Rapid formation of gold core-satellite nanostructures using Turkevich-synthesized satellites and dithiol linkers: the do's and don'ts for successful assembly.

Turkevich syntheses represent a foundational approach for forming colloids of monodisperse gold nanoparticles where the use of these structures as building blocks when forming multicomponent nanoassemblies is pervasive. The core-satellite motif, which is characterized by a central core structure onto which satellite structures are tethered, distinguishes itself in that it can realize numerous plasmonic nanogaps with nanometer scale widths. Established procedures for assembling these multicomponent structures are, to a large extent, empirically driven, time-consuming, difficult to reproduce, and in need of a strong mechanistic underpinning relating to the close-range electrostatic interactions needed to secure satellite structures onto core materials. Described herein is a rapid, repeatable procedure for assembling core-satellite structures using Turkevich-grown satellites and dithiol linkers. With this successful procedure acting as a baseline for benchmarking modified procedures, a rather complex parameter space is understood in terms of timeline requirements for various processing steps and an analysis of the factors that prove consequential to assembly. It is shown that seemingly innocuous procedures realize sparsely populated cores whereas cores initially obstructed with commonly used capping agents lead to few disruptions to satellite attachment. Once these factors are placed under control, then it is the ionic strength imposed by the reaction biproducts of the Turkevich synthesis that is the critical factor in assembly because they decide the spatial extent of the electrical double layer surrounding each colloidal nanoparticle. With this understanding, it is possible to control the ionic strength through the addition or subtraction of various ionic species and assert control over the assembly process. The work, hence, advances the rules for a robust core-satellite assembly process and, in a broader sense, contributes to the knowhow required for the precise, programmable, and controllable assembly of multicomponent systems.

Single-dose high-dose-rate brachytherapy versus two and three fractions for locally advanced prostate cancer.

BACKGROUND: Single-dose high-dose-rate brachytherapy (SD-HDR-BT) was compared to two or three fraction HDR BT in intermediate and high-risk localized prostate cancer with median follow-up of 10 years. MATERIALS AND METHODS: 293 patients received 1 × 19Gy or 1 × 20Gy (Group A = 49), 2 × 13Gy (Group B = 138), or 3 × 10.5 Gy (Group C = 106) HDR BT. The primary endpoint was biochemical relapse-free interval (bRFI). Late genitourinary (GU) and gastrointestinal (GI) morbidity used RTOG scales and the International Prostate Symptom Score (IPSS). Freedom from biochemical relapse (bRFI), overall survival (OS) and GU, GI and IPSS morbidity were calculated using Kaplan-Meier (K-M) method and log-rank test. Univariate and multivariate hazard ratios (HR) were obtained using Cox's proportional hazard. RESULTS: At 10 years, K-M estimates of bRFI were 64 % (Group A), 72 % (Group B), and 76 % (Group C) (p = 0.2). No statistically significant difference was seen in OS. In multivariate analysis risk-category and ADT administration, but not dose, were significant predictors of relapse (p = 0.0003 and 0.03, respectively). At ten years, GU grade 3 events were 8 % (A), 2 % (B) and 13 % (C); (p = 0.01). IPSS ≥ 20 was 31 % (A), 20 % (B) and 23 % (C); (p = 0.6) and grade 3 GI was 0 % in groups A and B and 2 % in C; (p = 0.3). No GU or GI grade-4 events were observed. Pre-treatment IPSS was a highly significant predictor of failure in multivariate analysis. CONCLUSIONS: Long-term outcome data show reduced but not statistically significant difference in PSA control, and no difference in overall survival, between SD-HDR-BT and 2 or 3 fractions of HDR-BT.

Site-Selective Deposition of Silica Nanoframes and Nanocages onto Faceted Gold Nanostructures Using a Primer-free Tetraethyl Orthosilicate Synthesis.

The Stöber method for forming spherical silica colloids is well-established as one of the pillars of colloidal synthesis. In a modified form, it has been extensively used to deposit both porous and protective shells over metal nanomaterials. Current best-practice techniques require that the vitreophobic surface of metal nanoparticles be primed with a surface ligand to promote silica deposition. Although such techniques have proved highly successful in forming core-shell configurations, the site-selective deposition of silica onto preselected areas of faceted metal nanostructures has proved far more challenging. Herein, a primer-free TEOS-based synthesis is demonstrated that is capable of forming architecturally complex nanoframes and nanocages on the pristine surfaces of faceted gold nanostructures. The devised synthesis overcomes vitreophobicity using elevated TEOS concentrations that trigger silica nucleation along the low-coordination sites where gold facets meet. Continued deposition sees the emergence of a well-connected frame followed by the lateral infilling of the openings formed over gold facets. With growth readily terminated at any point in this sequence, the synthesis distinguishes itself in being able to achieve patterned and tunable silica depositions expressing interfaces that are uncorrupted by primers. The so-formed structures are demonstrated as template materials capable of asserting high-level control over synthesis and assembly processes by using the deposited silica as a mask that deactivates selected areas against these processes while allowing them to proceed elsewhere. The work, hence, extends the capabilities and versatility of TEOS-based syntheses and provides pathways for forming multicomponent nanostructures and nanoassemblies with structurally engineered properties.

Burden and indirect cost of vaccine-preventable cancer mortality in Europe.

BACKGROUND: The economic and mortality burden of cancer is high worldwide. In Europe, cancer was responsible for 1.3 million deaths in 2020 and incurred an estimated cost of €50 billion from premature mortality. Human papillomavirus (HPV) and hepatitis B virus (HBV) are among the leading causes of infection-related cancers despite the availability of effective vaccines against these infections. This analysis estimated the mortality and productivity loss of HBV- and HPV-associated cancers that could be preventable through vaccination across European regions. MATERIALS AND METHODS: Institute for Health Metrics Evaluation (IHME) data were used to estimate mortality, years of life lost (YLL), and the value of years of life lost (VYLL) from five HBV- and HPV-related cancers (oral cavity, oropharynx, larynx, cervical, and liver cancers) across 40 European countries in 2019. Preventable deaths and YLL were estimated based on fractions attributable to infections. Data from the World Bank on GDP per capita were used to estimate the VYLL. The robustness of these results was explored with sensitivity and scenario analyses. RESULTS: In 2019, 31,906 cancer deaths resulted in an economic burden of €18,521,614,725 due to productivity losses across Europe. HPV-related cervical cancer had the highest mortality (19,473 deaths) and economic burden (€10,706,253,185). HBV-related liver cancer and HPV-related larynx, oral cavity, and oropharynx cancers also had a substantial burden, particularly in males. Eastern Europe had the highest YLL (308,179; 39%) and Western Europe was responsible for the greatest VYLL (€8,281,306,504; 45%), although the highest VYLL per death was in Northern Europe (€923,638). HPV-related oropharynx cancer had the highest VYLL per death (€656,607). CONCLUSION: HPV- and HBV-related cancer deaths are associated with substantial mortality and productivity losses in Europe, which could be reduced by the continued prioritization and implementation of prophylactic public health measures including systematic awareness, vaccination, and screening efforts.

Productivity costs due to human papillomavirus-related cancer mortality in the United Kingdom.

BACKGROUND: Human papillomavirus (HPV) causes several cancers such as cervical cancer and some head and neck (oral cavity, pharynx, and larynx), vulval, vaginal, anal, and penile cancers. As HPV vaccination is available, there is potential to prevent these cancers attributed to HPV and consequently the burden associated with them. The aim of this analysis was to estimate the number of HPV-related cancer deaths and the productivity costs due to years of life lost (YLL) in the United Kingdom (UK). METHOD: A model was developed utilizing UK 2019 mortality data sourced from country-specific databases for England, Scotland, Wales, and Northern Ireland for the following HPV-related cancers: head and neck (ICD-10 C00-14 and C32), cervix uteri (C53), vaginal (C51), vulval (C52), anal (C21), and penile (C60). The proportion of deaths and years of life lost (YLL) due to HPV were estimated using HPV attributable fractions for each anatomic location from the published literature. Labor force participation, retirement ages, and mean annual earnings, discounted at 3.5% annually, were applied to YLL to calculate the present value of future lost productivity (PVFLP). RESULTS: A total of 1817 deaths due to HPV-related cancers were reported in the UK in 2019 resulting in 31,804 YLL. Restricting to only YLL that occurred prior to retirement age yielded a total YPLL of 11,765 and a total PVFLP of £187,764,978. CONCLUSIONS: There is a high disease burden in the UK for HPV-related cancers, with a large economic impact on the wider economy due to productivity losses. Implementing and reinforcing public health measures to maintain high HPV vaccination coverage in both males and females may further facilitate reduction of this burden.

EXPRESS: The Phonological Store of Working Memory: A Critique and an Alternative, Perceptual-Motor, Approach to Verbal Short-Term Memory.

A key quality of a good theory is its fruitfulness, one measure of which might be the degree to which it compels researchers to test it, refine it, or offer alternative explanations of the same empirical data. Perhaps the most fruitful element of Baddeley and Hitch's (1974) Working Memory framework has been the concept of a short-term phonological store, a discrete cognitive module dedicated to the passive storage of verbal material that is architecturally fractionated from perceptual, language, and articulatory systems. This review discusses how the phonological store construct has served as the main theoretical springboard for an alternative perceptual-motor approach in which serial recall performance reflects the opportunistic co-opting of the articulatory planning system and, when auditory material is involved, the products of obligatory auditory perceptual organisation. It is argued that this approach, which rejects the need to posit a distinct short-term store, provides a better account of the two putative empirical hallmarks of the phonological store-the phonological similarity effect and the irrelevant speech effect-and that it shows promise too in being able to account for nonword repetition and word-form learning, the supposed evolved function of the phonological store. The neuropsychological literature cited as strong additional support for the phonological store concept is also scrutinised through the lens of the perceptual-motor approach for the first time and a tentative articulatory-planning deficit hypothesis for the 'short-term memory' patient profile is advanced. Finally, the relation of the perceptual-motor approach to other 'emergent-property' accounts of short-term memory is briefly considered.

Intratumoral antigen signaling traps CD8+ T cells to confine exhaustion to the tumor site.

Immunotherapy advances have been hindered by difficulties in tracking the behaviors of lymphocytes after antigen signaling. Here, we assessed the behavior of T cells active within tumors through the development of the antigen receptor signaling reporter (AgRSR) mouse, fate-mapping lymphocytes responding to antigens at specific times and locations. Contrary to reports describing the ready egress of T cells out of the tumor, we find that intratumoral antigen signaling traps CD8+ T cells in the tumor. These clonal populations expand and become increasingly exhausted over time. By contrast, antigen-signaled regulatory T cell (Treg) clonal populations readily recirculate out of the tumor. Consequently, intratumoral antigen signaling acts as a gatekeeper to compartmentalize CD8+ T cell responses, even within the same clonotype, thus enabling exhausted T cells to remain confined to a specific tumor tissue site.

Global burden and economic impact of vaccine-preventable cancer mortality.

BACKGROUND: Infections are responsible for approximately 13% of cancer cases worldwide and many of these infections can be prevented by vaccination. Human papillomavirus (HPV) and hepatitis B virus (HBV) are among the most common infections that cause cancer deaths globally, despite effective prophylactic vaccines being available. This analysis aims to estimate the global burden and economic impact of vaccine-preventable cancer mortality across World Health Organization (WHO) regions. METHODS: The number of deaths and years of life lost (YLL) due to five different vaccine-preventable cancer forms (oral cavity, liver, laryngeal, cervical, and oropharyngeal cancer) in each of the WHO regions (African, Eastern Mediterranean, European, the Americas, South-East Asia Pacific, and Western Pacific) were obtained from the Institute for Health Metrics Evaluation global burden of disease dataset. Vaccine-preventable mortality was estimated considering the fraction attributable to infection, to estimate the number of deaths and YLL potentially preventable through vaccination. Data from the World Bank on GDP per capita were used to estimate the value of YLL (VYLL). The robustness of these results was explored with sensitivity analysis. Given that several Epstein-Barr virus (EBV) vaccines are in development, but not yet available, the impact of a potential vaccine for EBV was evaluated in a scenario analysis. RESULTS: In 2019, there were 465,740 potentially vaccine-preventable cancer deaths and 14,171,397 YLL across all WHO regions. The estimated economic impact due to this mortality was $106.3 billion globally. The sensitivity analysis calculated a range of 403,025-582,773 deaths and a range in productivity cost of $78.8-129.0 billion. In the scenario analysis EBV-related cancer mortality increased the global burden by 159,723 deaths and $32.4 billion. CONCLUSION: Overall, the findings from this analysis illustrate the high economic impact of premature cancer mortality that could be potentially preventable by vaccination which may assist decision-makers in allocating limited resources among competing priorities. Improved implementation and increased vaccination coverage of HPV and HBV should be prioritized to decrease this burden.

The indirect costs of human papillomavirus-related cancer in Central and Eastern Europe: years of life lost and productivity costs.

BACKGROUND: Human papilloma virus (HPV) is a common cause of several types of cancer, including head and neck (oral cavity, pharynx, oropharynx, hypopharynx, nasopharynx, and larynx), cervical, vulval, vaginal, anal, and penile cancers. As HPV vaccines are available, there is potential to prevent HPV-related disease burden and related costs. METHOD: A model was developed for nine Central Eastern European (CEE) countries (Bulgaria, Croatia, Czechia, Hungary, Poland, Romania, Serbia, Slovakia, Slovenia). This model considered cancer patients who died from 11 HPV-related cancers (oropharynx, oral cavity, nasopharynx, hypopharynx, pharynx, anal, larynx, vulval, vaginal, cervical, and penile) in 2019. Due to data limitations, Bulgaria only included four cancer types. The model estimated the number of HPV-related deaths and years of life lost (YLL) based on published HPV-attributable fractions. YLL was adjusted with labor force participation, retirement age and then multiplied by mean annual earnings, discounted at a 3% annual rate to calculate the present value of future lost productivity (PVFLP). RESULTS: In 2019, there were 6,832 deaths attributable to HPV cancers resulting in 107,846 YLL in the nine CEE countries. PVFLP related to HPV cancers was estimated to be €46 M in Romania, €37 M in Poland, €19 M in Hungary, €15 M in Czechia, €12 M in Croatia, €10 M in Serbia, €9 M in Slovakia, €7 M in Bulgaria and €4 M in Slovenia. CONCLUSIONS: There is a high disease burden of HPV-related cancer-related deaths in the CEE region, with a large economic impact to society due to substantial productivity losses. It is critical to implement and reinforce public health measures with the aim to reduce the incidence of HPV-related diseases, and the subsequent premature cancer deaths. Improving HPV screening and increasing vaccination programs, in both male and female populations, could help reduce this burden.

Economic impact analysis of a minimally invasive temperature-controlled radiofrequency device versus nasal surgery for the treatment of nasal airway obstruction in the United States.

OBJECTIVE: To determine the economic impact of a minimally invasive temperature-controlled radiofrequency (TCRF) device for treating nasal airway obstruction (NAO). METHODS: A budget impact model was developed for two scenarios: a reference scenario of functional rhinoplasty surgery with concomitant septoplasty and inferior turbinate reduction (ITR) performed in the hospital outpatient department where TCRF is not an available treatment option and a new scenario consisting of in-office TCRF treatment of the nasal valve and ITR. A payor perspective was adopted with a hypothetical population plan size of one million members. Costs were estimated over a time horizon of 4 years. The eligible population included patients with severe/extreme NAO and nasal valve collapse (NVC) as the primary cause or significant contributor. Data inputs were sourced from targeted literature reviews. Uncertainty within the model structure and input parameters was assessed using one-way sensitivity analysis. RESULTS: The introduction of a TCRF device resulted in population-level cost savings of $20,015,123 and per-responder average cost savings of $3531 through a 4-year time horizon due to lower procedure costs and complication rates of the device relative to the surgical comparator. Results were robust when varying parameter values in sensitivity analyses, with cost savings being most sensitive to the prevalence of NAO and estimated response rates to functional rhinoplasty and TCRF. CONCLUSIONS: In patients with severe/extreme NAO, with NVC as the primary or major contributor, introducing TCRF with ITR as a treatment option demonstrates the potential for significant cost savings over functional rhinoplasty with septoplasty and ITR.

Nasal valve dysfunction is a common cause of nasal airway obstruction (NAO) that has a significant impact on heath and quality of life for affected individuals. Previously, patients were offered temporary measures or a type of surgery called functional rhinoplasty which is a highly complex surgery that can be costly, requires recovery time, and in rare cases, not be successful. Recently, a new minimally invasive treatment alternative for NAO called temperature-controlled radiofrequency (TCRF) that may be performed in a surgery center or a doctor's office has become available. This paper provides the results of budget impact analysis performed to assess whether adding the TCRF procedure in place of surgery as a choice for patients with NAO will result in cost savings to an insurance payer with 1 million covered individuals in the United States over a period of 4 years. Results show that TCRF may result in an average of 9,416 fewer rhinoplasty surgeries, provide an average 4-year cost-savings of $3,531 for every patient that responds to TCRF treatment, and a savings of $20,015,123 over 4 years for the insurance provider. These potential cost savings over 4 years would likely be due to reduced procedure costs and complication rates compared to surgery.

OptoProfilin: A Single Component Biosensor of Applied Cellular Stress.

The actin cytoskeleton is a biosensor of cellular stress and a potential prognosticator of human disease. In particular, aberrant cytoskeletal structures such as stress granules formed in response to energetic and oxidative stress are closely linked to ageing, cancer, cardiovascular disease, and viral infection. Whether these cytoskeletal phenomena can be harnessed for the development of biosensors for cytoskeletal dysfunction and, by extension, disease progression, remains an open question. In this work, we describe the design and development of an optogenetic iteration of profilin, an actin monomer binding protein with critical functions in cytoskeletal dynamics. We demonstrate that this optically activated profilin ('OptoProfilin') can act as an optically triggered biosensor of applied cellular stress in select immortalized cell lines. Notably, OptoProfilin is a single component biosensor, likely increasing its utility for experimentalists. While a large body of preexisting work closely links profilin activity with cellular stress and neurodegenerative disease, this, to our knowledge, is the first example of profilin as an optogenetic biosensor of stress-induced changes in the cytoskeleton.

Optogenetic Regulation of EphA1 RTK Activation and Signaling.

Eph receptors are ubiquitous class of transmembrane receptors that mediate cell-cell communication, proliferation, differentiation, and migration. EphA1 receptors specifically play an important role in angiogenesis, fetal development, and cancer progression; however, studies of this receptor can be challenging as its ligand, ephrinA1, binds and activates several EphA receptors simultaneously. Optogenetic strategies could be applied to circumvent this requirement for ligand activation and enable selective activation of the EphA1 subtype. In this work, we designed and tested several iterations of an optogenetic EphA1 - Cryptochrome 2 (Cry2) fusion, investigating their capacity to mimic EphA1-dependent signaling in response to light activation. We then characterized the key cell signaling target of MAPK phosphorylation activated in response to light stimulation. The optogenetic regulation of Eph receptor RTK signaling without the need for external stimulus promises to be an effective means of controlling individual Eph receptor-mediated activities and creates a path forward for the identification of new Eph-dependent functions.

The discovery of novel and potent indazole NLRP3 inhibitors enabled by DNA-encoded library screening.

NLRP3 is an intracellular sensor protein that detects a broad range of danger signals and environmental insults. Its activation results in a protective pro-inflammatory response designed to impair pathogens and repair tissue damage via the formation of the NLRP3 inflammasome. Assembly of the NLRP3 inflammasome leads to caspase 1-dependent secretory release of the pro-inflammatory cytokines IL-1ß and IL-18 as well as to gasdermin d-mediated pyroptotic cell death. Herein, we describe the discovery of a novel indazole series of high affinity, reversible inhibitors of NLRP3 activation through screening of DNA-encoded libraries and the potent lead compound 3 (BAL-0028, IC50 = 25 nM) that was identified directly from the screen. SPR studies showed that compound 3 binds tightly (KD range 104-123 nM) to the NACHT domain of NLRP3. A CADD analysis of the interaction of compound 3 with the NLRP3 NACHT domain proposes a binding site that is distinct from those of ADP and MCC950 and includes specific site interactions. We anticipate that compound 3 (BAL-0028) and other members of this novel indazole class of neutral inhibitors will demonstrate significantly different physical, biochemical, and biological properties compared to NLRP3 inhibitors previously identified.

Omernik's Ecoregion Framework: a Legacy for Understanding Regional Patterns in Attainable Resource Quality.

An initial and comprehensive map of ecological regions across the conterminous United States was provided by Omernik in 1987. Because that paper was the most-cited published by the Annals of the American Association of Geographers, we sought to assess and quantify its contribution to science. To do so, we conducted a scientometric analysis to address the following main questions: 1) What are the temporal and spatial citation trends? We expected that Omernik's paper would still be employed 36 years after its publication, and mostly in the United States of America. 2) For what types of environments and organisms has it been applied? Based on its generality, we expected that it had been applied to both terrestrial and aquatic ecosystems. 3) What are the main applications of Omernik's article? We predicted that it would mostly be used for describing and delineating study sites and management areas, as well as for selecting regional reference sites. The number of citations presented a positive temporal increase, indicating its continued applicability. Most papers dealt with aquatic environments, mainly in streams carried out predominantly in the United States of America, as was one of its earliest applications. The usefulness of ecoregions for assessing and managing biotic and abiotic patterns and distributions were the main topics addressed by scientists. Ecoregions have offered a general framework for developing regional expectations and rational regional management policies across large areas, as was their original intent. In addition, ecoregion maps were used for communicating patterns-or the lack of them-to interested scientists, citizens, and decision-makers. That comprehensiveness of Omernik's ecoregion approach has led to its widespread applicability and continued usefulness to a diverse set of scientific and management disciplines.

Factors associated with weight loss and health gains in a structured lifestyle modification programme for adults with severe obesity: a prospective cohort study.

Background: Individual responses to behavioural weight loss interventions can vary significantly, and a better understanding of the factors associated with successful treatment might help to target interventions for those who will benefit the most. We sought to identify demographic and clinical characteristics that predicted intervention "success" (defined as ≥5% weight loss) and other health gains in patients with severe obesity attending a ten-week structured lifestyle modification programme. Methods: We conducted a prospective cohort study of all 1122 patients (751 (66.9%) female, mean age 47.3 ± 11.9 years, mean body mass index (BMI) 46.7 ± 7.8 kgm-2) referred from our hospital-based obesity clinic, who started the structured lifestyle programme between 2012-2019. We compared routine clinical measures such as weight, fitness, blood pressure, lipids and HbA1c at baseline and follow-up. We also used validated questionnaires to quantify anxiety, depression and health-related quality of life. Results: Of 1122 patients who started, 877 (78.2%) completed the programme and attended for follow up. Of these, 12.8% lost ≥5% body weight. The amount of weight lost was a strong and consistent predictor of improvements in metabolic, cardiovascular, and mental health, even after adjusting for age, sex, programme attendance and baseline fitness. Older age, male sex, being physically active and having lower anxiety and depression scores at baseline predicted greater weight loss. Younger age, depression and longer wait time to start the intervention were associated with drop-out. Conclusions: In adults with severe obesity completing a structured lifestyle modification programme, older age and good mental health were associated with programme completion and attaining ≥5% weight loss. The magnitude of weight lost was a strong predictor of improvements in cardiovascular, metabolic and mental health associated with programme completion.

OptoProfilin: A Single Component Biosensor of Applied Cellular Stress.

The actin cytoskeleton is a biosensor of cellular stress and a potential prognosticator of human disease. In particular, aberrant cytoskeletal structures such as cofilin-actin rods and stress granules formed in response to energetic and oxidative stress are closely linked to neurodegenerative diseases such as Alzheimer's, Parkinson's, and ALS. Whether these cytoskeletal phenomena can be harnessed for the development of biosensors for cytoskeletal dysfunction and, by extension, neurodegenerative disease progression, remains an open question. In this work, we describe the design and development of an optogenetic iteration of profilin, an actin monomer binding protein with critical functions in cytoskeletal dynamics. We demonstrate that this optically activated profilin ('OptoProfilin') can act as an optically triggered biosensor of applied cellular stress in select immortalized cell lines. Notably, OptoProfilin is a single component biosensor, likely increasing its utility for experimentalists. While a large body of preexisting work closely links profilin activity with cellular stress and neurodegenerative disease, this, to our knowledge, is the first example of profilin as an optogenetic biosensor of stress-induced changes in the cytoskeleton.