDNA libraries that were enriched in genes up-regulated in Landes geese or Sichuan White geese. Using dot blot analysis we identified 128 of 600 randomly selected sequences that demonstrated differential expression between the two species. Of these differentially expressed genes, 115 sequences shared high homology with 46 known genes and 13 sequences corresponded to eight novel expressed sequence tags (ESTs). Based on functional clustering, up and down-regulated genes were mostly related to lipid metabolism, nuclear mRNA splicing, enzyme activity and transcription control. The expression of 18 selected clones was further studied by quantitative PCR. The data showed that eight clones similar to the genes ACSL5, CTGF, CIDEA, PPARγ, PCK, GSTS1, RPS4X, and THBS1 had significantly higher expression levels in the hepatocytes of Landes geese. In contrast, seven clones similar to the genes ADH5, YBX1, ASAH1, UCB, AOPVLDL, SCD-1, and ELOVL-6 had significantly higher expression levels in the hepatocytes of Sichuan White geese.