ATR limits Rad18-mediated PCNA monoubiquitination to preserve replication fork and telomerase-independent telomere stability.

Upon replication fork stalling, the RPA-coated single-stranded DNA (ssDNA) formed behind the fork activates the ataxia telangiectasia-mutated and Rad3-related (ATR) kinase, concomitantly initiating Rad18-dependent monoubiquitination of PCNA. However, whether crosstalk exists between these two events and the underlying physiological implications of this interplay remain elusive. In this study, we demonstrate that during replication stress, ATR phosphorylates human Rad18 at Ser403, an adjacent residue to a previously unidentified PIP motif (PCNA-interacting peptide) within Rad18. This phosphorylation event disrupts the interaction between Rad18 and PCNA, thereby restricting the extent of Rad18-mediated PCNA monoubiquitination. Consequently, excessive accumulation of the tumor suppressor protein SLX4, now characterized as a novel reader of ubiquitinated PCNA, at stalled forks is prevented, contributing to the prevention of stalled fork collapse. We further establish that ATR preserves telomere stability in alternative lengthening of telomere (ALT) cells by restricting Rad18-mediated PCNA monoubiquitination and excessive SLX4 accumulation at telomeres. These findings shed light on the complex interplay between ATR activation, Rad18-dependent PCNA monoubiquitination, and SLX4-associated stalled fork processing, emphasizing the critical role of ATR in preserving replication fork stability and facilitating telomerase-independent telomere maintenance.

USP8 promotes cancer progression and extracellular vesicle-mediated CD8+ T cell exhaustion by deubiquitinating the TGF-ß receptor TßRII.

TGF-ß signaling is a key player in tumor progression and immune evasion, and is associated with poor response to cancer immunotherapies. Here, we identified ubiquitin-specific peptidase 8 (USP8) as a metastasis enhancer and a highly active deubiquitinase in aggressive breast tumors. USP8 acts both as a cancer stemness-promoting factor and an activator of the TGF-ß/SMAD signaling pathway. USP8 directly deubiquitinates and stabilizes the type II TGF-ß receptor TßRII, leading to its increased expression in the plasma membrane and in tumor-derived extracellular vesicles (TEVs). Increased USP8 activity was observed in patients resistant to neoadjuvant chemotherapies. USP8 promotes TGF-ß/SMAD-induced epithelial-mesenchymal transition (EMT), invasion, and metastasis in tumor cells. USP8 expression also enables TßRII+ circulating extracellular vesicles (crEVs) to induce T cell exhaustion and chemoimmunotherapy resistance. Pharmacological inhibition of USP8 antagonizes TGF-ß/SMAD signaling, and reduces TßRII stability and the number of TßRII+ crEVs to prevent CD8+ T cell exhaustion and to reactivate anti-tumor immunity. Our findings not only reveal a novel mechanism whereby USP8 regulates the cancer microenvironment but also demonstrate the therapeutic advantages of engineering USP8 inhibitors to simultaneously suppress metastasis and improve the efficacy of cancer immunotherapy.

The ethylene-responsive transcription factor PpERF9 represses PpRAP2.4 and PpMYB114 via histone deacetylation to inhibit anthocyanin biosynthesis in pear.

Ethylene induces anthocyanin biosynthesis in most fruits, including apple (Malus domestica) and plum (Prunus spp.). By contrast, ethylene inhibits anthocyanin biosynthesis in pear (Pyrus spp.), but the underlying molecular mechanism remains unclear. In this study, we identified and characterized an ethylene-induced ETHYLENE RESPONSE FACTOR (ERF) transcription factor, PpETHYLENE RESPONSE FACTOR9 (PpERF9), which functions as a transcriptional repressor. Our analyses indicated PpERF9 can directly inhibit expression of the MYB transcription factor gene PpMYB114 by binding to its promoter. Additionally, PpERF9 inhibits the expression of the transcription factor gene PpRELATED TO APETALA2.4 (PpRAP2.4), which activates PpMYB114 expression, by binding to its promoter, thus forming a PpERF9-PpRAP2.4-PpMYB114 regulatory circuit. Furthermore, PpERF9 interacts with the co-repressor PpTOPLESS1 (PpTPL1) via EAR motifs to form a complex that removes the acetyl group on histone H3 and maintains low levels of acetylated H3 in the PpMYB114 and PpRAP2.4 promoter regions. The resulting suppressed expression of these 2 genes leads to decreased anthocyanin biosynthesis in pear. Collectively, these results indicate that ethylene inhibits anthocyanin biosynthesis by a mechanism that involves PpERF9-PpTPL1 complex-mediated histone deacetylation of PpMYB114 and PpRAP2.4. The data presented herein will be useful for clarifying the relationship between chromatin status and hormone signaling, with implications for plant biology research.

On-device phase engineering.

In situ tailoring of two-dimensional materials' phases under external stimulus facilitates the manipulation of their properties for electronic, quantum and energy applications. However, current methods are mainly limited to the transitions among phases with unchanged chemical stoichiometry. Here we propose on-device phase engineering that allows us to realize various lattice phases with distinct chemical stoichiometries. Using palladium and selenide as a model system, we show that a PdSe2 channel with prepatterned Pd electrodes can be transformed into Pd17Se15 and Pd4Se by thermally tailoring the chemical composition ratio of the channel. Different phase configurations can be obtained by precisely controlling the thickness and spacing of the electrodes. The device can be thus engineered to implement versatile functions in situ, such as exhibiting superconducting behaviour and achieving ultralow-contact resistance, as well as customizing the synthesis of electrocatalysts. The proposed on-device phase engineering approach exhibits a universal mechanism and can be expanded to 29 element combinations between a metal and chalcogen. Our work highlights on-device phase engineering as a promising research approach through which to exploit fundamental properties as well as their applications.

A new method to synthesize multiple gRNA libraries and functional mapping of mammalian H3K4me3 regions.

Genetic screening based on the clustered regularly interspaced palindromic repeat (CRISPR) system has been indicated to be a powerful tool for identifying regulatory genes or cis-elements. However, when applying CRISPR screens to pinpoint functional elements at particular loci, a large number of guide RNA (gRNA) spacers may be required to achieve saturated coverage. Here, we present a controlled template-dependent elongation (CTDE) method relying on reversible terminators to synthesize gRNA libraries with genomic regions of interest. By applying this approach to H3K4me3 chromatin immunoprecipitation (ChIP)-derived DNA of mammalian cells, mega-sized gRNA libraries were synthesized in a tissue-specific manner, with which we conducted screening experiments to annotate essential sites for cell proliferation. Additionally, we confirmed that an essential site within the intron of LINC00339 regulates its own mRNA and that LINC00339 is a novel regulator of the cell cycle that maintains HepG2 proliferation. The CTDE method has the potential to be automated with high efficiency at low cost, and will be widely used to identify functional elements in mammalian genomes.

Nanobodies and chemical cross-links advance the structural and functional analysis of PI3Kα.

Nanobodies and chemical cross-linking were used to gain information on the identity and positions of flexible domains of PI3Kα. The application of chemical cross-linking mass spectrometry (CXMS) facilitated the identification of the p85 domains BH, cSH2, and SH3 as well as their docking positions on the PI3Kα catalytic core. Binding of individual nanobodies to PI3Kα induced activation or inhibition of enzyme activity and caused conformational changes that could be correlated with enzyme function. Binding of nanobody Nb3-126 to the BH domain of p85α substantially improved resolution for parts of the PI3Kα complex, and binding of nanobody Nb3-159 induced a conformation of PI3Kα that is distinct from known PI3Kα structures. The analysis of CXMS data also provided mechanistic insights into the molecular underpinning of the flexibility of PI3Kα.

Evaluation of pancreatic iodine uptake and related influential factors in multiphase dual-energy CT.

OBJECTIVES: To establish normative values and identify potential factors influencing pancreatic iodine uptake using dual-energy CT (DECT). MATERIALS AND METHODS: This retrospective study included participants without pancreatic diseases undergoing DECT at two institutions with different platforms. Their protocols both included arterial phase (AP), portal venous phase (PP), and equilibrium phase (EP), defined as 35 s-40 s, 60 s-70 s, and 150 s-180 s after injection of contrast agent, respectively. Both iodine concentration (IC) and normalised IC (NIC) were measured. Demographic features, local measurements of the pancreas and visceral fat area (VFA) were considered as potential factors influencing iodine uptake using multivariate linear regression analyses. RESULTS: A total of 562 participants (median age 58 years [interquartile range: 47-67], with 282 men) were evaluated. The mean IC differed significantly between two institutions (all p < 0.001) across three contrast-enhanced phases, while the mean NIC showed no significant differences (all p > 0.05). The mean values of NIC were 0.22 at AP, 0.43 at PP and 0.45 at EP. NICAP was independently affected by VFA (ß = 0.362, p < 0.001), smoking (ß = -0.240, p = 0.001), and type-II diabetes (ß = -0.449, p < 0.001); NICPP by VFA (ß = -0.301, p = 0.017) and smoking (ß = -0.291, p < 0.001); and NICEP by smoking (ß = -0.154, p = 0.10) and alcohol consumption (ß = -0.350, p < 0.001) with statistical power values over 0.81. CONCLUSION: NIC values were consistent across institutions. Abdominal obesity, smoking, alcohol consumption, and diabetes are independent factors influencing pancreatic iodine uptake. CLINICAL RELEVANCE STATEMENT: This study has provided reference normative values, influential factors and effective normalisation methods of pancreatic iodine uptake in multiphase dual-energy CT for future studies in this area as a new biological marker. KEY POINTS: Evaluation of pancreatic iodine uptake measured by dual-energy CT is a promising method for future studies. Abdominal obesity, smoking, alcohol consumption, diabetes, and sex are independent factors influencing pancreatic iodine uptake. Utility of normalised iodine concentration is necessary to ensure the consistency across different institutions.

Fabrication of a MXene-based shape-memory hydrogel and its application in the wound repair of skin.

Wound dressings can generally complete hemostasis and provide temporary protection after skin damage. Herein, a MXene-based hydrogel was prepared from MXene, gelatin, poly(ethylene glycol)diacrylate (PEGDA) and N,N'-methylenebis(acrylamide) (HEAA) to prepare wound-dressing hydrogels for skin repair. HEAA and PEGDA crosslink polymerization formed the first layer of the network. Hydrogen bonds between MXene, PHEAA, and gelatin formed the second layer of the network. To make the hydrogel more suitable for skin repair, the mechanical properties of the hybrid hydrogel were adjusted. The MXene-based hydrogel could recover its original shape in 16 s upon immersion in water or for a few minutes under light irradiation. The obtained hydrogel showed good photothermal properties upon light irradiation (808 nm, 1 W cm-2) for 20 s, and its temperature on the surface could reach 86.4 °C. Due to its good photothermal properties, this MXene-based hydrogel was suitable for skin repair.

Association of sleep traits with myopia in children and adolescents: A meta-analysis and Mendelian randomization study.

PURPOSE: The association between sleep and myopia in children and adolescents has been reported, yet it remains controversial and inconclusive. This study aimed to investigate the influence of different sleep traits on the risk of myopia using meta-analytical and Mendelian randomization (MR) techniques. METHODS: The literature search was performed in August 31, 2023 based on PubMed, Embase, Web of Science, and Cochrane library. The meta-analysis of observational studies reporting the relationship between sleep and myopia was conducted. MR analyses were carried out to assess the causal impact of genetic pre-disposition for sleep traits on myopia. RESULTS: The results of the meta-analysis indicated a significant association between the risk of myopia and both short sleep duration [odds ratio (OR) = 1.23, 95% confidence interval (CI) = 1.08-1.42, P = 0.003] and long sleep duration (OR = 0.75, 95% CI = 0.66-0.86, P < 0.001). MR analyses revealed no significant causal associations of genetically determined sleep traits with myopia, including chronotype, sleep duration, short sleep duration and long sleep duration (all P > 0.05). CONCLUSIONS: No evidence was found to support a causal relationship between sleep traits and myopia. While sleep may not independently predict the risk of myopia, the potential impact of sleep on the occurrence and development of myopia cannot be disregarded.

EQ-5D-5L Population Norms for China Derived From a National Health Survey.

OBJECTIVES: To develop the EQ-5D-5L (5L) population norms for China and to assess the relationship between various factors and 5L data. METHODS: This study used data derived from the Psychology and Behavior Investigation of Chinese Residents, a national sample survey of 21 909 representative participants aged 12 years and above. Participants' health-related quality of life (HRQoL) was measured by the 5L. Their socioeconomic characteristics, behavioral factors, and health conditions were also obtained from the survey. Norm scores were generated and compared for different socioeconomic variables. Multiple linear and logistic regressions were used to assess the relationships of the 3 kinds of variables with the 5L utility, visual analog scale (VAS) scores and 5L health problems. RESULTS: The mean (SD) age of participants was 39.4 (18.9) years, and 50.0% of them were female. The mean (SD) utility and VAS scores were 0.940 (0.138) and 73.4 (21.6), respectively. Participants reported considerably more problems in anxiety/depression (26.2%) and pain/discomfort (22.2%) dimensions. The gender difference in HRQoL is attenuated. The participants older than 75 years suffered from a sharp decline in HRQoL; the participants in Shanghai and Tibet provinces reported lower utility and VAS scores and more health problems. Those who were younger, with better socioeconomic status and healthier lifestyles, and without diseases tended to report higher utility and VAS scores and fewer health problems. CONCLUSIONS: This study derived the 5L population norms for China based on a representative population sample.

Multimorbidity patterns and health-related quality of life among community-dwelling older adults: evidence from a rural town in Suzhou, China.

PURPOSE: The high prevalence of multimorbidity in aging societies has posed tremendous challenges to the healthcare system. The aim of our study was to comprehensively assess the association of multimorbidity patterns and health-related quality of life (HRQOL) among rural Chinese older adults. METHODS: This was a cross-sectional study. Data from 4,579 community-dwelling older adults aged 60 years and above was collected by the clinical examination and questionnaire survey. Information on 10 chronic conditions was collected and the 3-Level EQ-5D (EQ-5D-3L) was adopted to measure the HRQOL of older adults. An exploratory factor analysis was performed to determine multimorbidity patterns. Regression models were fitted to explore the associations of multimorbidity patterns with specific health dimensions and overall HRQOL. RESULTS: A total of 2,503 (54.7%) participants suffered from multimorbidity, and they reported lower HRQOL compared to those without multimorbidity. Three kinds of multimorbidity patterns were identified including cardiovascular-metabolic diseases, psycho-cognitive diseases and organic diseases. The associations between psycho-cognitive diseases/organic diseases and overall HRQOL assessed by EQ-5D-3L index score were found to be significant (ß = - 0.097, 95% CI - 0.110, - 0.084; ß = - 0.030, 95% CI - 0.038, - 0.021, respectively), and psycho-cognitive diseases affected more health dimensions. The impact of cardiovascular-metabolic diseases on HRQOL was largely non-significant. CONCLUSION: Multimorbidity was negatively associated with HRQOL among older adults from rural China. The presence of the psycho-cognitive diseases pattern or the organic diseases pattern contributed to worse HRQOL. The remarkable negative impact of psycho-cognitive diseases on HRQOL necessiates more attention and relevant medical assistance to older rural adults.

Refractive associations with corneal biomechanical properties among young adults: a population-based Corvis ST study.

PURPOSE: To assess the associations of corneal biomechanical properties as measured by the Corvis ST with refractive errors and ocular biometry in an unselected sample of young adults. METHODS: A total of 1645 healthy university students underwent corneal biomechanical parameters measurement by the Corvis ST. The refractive status of the participants was measured using an autorefractor without cycloplegia. Ocular biometric parameters were measured using the IOL Master. RESULTS: After adjusting for the effect of age, sex, biomechanical-corrected intraocular pressure and central corneal thickness, axial length was significantly associated with A1 velocity (A1v, ß = -10.47), A2 velocity (A2v, ß = 4.66), A2 deflection amplitude (A2DeflA, ß = -6.02), HC deflection amplitude (HC-DeflA, ß = 5.95), HC peak distance (HC-PD, ß = 2.57), deformation amplitude ratio max (DA Rmax, ß = -0.36), Ambrósio's relational thickness to the horizontal profile (ARTh, ß = 0.002). For axial length / corneal radius ratio, only A1v (ß = -2.01), A1 deflection amplitude (A1DeflA, ß = 2.30), HC-DeflA (ß = 1.49), HC-PD (ß = -0.21), DA Rmax (ß = 0.07), stress-strain index (SSI, ß = -0.29), ARTh (ß < 0.001) were significant associates. A1v (ß = 23.18), HC-DeflA (ß = -15.36), HC-PD (ß = 1.27), DA Rmax (ß = -0.66), SSI (ß = 3.53), ARTh (ß = -0.02) were significantly associated with spherical equivalent. CONCLUSION: Myopic eyes were more likely to have more deformable corneas and corneas in high myopia were easier to deform and were even softer compared with those in the mild/moderate myopia.

Distribution and determinants of corneal volume among healthy young Chinese adults: a cross-sectional study.

BACKGROUND: Several studies have previously reported the normal values of corneal volume (CV) in various populations, whereas little is known about the CV distribution in healthy young Chinese adults. Our study aimed to investigate the distribution of CV and its relationships with other ocular biometric parameters among healthy young Chinese adults. METHODS: A total of 1645 eyes from 1645 students at Dali University in Yunnan Province, China, were analyzed. Pentacam was used to measure CV. Central corneal thickness (CCT) and biomechanically corrected intraocular pressure (bIOP) were evaluated by Corvis-ST. Other biometrical parameters, including axial length (AL), keratometry, and white-to-white (WTW) distance, were measured using IOL Master. RESULTS: The mean age of the study population was 19.01 ± 0.92 years, and 68.81% of them were women. The CV was normally distributed in the whole sample, with a mean value of 61.23 ± 3.22 mm3. CV and CCT were significantly smaller in the Yi ethnic group than in the Han ethnic group (p < 0.01). CCT (coefficient: 0.085; p < 0.001) and keratometry (coefficient: 0.422; p < 0.001) were positively correlated with CV, while AL (coefficient: -0.204; p < 0.001), WTW distance (coefficient: -0.236; p < 0.001) and bIOP (coefficient: -0.06; p < 0.001) were inversely associated with CV. CONCLUSIONS: Our study provides an age-specific distribution of CV among healthy young Chinese adults. CCT, keratometry, AL, WTW distance and bIOP were important factors associated with CV.

Effect modification of time spent outdoors on the association between early childhood overweight and myopia: a one-year follow-up study.

BACKGROUND: This study examined the moderating role of outdoor time on the relationship between overweight and myopia. METHODS: The data for this study was obtained from a prospective study in Shanghai, where non-myopic children wore wristwear and were followed up for 1 year. Eye examinations were performed at each visit. The modification effect was assessed on the additive scale using multivariable logistic regression, and relative excess risk due to interaction was used to calculate the modification effect. RESULTS: A total of 4683 non-myopic children were included with 32.20% being overweight at baseline. Following a 1-year period, 17.42% of children had myopia. When compared to those who spent <90 minutes outdoors, children who spent >120 had a relative risk of myopia onset that was reduced to 0.61. As time spent outdoors decreased, more risks of myopia onset were identified among overweight children than among normal children, the modification effect on the additive scale was -0.007, with ~70% of this effect attributed to the modifying influence of outdoor time. CONCLUSIONS: Increasing outdoor time can reduce myopia more among overweight children than normal. Future interventions should focus on outdoor activities among overweight children to reduce myopia risks.

Multimorbidity patterns and the risk of falls among older adults: a community-based study in China.

BACKGROUND: Due to the high prevalence of multimorbidity and realistic health service demands for fall prevention, there is growing interest in the association between multimorbidity and falls. Our study aimed to identify multimorbidity patterns among Chinese older adults and explore the association between multimorbidity patterns and falls. METHODS: Data from 4,579 Chinese community-dwelling older adults was included in this analysis. Information regarding falls and 10 chronic conditions was collected. An exploratory factor analysis was performed to determine multimorbidity patterns. Regression models were fitted to explore the associations of individual chronic disease or multimorbidity patterns with falls. RESULTS: Among 4,579 participants, 368 (8.0%) were defined as fallers, including 92 (2.0%) frequent fallers, and multimorbidity affected 2,503 (54.7%) participants. Older adults with multimorbidity were more likely to be fallers [odds ratio (OR) = 1.3, P = 0.02] and frequent fallers (OR = 1.7, P = 0.04). Three multimorbidity patterns were identified (i.e., cardiovascular-metabolic diseases, psycho-cognitive diseases and organic diseases), and the associations between psycho-cognitive diseases/organic diseases and prevalent falls or frequent falls were found to be significant. CONCLUSIONS: The psycho-cognitive disease pattern and organic disease pattern are significantly associated with falls. Therefore, more attention should be paid to patients with psycho-cognitive diseases and timely, targeted diagnostic and treatment services should be provided in fall prevention.

Mapping Digital Public Health Interventions Among Existing Digital Technologies and Internet-Based Interventions to Maintain and Improve Population Health in Practice: Scoping Review.

BACKGROUND: The rapid progression and integration of digital technologies into public health have reshaped the global landscape of health care delivery and disease prevention. In pursuit of better population health and health care accessibility, many countries have integrated digital interventions into their health care systems, such as web-based consultations, electronic health records, and telemedicine. Despite the increasing prevalence and relevance of digital technologies in public health and their varying definitions, there has been a shortage of studies examining whether these technologies align with the established definition and core characteristics of digital public health (DiPH) interventions. Hence, the imperative need for a scoping review emerges to explore the breadth of literature dedicated to this subject. OBJECTIVE: This scoping review aims to outline DiPH interventions from different implementation stages for health promotion, primary to tertiary prevention, including health care and disease surveillance and monitoring. In addition, we aim to map the reported intervention characteristics, including their technical features and nontechnical elements. METHODS: Original studies or reports of DiPH intervention focused on population health were eligible for this review. PubMed, Web of Science, CENTRAL, IEEE Xplore, and the ACM Full-Text Collection were searched for relevant literature (last updated on October 5, 2022). Intervention characteristics of each identified DiPH intervention, such as target groups, level of prevention or health care, digital health functions, intervention types, and public health functions, were extracted and used to map DiPH interventions. MAXQDA 2022.7 (VERBI GmbH) was used for qualitative data analysis of such interventions' technical functions and nontechnical characteristics. RESULTS: In total, we identified and screened 15,701 records, of which 1562 (9.94%) full texts were considered relevant and were assessed for eligibility. Finally, we included 185 (11.84%) publications, which reported 179 different DiPH interventions. Our analysis revealed a diverse landscape of interventions, with telemedical services, health apps, and electronic health records as dominant types. These interventions targeted a wide range of populations and settings, demonstrating their adaptability. The analysis highlighted the multifaceted nature of digital interventions, necessitating precise definitions and standardized terminologies for effective collaboration and evaluation. CONCLUSIONS: Although this scoping review was able to map characteristics and technical functions among 13 intervention types in DiPH, emerging technologies such as artificial intelligence might have been underrepresented in our study. This review underscores the diversity of DiPH interventions among and within intervention groups. Moreover, it highlights the importance of precise terminology for effective planning and evaluation. This review promotes cross-disciplinary collaboration by emphasizing the need for clear definitions, distinct technological functions, and well-defined use cases. It lays the foundation for international benchmarks and comparability within DiPH systems. Further research is needed to map intervention characteristics in this still-evolving field continuously. TRIAL REGISTRATION: PROSPERO CRD42021265562; https://tinyurl.com/43jksb3k. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/33404.

Developing and Evaluating Digital Public Health Interventions Using the Digital Public Health Framework DigiPHrame: A Framework Development Study.

BACKGROUND: Digital public health (DiPH) interventions may help us tackle substantial public health challenges and reach historically underserved populations, in addition to presenting valuable opportunities to improve and complement existing services. However, DiPH interventions are often triggered through technological advancements and opportunities rather than public health needs. To develop and evaluate interventions designed to serve public health needs, a comprehensive framework is needed that systematically covers all aspects with relevance for public health. This includes considering the complexity of the technology, the context in which the technology is supposed to operate, its implementation, and its effects on public health, including ethical, legal, and social aspects. OBJECTIVE: We aimed to develop such a DiPH framework with a comprehensive list of core principles to be considered throughout the development and evaluation process of any DiPH intervention. METHODS: The resulting digital public health framework (DigiPHrame) was based on a scoping review of existing digital health and public health frameworks. After extracting all assessment criteria from these frameworks, we clustered the criteria. During a series of multidisciplinary meetings with experts from the Leibniz ScienceCampus Digital Public Health, we restructured each domain to represent the complexity of DiPH. In this paper, we used a COVID-19 contact-tracing app as a use case to illustrate how DigiPHrame may be applied to assess DiPH interventions. RESULTS: The current version of DigiPHrame consists of 182 questions nested under 12 domains. Domain 1 describes the current status of health needs and existing interventions; domains 2 and 3, the DiPH technology under assessment and aspects related to human-computer interaction, respectively; domains 4 and 5, structural and process aspects, respectively; and domains 6-12, contextual conditions and the outcomes of the DiPH intervention from broad perspectives. In the CWA use case, a number of questions relevant during its development but also important for assessors once the CWA was available were highlighted. CONCLUSIONS: DigiPHrame is a comprehensive framework for the development and assessment of digital technologies designed for public health purposes. It is a living framework and will, therefore, be updated regularly and as new public health needs and technological advancements emerge.

Highly Stable HfO2 Memristors through van der Waals Electrode Lamination and Delamination.

Memristors have attracted considerable attention in the past decade, holding great promise for future neuromorphic computing. However, the intrinsic poor stability and large device variability remain key limitations for practical application. Here, we report a simple method to directly visualize the origin of poor stability. By mechanically removing the top electrodes of memristors operated at different states (such as SET or RESET), the memristive layer could be exposed and directly characterized through conductive atomic force microscopy, providing two-dimensional area information within memristors. Based on this technique, we observed the existence of multiple conducting filaments during the formation process and built up a physical model between filament numbers and the cycle-to-cycle variation. Furthermore, by improving the interface quality through the van der Waals top electrode, we could reduce the filament number down to a single filament during all switching cycles, leading to much controlled switching behavior and reliable device operation.

Buffer Chain Model for Understanding Crystallization Competition in Conjugated Polymers.

It remains challenging to comprehensively understand the packing models of conjugated polymers, in which side chains play extremely critical roles. The side chains are typically flexible and non-conductive and are widely used to improve the polymer solubility in organic solutions. Herein, a buffer chain model is proposed to describe link between conjugated backbone and side chains for understanding the relationship of crystallization competition of conductive conjugated backbones and non-conductive side chains. A longer buffer chain is beneficial for alleviating such crystallization competition and further promoting the spontaneous packing of conjugated backbones, resulting in enhanced charge transport properties. Our results provide a novel concept for designing conjugated polymers towards ordered organization and enhanced electronic properties and highlight the importance of balancing the competitive interactions between different parts of conjugated polymers.

Immune-Hot tumor features associated with recurrence in early-stage ovarian clear cell carcinoma.

Ovarian clear cell carcinoma (OCCC) is a distinct histotype of ovarian cancer, which usually presages a worse prognosis upon recurrence. Identifying patients at risk for relapse is an unmet need to improve outcomes. A retrospective cohort analysis of 195 early-stage OCCC patients diagnosed between January 2011 and December 2019 at National Taiwan University Hospital was conducted to identify prognostic factors for recurrence, progression-free survival (PFS) and overall survival (OS). Molecular profiling of tumors was performed in a case-controlled cohort matched for adjuvant therapy for biomarker discovery. Multivariate Cox proportional hazard model revealed that paclitaxel-based chemotherapy was associated with better PFS than nonpaclitaxel chemotherapy (HR = 0.19, P = .006). The addition of bevacizumab was associated with better PFS, compared to no bevacizumab (HR = 0.09, P = .02). Neither showed significant improvement in OS. Recurrence is associated with an Immune-Hot tumor feature (P = .03), the CTLA-4-high subtype (P = .01) and increased infiltration of immune cells in general. The Immune-Hot feature (HR = 3.39, P = .005) and the CTLA-4-high subtype (HR = 2.13, P = .059) were associated with worse PFS. Immune-Hot tumor features could prognosticate recurrence in early-stage OCCC.