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Shape stability is key to avoiding degradation of performance for metallic nanocrystals synthesized with facetted non-equilibrium shapes to optimize properties for catalysis, plasmonics, and so on. Reshaping of facetted nanocrystals is controlled by the surface diffusion-mediated nucleation and growth of new outer layers of atoms. Kinetic Monte Carlo (KMC) simulation of a realistic stochastic atomistic-level model is applied to precisely track the reshaping of Pd octahedra and nanocubes. Unexpectedly, separate constrained equilibrium Monte Carlo analysis of the free energy profile during reshaping reveals a fundamental failure of the classical nucleation theory (CNT) prediction for the reshaping barrier and rate. Why? Nucleation barriers can be relatively low for these processes, so the system is not locally equilibrated before crossing the barrier, as assumed in CNT. This claim is supported by an analysis of a first-passage problem for reshaping within a master equation framework for the model that reasonably captures the behavior in KMC simulations. [ABSTRACT FROM AUTHOR]

Argumentation as the public exchange of reasons is widely thought to enhance deliberative interactions that generate and justify reasonable public policies. Adopting an argumentation-theoretic perspective, we survey the norms that should govern public argumentation and address some of the complexities that scholarly treatments have identified. Our focus is on norms associated with the ideals of correctness and participation as sources of a politically legitimate deliberative outcome. In principle, both ideals are mutually coherent. If the information needed for a correct deliberative outcome is distributed among agents, then maximising participation increases information diversity. But both ideals can also be in tension. If participants lack competence or are prone to biases, a correct deliberative outcome requires limiting participation. The central question for public argumentation, therefore, is how to strike a balance between both ideals. Rather than advocating a preferred normative framework, our main purpose is to illustrate the complexity of this theme. [ABSTRACT FROM AUTHOR]

New strategies are needed to reduce the incidence of malaria, and promising approaches include vaccines targeting the circumsporozoite protein (CSP). To improve upon the malaria vaccine, RTS,S/AS01, it is essential to standardize preclinical assays to measure the potency of next-generation vaccines against this benchmark. We focus on RTS,S/AS01-induced antibody responses and functional activity in conjunction with robust statistical analyses. Transgenic Plasmodium berghei sporozoites containing full-length P. falciparum CSP (tgPb-PfCSP) allow two assessments of efficacy: quantitative reduction in liver infection following intravenous challenge, and sterile protection from mosquito bite challenge. Two or three doses of RTS,S/AS01 were given intramuscularly at 3-week intervals, with challenge 2-weeks after the last vaccination. Minimal inter- and intra-assay variability indicates the reproducibility of the methods. Importantly, the range of this model is suitable for screening more potent vaccines. Levels of induced anti-CSP antibody 2A10 equivalency were also associated with activity: 105 μg/mL (95% CI: 68.8, 141) reduced liver infection by 50%, whereas 285 μg/mL (95% CI: 166, 404) is required for 50% sterile protection from mosquito bite challenge. Additionally, the liver burden model was able to differentiate between protected and non-protected human plasma samples from a controlled human malaria infection study, supporting these models' relevance and predictive capability. Comparison in animal models of CSP-based vaccine candidates to RTS,S/AS01 is now possible under well controlled conditions. Assessment of the quality of induced antibodies, likely a determinant of durability of protection in humans, should be possible using these methods. [ABSTRACT FROM AUTHOR]

Background: Core temperature changes during obstetric spinal anaesthesia are likely underestimated because monitoring is challenging and often not performed. This study aimed to describe the incidence and severity of perioperative hypothermia in patients undergoing caesarean delivery under spinal anaesthesia in a resource-limited setting. Methods: We performed a prospective observational study of parturients undergoing either elective or emergency caesarean delivery under spinal anaesthesia in a South African regional hospital. We used dual-sensor heat flux technology to monitor their core temperature during the perioperative period. The primary outcome was the incidence of clinically relevant hypothermia (defined as core temperature decrease from baseline of > 1 °C) following spinal anaesthesia. Smoothing splines were used to estimate maximum changes in core temperature. Results: We included 166 patients in our analysis. A decrease of > 1 °C occurred in 49% of participants (95% CI 40-63%) while hypothermia (temperature < 36 °C) occurred in 67% (49-78%). Discharge from recovery room with core temperature < 35 °C occurred in 26% (20-34%) of the participants. There was a higher incidence of vomiting in those participants who experienced temperature decreases of > 1 °C (18% vs 6%, p = 0.03). Conclusion: In this resource-constrained environment, clinically relevant hypothermia during obstetric spinal anaesthesia occurred in half of participants. Hypothermia was often severe and participants did not recover by the time of discharge from anaesthesia care. Monitoring of a patient's core temperature should be a standard of care, and further research into the clinical impact of perioperative hypothermia and warming strategies in these settings is warranted. [ABSTRACT FROM AUTHOR]

Malaria transmission-blocking vaccines (TBVs) aim to induce antibodies that block Plasmodium parasite development in the mosquito midgut, thus preventing mosquitoes from becoming infectious. While the Pro-domain and first of fourteen 6-Cysteine domains (Pro-D1) of the Plasmodium gamete surface protein Pfs230 are known targets of transmission-blocking antibodies, no studies to date have discovered other Pfs230 domains that are functional targets. Here, we show that a murine monoclonal antibody (mAb), 18F25.1, targets Pfs230 Domain 7. We generated a subclass-switched complement-fixing variant, mAb 18F25.2a, using a CRISPR/Cas9-based hybridoma engineering method. This subclass-switched mAb 18F25.2a induced lysis of female gametes in vitro. Importantly, mAb 18F25.2a potently reduced P. falciparum infection of Anopheles stephensi mosquitoes in a complementdependent manner, as assessed by standard membrane feeding assays. Together, our data identify Pfs230 Domain 7 as target for transmission-blocking antibodies and provide a strong incentive to study domains outside Pfs230Pro-D1 as TBV candidates. [ABSTRACT FROM AUTHOR]

Preprocessing fMRI data requires striking a fine balance between conserving signals of interest and removing noise. Typical steps of preprocessing include motion correction, slice timing correction, spatial smoothing, and high‐pass filtering. However, these standard steps do not remove many sources of noise. Thus, noise‐reduction techniques, for example, CompCor, FIX, and ICA‐AROMA have been developed to further improve the ability to draw meaningful conclusions from the data. The ability of these techniques to minimize noise while conserving signals of interest has been tested almost exclusively in resting‐state fMRI and, only rarely, in task‐related fMRI. Application of noise‐reduction techniques to task‐related fMRI is particularly important given that such procedures have been shown to reduce false positive rates. Little remains known about the impact of these techniques on the retention of signal in tasks that may be associated with systemic physiological changes. In this paper, we compared two ICA‐based, that is FIX and ICA‐AROMA, two CompCor‐based noise‐reduction techniques, that is aCompCor, and tCompCor, and standard preprocessing using a large (n = 101) fMRI dataset including noxious heat and non‐noxious auditory stimulation. Results show that preprocessing using FIX performs optimally for data obtained using noxious heat, conserving more signals than CompCor‐based techniques and ICA‐AROMA, while removing only slightly less noise. Similarly, for data obtained during non‐noxious auditory stimulation, FIX noise‐reduction technique before analysis with a covariate of interest outperforms the other techniques. These results indicate that FIX might be the most appropriate technique to achieve the balance between conserving signals of interest and removing noise during task‐related fMRI. [ABSTRACT FROM AUTHOR]

All-trans-retinoic acid (ATRA), the retinoic acid receptors (RARs) agonist, regulates cell growth, differentiation, immunity, and survival. We report that ATRA-treatment repressed cancer growth in syngeneic immunocompetent, but not immunodeficient mice. The tumor microenvironment was implicated: CD8+ T cell depletion antagonized ATRA's anti-tumorigenic effects in syngeneic mice. ATRA-treatment with checkpoint blockade did not cooperatively inhibit murine lung cancer growth. To augment ATRA's anti-tumorigenicity without promoting its pro-tumorigenic potential, an RARγ agonist (IRX4647) was used since it regulates T cell biology. Treating with IRX4647 in combination with an immune checkpoint (anti-PD-L1) inhibitor resulted in a statistically significant suppression of syngeneic 344SQ lung cancers in mice—a model known for its resistance to checkpoints and characterized by low basal T cell and PD-L1 expression. This combined treatment notably elevated CD4+ T-cell presence within the tumor microenvironment and increased IL-5 and IL-13 tumor levels, while simultaneously decreasing CD38 in the tumor stroma. IL-5 and/or IL-13 treatments increased CD4+ more than CD8+ T-cells in mice. IRX4647-treatment did not appreciably affect in vitro lung cancer growth, despite RARγ expression. Pharmacokinetic analysis found IRX4647 plasma half-life was 6 h in mice. Yet, RARα antagonist (IRX6696)-treatment with anti-PD-L1 did not repress syngeneic lung cancer growth. Together, these findings provide a rationale for a clinical trial investigating an RARγ agonist to augment check point blockade response in cancers. [ABSTRACT FROM AUTHOR]

All-trans-retinoic acid (ATRA), the retinoic acid receptors (RARs) agonist, regulates cell growth, differentiation, immunity, and survival. We report that ATRA-treatment repressed cancer growth in syngeneic immunocompetent, but not immunodeficient mice. The tumor microenvironment was implicated: CD8+ T cell depletion antagonized ATRA's anti-tumorigenic effects in syngeneic mice. ATRA-treatment with checkpoint blockade did not cooperatively inhibit murine lung cancer growth. To augment ATRA's anti-tumorigenicity without promoting its pro-tumorigenic potential, an RARγ agonist (IRX4647) was used since it regulates T cell biology. Treating with IRX4647 in combination with an immune checkpoint (anti-PD-L1) inhibitor resulted in a statistically significant suppression of syngeneic 344SQ lung cancers in mice—a model known for its resistance to checkpoints and characterized by low basal T cell and PD-L1 expression. This combined treatment notably elevated CD4+ T-cell presence within the tumor microenvironment and increased IL-5 and IL-13 tumor levels, while simultaneously decreasing CD38 in the tumor stroma. IL-5 and/or IL-13 treatments increased CD4+ more than CD8+ T-cells in mice. IRX4647-treatment did not appreciably affect in vitro lung cancer growth, despite RARγ expression. Pharmacokinetic analysis found IRX4647 plasma half-life was 6 h in mice. Yet, RARα antagonist (IRX6696)-treatment with anti-PD-L1 did not repress syngeneic lung cancer growth. Together, these findings provide a rationale for a clinical trial investigating an RARγ agonist to augment check point blockade response in cancers. [ABSTRACT FROM AUTHOR]

Context: Streams on subantarctic Macquarie Island were first sampled for freshwater invertebrates in 1992 when rabbit numbers were low. Then an average 11.6 taxa per site were recorded. Between 2000 and 2011, vegetation was overgrazed as rabbit numbers increased. In 2008 and 2010, 7.4–8.4 taxa per site were recorded, abundance of most taxa had decreased and greatest compositional changes occurred at sites exposed to moderate or severe vegetation damage. Rabbits were eradicated in 2011 and substantial regrowth of vegetation was evident by 2016. Aims: Sites were resampled in 2016 to determine the extent to which the invertebrate communities had changed after rabbit removal. Methods: In all, 13 of the original 15 sites sampled in 1992 were resampled. Five kick samples were taken at each site. Key results: Mean taxon richness (8.2 taxa per site) and community composition at individual sites remained, in 2016, very similar to that recorded in 2008 and 2010 when the island was heavily grazed. Conclusions: Recovery of stream invertebrate communities appeared to be slow, possibly because few refuges were available. Minor changes in climate and water quality did not influence recovery. Implications: Stream invertebrate communities could take a decade or more to recover. Species richness and community composition of stream invertebrates in 2016, after rabbits were eradicated from Macquarie Island in 2011, remain unchanged from what was observed in 2008 and 2010. Recovery and recolonisation appear slow, possibly because few refuges are available. Stream invertebrate communities could take a decade or more to recover. [ABSTRACT FROM AUTHOR]

This document is a reply to a letter written by S. Gim et al. regarding a study on interindividual differences in pain. The authors of the reply express gratitude for the interest in their manuscript and acknowledge the potential impact it may have on the use of BOLD to study pain mechanisms. They clarify that their study focused on identifying brain mechanisms of interindividual differences in pain and did not aim to predict pain using sociodemographic and psychological factors. The authors also discuss the differences between their findings and those of Gim et al., highlighting the limitations of BOLD activation studies in understanding chronic pain. They emphasize the need for new approaches to better comprehend the complex mechanisms associated with chronic pain. [Extracted from the article]

OBJECTIVE To examine the psychological impact of lockdown due to the COVID-19 pandemic on the university community in Greece and Cyprus. METHOD A cross-sectional study was conducted, with a total sample of 308 faculty and students. Mental health was evaluated with the Hospital Anxiety and Depression Scale (HADS), while the EQ-5D-L was used to assess quality of life. Changes in habits like smoking and drinking were also examined. In addition, the relation between mental health and physical health (as measured with the McGill Pain Questionnaire [SF-MP]) was studied. Various statistical tests (mostly non-parametric) were implemented. RESULTS During lockdown, the members of the academic community switched to online education and experienced a restriction of indoor and outdoor activities. Overall, caffeine consumption increased (p=0.024), while alcohol consumption reduced (p<0.001). Most participants had normal levels of anxiety and depression; however 17% were classified as abnormal cases. Those with high levels of anxiety experienced high levels of depression (p<0.001). Increasing smoking was related to higher anxiety (p=0.027). Higher pain intensity was also significantly related with higher levels of mental health problems (all p<0.05). The quality of life was satisfactory. However, those with higher pain intensity, as well as those with changes in daily habits, such as smoking, had significantly lower quality of life (p<0.05). CONCLUSIONS Lockdown periods due to the COVID-19 pandemic appear to have had a negative effect on the university community. The change in work routine and daily habits and restrictions of activities were associated with psychological consequences and mental distress, including anxiety and depression. Mental health issues lower the general quality of life and thus special attention should be given to self-care or targeted interventions for groups at risk. [ABSTRACT FROM AUTHOR]

Background: Mobile technology offers unique opportunities for monitoring short-term suicide risk in daily life. In this study of suicidal adolescent inpatients, theoretically informed risk factors were assessed daily following discharge to predict near-term suicidal ideation and inform decision algorithms for identifying elevations in daily level risk, with implications for real-time suicide-focused interventions. Methods: Adolescents (N = 78; 67.9% female) completed brief surveys texted daily for 4 weeks after discharge (n = 1621 observations). Using multi-level classification and regression trees (CARTSs) with repeated 5-fold cross-validation, we tested (a) a simple prediction model incorporating previous-day scores for each of 10 risk factors, and (b) a more complex model incorporating, for each of these factors, a time-varying person-specific mean over prior days together with deviation from that mean. Models also incorporated missingness and contextual (study week, day of the week) indicators. The outcome was the presence/absence of next-day suicidal ideation. Results: The best-performing model (cross-validated AUC = 0.86) was a complex model that included ideation duration, hopelessness, burdensomeness, and self-efficacy to refrain from suicidal action. An equivalent model that excluded ideation duration had acceptable overall performance (cross-validated AUC = 0.78). Models incorporating only previous-day scores, with and without ideation duration (cross-validated AUC of 0.82 and 0.75, respectively), showed relatively weaker performance. Conclusions: Results suggest that specific combinations of dynamic risk factors assessed in adolescents' daily life have promising utility in predicting next-day suicidal thoughts. Findings represent an important step in the development of decision tools identifying short-term risk as well as guiding timely interventions sensitive to proximal elevations in suicide risk in daily life. [ABSTRACT FROM AUTHOR]

The Gelfand representation of S n is the multiplicity-free direct sum of the irreducible representations of S n . In this paper, we use a result of Adin, Postnikov, and Roichman to find a generating function for the Gelfand character. In order to find this generating function, we investigate descents of so-called λ -unimodal involutions. [ABSTRACT FROM AUTHOR]

Background: Concerns have been raised about the utility of self-report assessments in predicting future suicide attempts. Clinicians in pediatric emergency departments (EDs) often are required to assess suicidal risk. The Death Implicit Association Test (IAT) is an alternative to self-report assessment of suicidal risk that may have utility in ED settings. Methods: A total of 1679 adolescents recruited from 13 pediatric emergency rooms in the Pediatric Emergency Care Applied Research Network were assessed using a self-report survey of risk and protective factors for a suicide attempt, and the IAT, and then followed up 3 months later to determine if an attempt had occurred. The accuracy of prediction was compared between self-reports and the IAT using the area under the curve (AUC) with respect to receiver operator characteristics. Results: A few self-report variables, namely, current and past suicide ideation, past suicidal behavior, total negative life events, and school or social connectedness, predicted an attempt at 3 months with an AUC of 0.87 [95% confidence interval (CI), 0.84–0.90] in the entire sample, and AUC = 0.91, (95% CI 0.85–0.95) for those who presented without reported suicidal ideation. The IAT did not add significantly to the predictive power of selected self-report variables. The IAT alone was modestly predictive of 3-month attempts in the overall sample ((AUC = 0.59, 95% CI 0.52–0.65) and was a better predictor in patients who were non-suicidal at baseline (AUC = 0.67, 95% CI 0.55–0.79). Conclusions: In pediatric EDs, a small set of self-reported items predicted suicide attempts within 3 months more accurately than did the IAT. [ABSTRACT FROM AUTHOR]

Background: Field hockey has a high risk for sports-related concussion (SRC) injuries due to the speed and intensity of the game, current rules, field surfaces and equipment composition. Head injuries are the second most common reported injury and up to 75% of SRCs go unreported or undetected. This increases the subsequent injury risk, longterm health consequences and prolonged injury recovery. Objectives: This study aimed to examine the prevalence of SRC in hockey players within the Southern Gauteng Hockey Association (SGHA) premier league. Concussion knowledge and attitudes of hockey players, coaches, umpires, and officials were also investigated. Methods: A partially mixed sequential dominant status design (QUANT–qual) was used, divided into two phases. In Phase One hockey players, coaches, umpires, and technical officials (n=119) completed a modified RoCKAS-ST questionnaire. In Phase Two, a focus group discussion with umpires (n=3) and interviews with coaches (n=3) were conducted. Results: Injuries to the shoulder, neck, head, and face were reported from stick use (n=98); ball use (n=102) and collisions (n=187). Only 19% of hockey players were diagnosed with SRC, indicating that many of these injuries were undetected or not reported. Responses from the focus group discussion and interviews indicated that coaches, umpires, and officials felt they had insufficient knowledge of SRC. Conclusion: The recognition and management of on-field injuries require improvement to enhance the injury detection system. [ABSTRACT FROM AUTHOR]

OBJECTIVE To evaluate the impact of lockdown on pain and stiffness, associated with changes in daily habits, work routine and activities, in the academic community in Greece and Cyprus. METHOD A cross-sectional study was conducted with 308 university faculty members and students. Pain was measured with the short form McGill Pain Questionnaire (SF-MPQ), and pain intensity, stiffness, daily activities and work routine changes were assessed. RESULTS Daily habits and work routine changed during lockdown, with an increase in sedentary mode, and the changes were significantly related to pain (p<0.05). Most participants reported stiffness, especially after prolonged sitting, which was reduced when they exercised, especially with walking or running (p=0.013). Pain was significantly greater during lockdown (p<0.001), primarily in the back and neck, but also in the form of headache/migraines. The respondents perceived their pain mainly as “tiring-exhausting”. Sitting for long hours significantly increased pain intensity (mean score=4.35, on a scale from 1 to 6). CONCLUSIONS Working from home indirectly forces university faculty members and students into a sedentary lifestyle. Online teaching and learning entail prolonged sitting in front of the computer, which is associated with bad sitting postures, disturbed sleep habits and long periods of physical inactivity. These are related to stiffness and pain, especially in the back, neck and head. As the pandemic continues and distance learning is expected to remain as an alternative mode in universities, even after the pandemic, emphasis should be given to the occupational health of people in the academic community. Intervention strategies are needed to prevent chronic musculoskeletal problems, with promotion of awareness of ergonomic training and ergonomic working arrangements at home, and encouragement of physical exercise of any type, especially walking or running. [ABSTRACT FROM AUTHOR]

The aim of this study was to explore provider practices and attitudes towards routine follow-up counselling after prescription of contraceptives. An anonymous 16-item survey was pilot-tested and sent to providers of the Internal Medicine, Family Medicine, Pediatrics, and OBGYN departments of Thomas Jefferson University Hospitals (TJUH), an urban academic medical centre in Philadelphia, PA, USA. Frequency and descriptive statistics were used to analyse quantitative data while a framework analysis approach was applied to open-ended questions. Fifty percent of providers said they typically follow up with patients regarding a newly prescribed contraceptive. Only 15.3% said they do for an existing prescription. Eighty-three percent reported that it is important though only 30% believed follow-up guidelines were clear. Ultimately, there is a gap between providers' interest in delivering follow-up care and established direction on how to do so. What is already known on the subject? Prescription contraceptive adherence is suboptimal. However, it is known that proactive follow-up has positive effects on prescription contraceptive adherence. What do the results of the study add? Most respondents believe that patients take their prescription contraception as prescribed. In light of this finding, providers are less likely to follow up with an existing prescription contraceptive. Interestingly, most respondents do believe that follow-up is important for patients using prescribed contraception but endorse that guidelines about follow-up are neither established nor clear. What are the implications of these findings for clinical practice and/or further research? Patient adherence to prescription contraceptives can be improved through optimised routine patient follow-up after initial prescription. This must be done in ways that minimise burdens to both patients and providers. Providers could benefit from clear guidelines regarding best practices. Future research is needed to understand how providers can best support patients on their contraceptive journey. [ABSTRACT FROM AUTHOR]

This article, published in the journal Colorectal Disease, discusses laparoscopic low anterior resection as a surgical treatment for deeply infiltrating endometriosis. The authors explain that intestinal endometriosis is commonly found in the upper rectum and lower sigmoid colon, and that the rectovaginal septum is often affected. They describe the preparation for surgery, the critical steps involved in the procedure, and the testing of the anastomosis. The authors also state that they have no conflicts of interest and that the data supporting their findings are available in the supplementary material of the article. [Extracted from the article]

A vaccine targeting multiple stages of the Plasmodium falciparum parasite life cycle is desirable. The sporozoite surface Circumsporozoite Protein (CSP) is the target of leading anti-infective P. falciparum pre-erythrocytic vaccines. Pfs230, a sexual-stage P. falciparum surface protein, is currently in trials as the basis for a transmission-blocking vaccine, which inhibits parasite development in the mosquito vector. Here, recombinant full-length CSP and a Pfs230 fragment (Pfs230D1+) are co-displayed on immunogenic liposomes to induce immunity against both infection and transmission. Liposomes contain cobalt-porphyrin phospholipid (CoPoP), monophosphoryl lipid A and QS-21, and rapidly bind His-tagged CSP and Pfs230D1+ upon admixture to form bivalent particles that maintain reactivity with conformational monoclonal antibodies. Use of multicolor fluorophore-labeled antigens reveals liposome binding upon admixture, stability in serum and enhanced uptake in murine macrophages in vitro. Bivalent liposomes induce humoral and cellular responses against both CSP and Pfs230D1+. Vaccine-induced antibodies reduce parasite numbers in mosquito midguts in a standard membrane feeding assay. Mice immunized with liposome-displayed antigens or that passively receive antibodies from immunized rabbits have reduced parasite liver burden following challenge with transgenic sporozoites expressing P. falciparum CSP. Co-display of two P. falciparum malaria vaccine antigens (Pfs230D1+ and CSP) on the surface of immunogenic liposomes results in functional immune responses upon immunization of mice and rabbits. Combining both antigens produces immune responses that both block transmission and prevent infection. [ABSTRACT FROM AUTHOR]

Rotator cuff related shoulder pain (RCRSP) is a common and disabling shoulder condition and surgical management is becoming more common. The rates and costs of surgical interventions have been on the rise. Understanding decision-making related to surgery and providing adequate information to people with RCRSP may improve patient-centred care and potentially reduce rates of surgery. To explore the decision-making processors of people who have undertaken surgery for RCRSP. An in-depth thematic analysis. Interviews were conducted with patients from Melbourne who had had surgical management for RCRSP. Data were analysed using an inductive thematic approach. Fifteen participants were recruited. Six key themes emerged: (1) Needing to get it done: "It was necessary to remedy the dire situation"; (2) Non-surgical treatment experience:" I knew that I'd done all I could"; (3) Mechanical problem:" Physio's not going to repair a torn tendon"; (4) Trust in medical professionals "If they told me that I needed to swallow a thousand spiders, I would have done it."; (5) Varied information sources "Dr Google played a big part in it"; (6) Organisational barriers "It was absolutely useless, my insurance." Surgery appears to be commonly precipitated by unremitted severe symptoms and failed non-surgical treatment. While there was strong trust in highly trained surgeons, decision to undergo surgery also drew on questionable pathoanatomical beliefs and instances of inadequate patient information about treatment choices and risks that may be addressed by adopting a more patient-centred care approach. Understanding decision-making related to surgery and providing adequate information to people with rotator cuff related shoulder pain may improve patient-centred care. Surgery appears to be commonly precipitated by unremitted severe symptoms and failed non-surgical treatment. Decision to undergo surgery sometimes drew on questionable pathoanatomical beliefs. There was strong trust in highly trained surgeons but there were instances of inadequate patient information about treatment choices and risks. [ABSTRACT FROM AUTHOR]

Pain is an individual experience. Previous studies have highlighted changes in brain activation and morphology associated with within- and interindividual pain perception. In this study we sought to characterize brain mechanisms associated with between-individual differences in pain in a sample of healthy adolescent and adult participants (N = 101). Here we show that pain ratings varied widely across individuals and that individuals reported changes in pain evoked by small differences in stimulus intensity in a manner congruent with their pain sensitivity, further supporting the utility of subjective reporting as a measure of the true individual experience. Furthermore, brain activation related to interindividual differences in pain was not detected, despite clear sensitivity of the Blood Oxygenation Level-Dependent (BOLD) signal to small differences in noxious stimulus intensities within individuals. These findings suggest fMRI may not be a useful objective measure to infer reported pain intensity. Previous work had suggested that fMRI measures can be used as a marker of pain experience. Here the authors find no evidence for a link between perceived pain intensity and fMRI activation. [ABSTRACT FROM AUTHOR]

The dynamics of nanoscale clusters can be distinct from macroscale behavior described by continuum formalisms. For diffusion of 2D clusters of N atoms in homoepitaxial systems mediated by edge atom hopping, macroscale theory predicts simple monotonic size scaling of the diffusion coefficient, DN - Nβ , with β = 3/2. However, modeling for nanoclusters on metal(100) surfaces reveals that slow nucleation-mediated diffusion displaying weak size scaling β < 1 occurs for "perfect" sizes Np = L2 and L(L+1) for integer L = 3,4,. . . (with unique square or near-square ground state shapes) and also for Np+3, Np+4,. . . . In contrast, fast facile nucleation-free diffusion displaying strong size scaling β≈2.5 occurs for sizesNp+1 andNp+2.DN versusNoscillates strongly between the slowest branch (for Np+3) and the fastest branch (for Np+1). All branches merge for N = O(102), but macroscale behavior is only achieved for much larger N = O(103). This analysis reveals the unprecedented diversity of behavior on the nanoscale. [ABSTRACT FROM AUTHOR]

Potent and durable vaccine responses will be required for control of malaria caused by Plasmodium falciparum (Pf). RTS,S/AS01 is the first, and to date, the only vaccine that has demonstrated significant reduction of clinical and severe malaria in endemic cohorts in Phase 3 trials. Although the vaccine is protective, efficacy declines over time with kinetics paralleling the decline in antibody responses to the Pf circumsporozoite surface protein (PfCSP). Although most attention has focused on antibodies to repeat motifs on PfCSP, antibodies to other regions may play a role in protection. Here, we expressed and characterized seven monoclonal antibodies to the C-terminal domain of CSP (ctCSP) from volunteers immunized with RTS,S/AS01. Competition and crystal structure studies indicated that the antibodies target two different sites on opposite faces of ctCSP. One site contains a polymorphic region (denoted α-ctCSP) and has been previously characterized, whereas the second is a previously undescribed site on the conserved β-sheet face of the ctCSP (denoted β-ctCSP). Antibodies to the β-ctCSP site exhibited broad reactivity with a diverse panel of ctCSP peptides whose sequences were derived from field isolates of P. falciparum whereas antibodies to the α-ctCSP site showed very limited cross reactivity. Importantly, an antibody to the β-site demonstrated inhibition activity against malaria infection in a murine model. This study identifies a previously unidentified conserved epitope on CSP that could be targeted by prophylactic antibodies and exploited in structure-based vaccine design. Author summary: The most advanced malaria vaccine candidate to date, RTS,S, is composed of the central repeat region, so called because it consists of repeats of the NANP amino-acid sequence, and the C-terminal domain from the Plasmodium falciparum circumsporozoite protein (PfCSP). RTS,S is about 50% effective against the liver stage of the malaria parasite, but its efficacy decreases over time, concomitant with waning of antibodies that target PfCSP. Thus, further understanding of which antibodies are effective in the immune response to PfCSP is needed to facilitate design of next-generation malaria vaccines. While much is known about antibodies to the NANP repeat region, the nature and efficacy of antibodies that target the PfCSP C-terminal domain (ctCSP) is underexplored. Here, we characterize antibodies against ctCSP that were derived from volunteers in a phase 2a trial of RTS,S with a fractional dose regimen. We find that some antibodies bind to a previously identified polymorphic site on ctCSP, but others bind to a novel site that is highly conserved across different P. falciparum isolates. Furthermore, these antibodies show protection against P. falciparum infection in a mouse model. Thus, a previously unidentified and conserved site on ctCSP can be targeted by antibodies and will aid in design of more effective next-generation PfCSP-based malaria vaccines and therapeutics. [ABSTRACT FROM AUTHOR]

As people, animals and materials are transported across increasingly large distances in a globalized world, threats to our biosecurity and food security are rising. Aotearoa New Zealand is an island nation with many endemic species, a strong local agricultural industry, and a need to protect these from pest threats, as well as the economy from fraudulent commodities. Mitigation of such threats is much more effective if their origins and pathways for entry are understood. We propose that this may be addressed in Aotearoa using strontium isotope analysis of both pests and products. Bioavailable radiogenic isotopes of strontium are ubiquitous markers of provenance that are increasingly used to trace the origin of animals and plants as well as products, but currently a baseline map across Aotearoa is lacking, preventing use of this technique. Here, we have improved an existing methodology to develop a regional bioavailable strontium isoscape using the best available geospatial datasets for Aotearoa. The isoscape explains 53% of the variation (R2 = 0.53 and RMSE = 0.00098) across the region, for which the primary drivers are the underlying geology, soil pH, and aerosol deposition (dust and sea salt). We tested the potential of this model to determine the origin of cow milk produced across Aotearoa. Predictions for cow milk (n = 33) highlighted all potential origin locations that share similar 87Sr/86Sr values, with the closest predictions averaging 7.05 km away from their true place of origin. These results demonstrate that this bioavailable strontium isoscape is effective for tracing locally produced agricultural products in Aotearoa. Accordingly, it could be used to certify the origin of Aotearoa's products, while also helping to determine if new pest detections were of locally breeding populations or not, or to raise awareness of imported illegal agricultural products. [ABSTRACT FROM AUTHOR]

Both neuronal and genetic mechanisms regulate brain function. While there are excellent methods to study neuronal activity in vivo, there are no nondestructive methods to measure global gene expression in living brains. Here, we present a method, epigenetic MRI (eMRI), that overcomes this limitation via direct imaging of DNA methylation, a major gene-expression regulator. eMRI exploits the methionine metabolic pathways for DNA methylation to label genomic DNA through 13C-enriched diets. A 13C magnetic resonance spectroscopic imaging method then maps the spatial distribution of labeled DNA. We validated eMRI using pigs, whose brains have stronger similarity to humans in volume and anatomy than rodents, and confirmed efficient 13C-labeling of brain DNA. We also discovered strong regional differences in global DNA methylation. Just as functional MRI measurements of regional neuronal activity have had a transformational effect on neuroscience, we expect that the eMRI signal, both as a measure of regional epigenetic activity and as a possible surrogate for regional gene expression, will enable many new investigations of human brain function, behavior, and disease. [ABSTRACT FROM AUTHOR]

Humpback whales (Megaptera novaeangliae) exhibit maternally driven fidelity to feeding grounds, and yet occasionally occupy new areas. Humpback whale sightings and mortalities in the New York Bight apex (NYBA) have been increasing over the last decade, providing an opportunity to study this phenomenon in an urban habitat. Whales in this area overlap with human activities, including busy shipping traffic leading into the Port of New York and New Jersey. The site fidelity, population composition and demographics of individual whales were analysed to better inform management in this high-risk area. Whale watching and other opportunistic data collections were used to identify 101 individual humpback whales in the NYBA from spring through autumn, 2012–2018. Although mean occurrence was low (2.5 days), mean occupancy was 37.6 days, and 31.3% of whales returned from one year to the next. Individuals compared with other regional and ocean-basin-wide photo-identification catalogues (N = 52) were primarily resighted at other sites along the US East Coast, including the Gulf of Maine feeding ground. Sightings of mother-calf pairs were rare in the NYBA, suggesting that maternally directed fidelity may not be responsible for the presence of young whales in this area. Other factors including shifts in prey species distribution or changes in population structure more broadly should be investigated. [ABSTRACT FROM AUTHOR]

Mechanophores are molecular motifs that respond to mechanical perturbance with targeted chemical reactions toward desirable changes in material properties. A large variety of mechanophores have been investigated, with applications focusing on functional materials, such as strain/stress sensors, nanolithography, and selfhealing polymers, among others. The responses of engineered mechanophores, such as light emittance, change in fluorescence, and generation of free radicals (FRs), have potential for bioimaging and therapy. However, the biomedical applications of mechanophores are not well explored. Herein, we report an in vitro demonstration of an FR-generating mechanophore embedded in biocompatible hydrogels for noninvasive cancer therapy. Controlled by high-intensity focused ultrasound (HIFU), a clinically proven therapeutic technique, mechanophores were activated with spatiotemporal precision to generate FRs that converted to reactive oxygen species (ROS) to effectively kill tumor cells. The mechanophore hydrogels exhibited no cytotoxicity under physiological conditions. Upon activation with HIFU sonication, the therapeutic efficacies in killing in vitro murine melanoma and breast cancer tumor cells were comparable with lethal doses of H2O2. This process demonstrated the potential for mechanophoreintegrated HIFU combination as a noninvasive cancer treatment platform, named "mechanochemical dynamic therapy" (MDT). MDT has two distinct advantages over other noninvasive cancer treatments, such as photodynamic therapy (PDT) and sonodynamic therapy (SDT). 1) MDT is ultrasound based, with larger penetration depth than PDT. 2) MDT does not rely on sonosensitizers or the acoustic cavitation effect, both of which are necessary for SDT. Taking advantage of the strengths of mechanophores and HIFU, MDT can provide noninvasive treatments for diverse cancer types. [ABSTRACT FROM AUTHOR]

Pfs230 is a leading malaria transmission blocking vaccine (TBV) candidate. Comprising 3135 amino acids (aa), the large size of Pfs230 necessitates the use of sub-fragments as vaccine immunogens. Therefore, determination of which regions induce functional antibody responses is essential. We previously reported that of 27 sub-fragments spanning the entire molecule, only five induced functional antibodies. A "functional" antibody is defined herein as one that inhibits Plasmodium falciparum parasite development in mosquitoes in a standard membrane-feeding assay (SMFA). These five sub-fragments were found within the aa 443–1274 range, and all contained aa 543–730. Here, we further pinpoint the location of epitopes within Pfs230 that are recognized by functional antibodies using antibody depletion and enrichment techniques. Functional epitopes were not found within the aa 918–1274 region. Within aa 443–917, further analysis showed the existence of functional epitopes not only within the aa 543–730 region but also outside of it. Affinity-purified antibodies using a synthetic peptide matching aa 543–588 showed activity in the SMFA. Immunization with a synthetic peptide comprising this segment, formulated either as a carrier-protein conjugate vaccine or with a liposomal vaccine adjuvant system, induced antibodies in mice that were functional in the SMFA. These findings provide key insights for Pfs230-based vaccine design and establish the feasibility for the use of synthetic peptide antigens for a malaria TBV. [ABSTRACT FROM AUTHOR]

Metaplastic breast carcinoma (MBC) is a rare breast cancer subtype with rapid growth, high rates of metastasis, recurrence and drug resistance, and diverse molecular and histological heterogeneity. Patient-derived xenografts (PDXs) provide a translational tool and physiologically relevant system to evaluate tumor biology of rare subtypes. Here, we provide an in-depth comprehensive characterization of a new PDX model for MBC, TU-BcX-4IC. TU-BcX-4IC is a clinically aggressive tumor exhibiting rapid growth in vivo, spontaneous metastases, and elevated levels of cell-free DNA and circulating tumor cell DNA. Relative chemosensitivity of primary cells derived from TU-BcX-4IC was performed using the National Cancer Institute (NCI) oncology drug set, crystal violet staining, and cytotoxic live/dead immunofluorescence stains in adherent and organoid culture conditions. We employed novel spheroid/organoid incubation methods (Pu·MA system) to demonstrate that TU-BcX-4IC is resistant to paclitaxel. An innovative physiologically relevant system using human adipose tissue was used to evaluate presence of cancer stem cell-like populations ex vivo. Tissue decellularization, cryogenic-scanning electron microscopy imaging and rheometry revealed consistent matrix architecture and stiffness were consistent despite serial transplantation. Matrix-associated gene pathways were essentially unchanged with serial passages, as determined by qPCR and RNA sequencing, suggesting utility of decellularized PDXs for in vitro screens. We determined type V collagen to be present throughout all serial passage of TU-BcX-4IC tumor, suggesting it is required for tumor maintenance and is a potential viable target for MBC. In this study we introduce an innovative and translational model system to study cell–matrix interactions in rare cancer types using higher passage PDX tissue. [ABSTRACT FROM AUTHOR]

Proteasome substrate receptor hRpn13 is a promising anti-cancer target. By integrated in silico and biophysical screening, we identified a chemical scaffold that binds hRpn13 with non-covalent interactions that mimic the proteasome and a weak electrophile for Michael addition. hRpn13 Pru domain binds proteasomes and ubiquitin whereas its DEUBAD domain binds deubiquitinating enzyme UCHL5. NMR revealed lead compound XL5 to interdigitate into a hydrophobic pocket created by lateral movement of a Pru β-hairpin with an exposed end for Proteolysis Targeting Chimeras (PROTACs). Implementing XL5-PROTACs as chemical probes identified a DEUBAD-lacking hRpn13 species (hRpn13Pru) present naturally with cell type-dependent abundance. XL5-PROTACs preferentially target hRpn13Pru, causing its ubiquitination. Gene-editing and rescue experiments established hRpn13 requirement for XL5-PROTAC-triggered apoptosis. These data establish hRpn13 as an anti-cancer target for multiple myeloma and introduce an hRpn13-targeting scaffold that can be optimized for preclinical trials against hRpn13Pru-producing cancer types. Rpn13 is a substrate receptor of the 26S proteasome and an anti-cancer drug target. Here, the authors identify and characterize XL5, a lead compound that binds to the N-terminal Pru domain of human Rpn13 (hRpn13), solve the NMR structure of XL5-ligated hRpn13 Pru and develop XL5-PROTACs that preferentially target an identified hRpn13 Pru fragment present in multiple myeloma cells. [ABSTRACT FROM AUTHOR]

Postoperative hypotension is common (occurring in one third of patients) and is associated with worse clinical outcomes. The LiDCO CNAP (continuous non-invasive arterial pressure) device measures haemodynamics but has not been widely adopted in ward environments. Improved early detection of hypotension by CNAP might guide interventions to improve clinical outcomes. We aimed to find the proportion of patients who tolerated LiDCO CNAP for 12 h postoperatively, to unmask episodes of hypotension detected by continuous monitoring and to characterise the haemodynamic profile at the time of hypotension. In this feasibility study, patients undergoing major elective surgery were continuously postoperatively monitored using CNAP. Haemodynamic data gathered from CNAP, including nSVRI (nominal systemic vascular resistance index), nSVI (nominal stroke volume index), SVV (stroke volume variation) and blood pressure, were analysed using Microsoft Excel and GraphPad Prism 8. 104 patients (age (mean ± sd): 68 ± 14, male (56%)) had CNAP sited postoperatively. 39% tolerated the CNAP device for at least 12 h. Within the 104 patients a mean of 81.2 min of hypotension detected by CNAP was not detected by usual care. The proportion of low/normal/high nSVI was 71%, 27% and 2%, nSVRI was 43%, 17% and 40%, respectively. CNAP monitoring was not tolerated for 12 h in the majority of patients. There were many episodes of hypotension unmasked through continuous monitoring. Based on the advanced haemodynamic data provided it is possible that the underlying cause of a third of postoperative hypotensive episodes is vasodilation rather than hypovolaemia.Trial registry number: NCT04010058 (ClinicalTrials.gov) Date of registration: 08/07/2019. [ABSTRACT FROM AUTHOR]

Human epithelial tissues accumulate cancer-driver mutations with age1–9, yet tumour formation remains rare. The positive selection of these mutations suggests that they alter the behaviour and fitness of proliferating cells10–12. Thus, normal adult tissues become a patchwork of mutant clones competing for space and survival, with the fittest clones expanding by eliminating their less competitive neighbours11–14. However, little is known about how such dynamic competition in normal epithelia influences early tumorigenesis. Here we show that the majority of newly formed oesophageal tumours are eliminated through competition with mutant clones in the adjacent normal epithelium. We followed the fate of nascent, microscopic, pre-malignant tumours in a mouse model of oesophageal carcinogenesis and found that most were rapidly lost with no indication of tumour cell death, decreased proliferation or an anti-tumour immune response. However, deep sequencing of ten-day-old and one-year-old tumours showed evidence of selection on the surviving neoplasms. Induction of highly competitive clones in transgenic mice increased early tumour removal, whereas pharmacological inhibition of clonal competition reduced tumour loss. These results support a model in which survival of early neoplasms depends on their competitive fitness relative to that of mutant clones in the surrounding normal tissue. Mutant clones in normal epithelium have an unexpected anti-tumorigenic role in purging early tumours through cell competition, thereby preserving tissue integrity.The rarity of tumour formation despite the high proportion of cancer-driver mutations in epithelia is explained by the competitive fitness of tumour cells relative to that of surrounding mutant epithelial cells. [ABSTRACT FROM AUTHOR]

In May 2020, the EU Reference Laboratory for alternatives to animal testing (EURL ECVAM) published a recommendation report entitled "Recommendation on nonanimal-derived antibodies". In this report, the EURL ECVAM specifically states: "Therefore, taking into consideration the ESAC Opinion on the scientific validity of replacements for animal-derived antibodies, EURL ECVAM recommends that animals should no longer be used for the development and production of antibodies for research, regulatory, diagnostic and therapeutic applications. The provisions of Directive 2010/63/EU should be respected, and EU countries should no longer authorise the development and production of antibodies through animal immunisation, where robust, legitimate scientific justification is lacking." (1). Here, we are providing the American Association of Pharmaceutical Scientists (AAPS) opinion on the EURL ECVAM recommendation report. In brief, there has been a clear and strong progress in reduction of animal use in the drug discovery and development process, including significant reduction of animal use in production of antibody reagents. Yet, it is proposed that more data need to be generated, shared and discussed within the scientific community before a decision to implement the change to non-animal derived antibodies is made. [ABSTRACT FROM AUTHOR]

Laboratory experiments are conducted to investigate the mechanism controlling the formation of stable and unstable acoustic fountains at the free surface of a quiescent body of water. Fountains are induced by focused ultrasonic, a new modality that allows for better spatiotemporal control of water flow. Particle image velocimetry was used to characterize the induced flow field in the vicinity of the ultrasonic focal spot. We used two types of ultrasonic transducers with distinct wave frequencies. We examined three fountain formation regimes by varying the pressure level of the transducers, namely weak, intermediate (stable) and highly forced fountains (explosive). Between different regimes, the fountain height underwent a step-change in response to the increase in acoustic pressure. A force estimation obtained from the flow field shows that the magnitude of axial momentum flux is orders of magnitude lower than that of gravity and surface tension, indicating that the dominant driving force for the fountain generation is the acoustic radiation force (Nightingale et al., Ultrasound Med. Biol., vol. 28, 2002, pp. 227–235). We propose a simple model to estimate the shape of a stable fountain; it accounts for the applied acoustic pressure, gravity, surface tension and axial momentum. The model neglects viscous force, which precludes capturing the intermediate fountain surface curvature. However, the model successfully predicts the geometry of the weak and intermediate fountains. [ABSTRACT FROM AUTHOR]

The most advanced P. falciparum circumsporozoite protein-based malaria vaccine, RTS,S/AS01 (RTS,S), confers partial protection but with antibody titers that wane relatively rapidly, highlighting the need to elicit more potent and durable antibody responses. Here, we elucidate crystal structures, binding affinities and kinetics, and in vivo protection of eight anti-NANP antibodies derived from an RTS,S phase 2a trial and encoded by three different heavy-chain germline genes. The structures reinforce the importance of homotypic Fab-Fab interactions in protective antibodies and the overwhelmingly dominant preference for a germline-encoded aromatic residue for recognition of the NANP motif. In this study, antibody apparent affinity correlates best with protection in an in vivo mouse model, with the more potent antibodies also recognizing epitopes with repeating secondary structural motifs of type I β- and Asn pseudo 310 turns; such insights can be incorporated into design of more effective immunogens and antibodies for passive immunization. The most advanced P. falciparum circumsporozoite protein (PfCSP)-based malaria vaccine confers partial protection. Here, Pholcharee et al. present crystal structures, binding affinities/kinetics, and in vivo protection of 8 anti-NANP antibodies to understand in vivo protection of PfCSP-targeting antibodies. [ABSTRACT FROM AUTHOR]

Heat shock protein expression can be induced by heat shock making it possible to artificially modulate their levels noninvasively in vivo in a spatially and temporally controlled manner. Here, we report the use of the major heat shock protein 70 (HSP70) as an inducible target by using the small molecule deoxyspergualin (DSG) conjugated to the near-infrared fluorophore (Cy5.5). We demonstrate that heat induction in the form of localized hyperthermia of normal tissue in living mice results in sufficient HSP70 overexpression for detection with DSG-Cy5.5 conjugate. This effect is dependent on total energy delivered and reaches maximum fluorescence signal in 6 to 8 hours post heat induction and declines over a period of up to 24 hours. These results suggest that DSG-Cy5.5 agent accumulates in tissue with elevated HSP70 by heat. [ABSTRACT FROM AUTHOR]

Insufficient moisture availability often limits soybean [Glycine max (L.) Merr.] yield. Carbon isotope ratio (δ13C) provides an integrated measure of water use efficiency in C3 plants due to its substantial genetic variance, high heritability, and small genotype × environment interaction (G × E). The objective of this study was to identify quantitative trait loci (QTLs) associated with δ13C using a recombinant inbred line population derived from a cross between 'KS4895' and 'Jackson'. The field experiment was conducted in five environments to evaluate δ13C under rainfed and irrigated conditions. Analysis of variance of δ13C averaged over environment and irrigation treatment showed significant effects of genotype (G), environment (E), and G × E interactions. Heritability of δ13C in different environments and irrigation treatments ranged from 66 to 79%. Averaged over environments and irrigation treatments, heritability was 83%. A total of 24 QTLs associated with δ13C were identified and clustered in nine genomic regions on seven chromosomes. The QTL clusters on Gm05 (1), Gm06 (2) and Gm20 (1) were detected across different environments and irrigation regimes. Collectively, these four QTL clusters accounted for 55% of the phenotypic variation in δ13C. The QTLs on Gm06 and Gm20 also showed additive × additive epistasis that contributed approximately 4.2% to the total phenotypic variation. Several identified δ13C QTLs overlapped with QTLs associated with other physiological traits related to plant water status, biological nitrogen fixation, and plant morphology. The identified genomic regions may be an important resource in genomic selection studies to improve drought tolerance in soybean. [ABSTRACT FROM AUTHOR]

Population genetic analysis revealed that Plasmodium knowlesi infections in Malaysian Borneo are caused by 2 divergent parasites associated with long-tailed (cluster 1) and pig-tailed (cluster 2) macaques. Because the transmission ecology is likely to differ for each macaque species, we developed a simple genotyping PCR to efficiently distinguish between and survey the 2 parasite subpopulations. This assay confirmed differences in the relative proportions in areas of Kapit division of Sarawak state, consistent with multilocus microsatellite analyses. Analyses of 1,204 human infections at Kapit Hospital showed that cluster 1 caused approximately two thirds of cases with no significant temporal changes from 2000 to 2018. We observed an apparent increase in overall numbers in the most recent 2 years studied, driven mainly by increased cluster 1 parasite infections. Continued monitoring of the frequency of different parasite subpopulations and correlation with environmental alterations are necessary to determine whether the epidemiology will change substantially. [ABSTRACT FROM AUTHOR]

Soybean [Glycine max (L.) Merr.] nitrogen fixation is sensitive differentially to drought among different genotypes at different growth and development stages, which directly affects soybean yield. Acetylene reduction activity (ARA) response to a gradual drought and rewatering period at late podding (late R3) and late seed fill (late R5) were evaluated in two different water use efficiency (WUE) genotypes. Drought-stressed plants with high WUE (PI 372413) decreased ARA more insensitively than that of low WUE (PI 548534), and drought-stressed plants with low WUE (PI 548534) maintained low ARA level after stress alleviation at late R5. The recovery ability of N2 fixation was a genotypic difference with WUE at late reproductive development (late R5), especially. Analysing relation between fraction of transpirable soil water (FTSW) and relative ARA, it was confirmed that PI 372413 with high WUE was more insensitive to water deficit and had drought tolerance by N2 fixation and recovery ability with a threshold of 0.139-0.147 FTSW than PI 548534 with a threshold of 0.192-0.209 FTSW. The ability to recover N2 fixation following drought during the reproductive developmental stage would be of an important value in the actual planting environment. [ABSTRACT FROM AUTHOR]

Soybean [Glycine max (L.) Merr.] lines R10‐2436 (Reg. no. GP‐439, PI 692971) and R10‐2710 (Reg. no. GP‐440, PI 692972) are high‐yielding and drought‐tolerant conventional germplasm released by the Arkansas Agricultural Experiment Station in February 2017. R10‐2436 and R10‐2710 have a relative maturity of 5.6 and 5.8, respectively. R10‐2436 is an F4–derived line from the cross R01‐52F × R02‐6268F, and R10‐2710 is an F2–derived line from R01‐52F × 'USDA‐N7002'. In 6 yr of testing, R10‐2436 and R10‐2710 significantly outyielded the maturity group 5 check mean under moderate water‐deficit stress in Stuttgart, AR (2,893, 2,889, and 2,506 kg ha−1, respectively) and were on a par with the checks under full irrigation in Stuttgart (4,644, 4,511, and 4,613 kg ha−1, respectively) and in five additional irrigated Arkansas environments. The water‐deficit treatment consisted of normal irrigation until blooming, after which irrigation was suspended for the rest of the season. In greenhouse pot studies, both releases exhibited sustained nitrogen fixation during a dry‐down cycle. This trait was presumably inherited from their ancestor 'Jackson'. R10‐2436 also exhibited slow wilting in multiple drought‐stressed environments in Arkansas and North Carolina, likely inherited from PI 416937. Because of their yield potential under drought and irrigation, as well as their good agronomic characteristics, R10‐2436 and R10‐2710 can be easily incorporated in applied breeding programs to transfer drought tolerance into elite high‐yielding cultivars. [ABSTRACT FROM AUTHOR]

We use a variety of experimental techniques to characterize Cu clusters on bulk MoS2 formed via physical vapor deposition of Cu in ultrahigh vacuum, at temperatures ranging from 300 K to 900 K. We find that large facetted clusters grow at elevated temperatures, using high Cu exposures. The cluster size distribution is bimodal, and under some conditions, large clusters are surrounded by a denuded zone. We propose that defect-mediated nucleation, and coarsening during deposition, are both operative in this system. At 780 K, a surprising type of facetted cluster emerges, and at 900 K this type predominates: pyramidal clusters with a triangular base, exposing (311) planes as side facets. This is a growth shape, rather than an equilibrium shape. [ABSTRACT FROM AUTHOR]

Background: New strategies are needed to reduce the incidence of malaria, and promising approaches include the development of vaccines and monoclonal antibodies (mAbs) that target the circumsporozoite protein (CSP). To select the best candidates and speed development, it is essential to standardize preclinical assays to measure the potency of such interventions in animal models. Methods: Two assay configurations were studied using transgenic Plasmodium berghei expressing Plasmodium falciparum full-length circumsporozoite protein. The assays measured (1) reduction in parasite infection of the liver (liver burden) following an intravenous (i.v) administration of sporozoites and (2) protection from parasitaemia following mosquito bite challenge. Two human CSP mAbs, AB311 and AB317, were compared for their ability to inhibit infection. Multiple independent experiments were conducted to define assay variability and resultant impact on the ability to discriminate differences in mAb functional activity. Results: Overall, the assays produced highly consistent results in that all individual experiments showed greater functional activity for AB317 compared to AB311 as calculated by the dose required for 50% inhibition (ID50) as well as the serum concentration required for 50% inhibition (IC50). The data were then used to model experimental designs with adequate statistical power to rigorously screen, compare, and rank order novel anti-CSP mAbs. Conclusion: The results indicate that in vivo assays described here can provide reliable information for comparing the functional activity of mAbs. The results also provide guidance regarding selection of the appropriate experimental design, dose selection, and group sizes. [ABSTRACT FROM AUTHOR]

Lasting protection has long been a goal for malaria vaccines. The major surface antigen on Plasmodium falciparum sporozoites, the circumsporozoite protein (PfCSP), has been an attractive target for vaccine development and most protective antibodies studied to date interact with the central NANP repeat region of PfCSP. However, it remains unclear what structural and functional characteristics correlate with better protection by one antibody over another. Binding to the junctional region between the N-terminal domain and central NANP repeats has been proposed to result in superior protection: this region initiates with the only NPDP sequence followed immediately by NANP. Here, we isolated antibodies in Kymab mice immunized with full-length recombinant PfCSP and two protective antibodies were selected for further study with reactivity against the junctional region. X-ray and EM structures of two monoclonal antibodies, mAb667 and mAb668, shed light on their differential affinity and specificity for the junctional region. Importantly, these antibodies also bind to the NANP repeat region with equal or better affinity. A comparison with an NANP-only binding antibody (mAb317) revealed roughly similar but statistically distinct levels of protection against sporozoite challenge in mouse liver burden models, suggesting that junctional antibody protection might relate to the ability to also cross-react with the NANP repeat region. Our findings indicate that additional efforts are necessary to isolate a true junctional antibody with no or much reduced affinity to the NANP region to elucidate the role of the junctional epitope in protection. Author summary: The circumsporozoite protein (CSP) of Plasmodium falciparum malaria has been the foundation for the design of transmission blocking malaria vaccines. To date, the most promising CSP-based vaccine candidate is RTS,S, which consists of the central repeating NANP amino-acid sequence and the C-terminal domain of CSP fused to hepatitis B surface antigen that assembles into virus-like particles. Potential shortcomings of RTS,S includes the lack of other potential CSP epitopes such as the junctional epitope, which is located between the N-terminal domain of CSP and the start of the NANP repeat region. Here, we elicited antibodies against full-length CSP and screened for junctional epitope binding. We then used an array of biophysical techniques to elucidate the nature of the binding and tested the level of two protective antibodies in a mouse challenge model. Although the antibodies were able to bind both junctional and NANP epitopes, the in vivo data showed distinct levels of protection between themselves and also to an NANP-only binder. Our data suggest that their protection ability may be related to the strong cross-reactivity with NANP epitopes. Since all reported junctional antibodies to date have dual-specificity, we suggest that a true junctional binder with no or very low NANP affinity, if one can be found, is essential to evaluate the contribution of the junctional epitope to protection. [ABSTRACT FROM AUTHOR]

The Plasmodium falciparum gametocyte surface protein, Pfs48/45, is a potential target for malaria transmission-blocking vaccines. However, due to its size and complexity, expression of the full-length protein has been difficult, leading to focus on the C-terminal six cysteine domain (6C) with the use of fusion proteins to facilitate expression and folding. In this study, we utilized the baculovirus system to evaluate the expression of three Pfs48/45 proteins including the full-length protein, the 6C domain fragment and the 6C domain mutant to prevent glycosylation. Expression of the recombinant Pfs48/45 proteins was conducted in super Sf9 cells combined with the use of tunicamycin to prevent N-glycosylation. The proteins were then evaluated as immunogens in mice to demonstrate the induction of functionally active polyclonal antibody responses as measured in the standard membrane feeding assay (SMFA). Only the 6C protein was found to exhibit significant transmission-reducing activity. Further characterization of the biologically active 6C protein demonstrated it was homogeneous in terms of size, charge, conformation, absence of glycosylation, and containing proper disulfide bond pairings. This study presents an alternative expression system, without the need of a fusion protein partner, for the Pfs48/45 6C protein fragment including further evaluation as a potential transmission-blocking vaccine candidate. [ABSTRACT FROM AUTHOR]