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The near-zero-field magnetoresistance (NZFMR) response has proven to be a useful tool for studying atomic-scale, paramagnetic defects that are relevant to the reliability of semiconductor devices. The measurement is simple to make and, in some cases, simple to interpret. In other cases, more sophisticated modeling based on the stochastic Liouville equation (SLE) is needed to access valuable information from NZFMR results. It has been shown that hyperfine and dipolar coupling interactions at atomic-scale defects affect the NZFMR line shape, but experimental parameters related to the detection method of NZFMR can also affect the nature of the response. Here, we demonstrate four distinct NZFMR detection methods in Si MOSFETs, which all access identical Si/SiO2 interface defects. In all four cases, we show that the line shape of the response is tunable based on experimental parameters alone. Using SLE-based modeling, we verify that time constants connected to physical carrier capture rates at the defect sites lead to these NZFMR line shape changes. The results demonstrate a method to extract some atomic-scale information for the purpose of defect identification. They also have broader applications to the continued development of ultra-sensitive magnetometers based on NZFMR in semiconductors. Additionally, the NZFMR effect in common Si-based devices may provide an inexpensive and accessible platform that mimics similar radical pair mechanisms that have become increasingly important in various biology fields. [ABSTRACT FROM AUTHOR]

CEOs are increasingly called upon to take public stands on political issues, a phenomenon dubbed "political activism." These stands tend to have either moral foundations or moral implications, yet it is unclear whether stakeholders truly want CEOs to make stands, and, if so, how philosophically grounded they are in their stated positions. This paper explores the philosophical worldview questions relevant to current issues facing organizations, particularly those that have been characterized as "wokeism." It then examines how these worldview positions translate or apply to these issues in ways that seemingly contradict CEOs' stands. Finally, it explores how the concept of the social imaginary, CEOs' political beliefs, mass media's reciprocal effects, and CEO narcissism may influence CEOs to take "woke" political activist positions. [ABSTRACT FROM AUTHOR]

Trilobites with malformations present important insight into the paleoecology of the wholly extinct arthropod group. This includes records of failed predation, developmental complications, and parasitic interactions. The documentation of malformed trilobites therefore allows for a more thorough understanding of these animals. Such summaries also permit larger-scale, synthetic works that consider patterns and processes associated with malformations to be developed. To expand the current record of malformed Cambrian through to Devonian trilobites, we report 16 novel specimens across 12 genera from deposits spanning Australia, Bolivia, Canada, the United States, and Wales. These specimens illustrate examples of injuries potentially caused by predation, molting, and accidental injury, teratological malformations, and pathological infestation. Possible predators; explanations for developmental, genetic, and recovery issues; as well as infestations are considered. Comparison of size distributions of malformed and nonmalformed Elrathia kingii indicates that primarily the largest specimens preserve malformations. This implies that either smaller specimens fully recovered from malformations or did not survive once the malformations were incurred. Continued documentation of malformed specimens will allow larger datasets to be compiled and further promote the use of malformations in understanding trilobite paleoecology. [ABSTRACT FROM AUTHOR]

Malformed trilobites have been well documented within the arthropod fossil record and serve as valuable evidence for illustrating aspects of trilobite paleoecology associated with development, predation, and pathologies. Ongoing efforts to comprehensively document these malformations have uncovered important, often unique records for the extinct group, shedding light on post-malformation recovery processes and potential predators. A key means of recording new examples of these specimens has been the examination of historically important paleontological collections. To expand this approach, we examined the Deiss collection in the Indiana University Paleontology Collection and present four examples of malformations from Cambrian (Asaphiscus wheeleri, Dorypyge bispinosa, Wanneria walcottana), and Ordovician (Isotelus iowensis) species. These specimens reveal evidence of injuries, failed predation, and developmental complications. We explore the possible explanations for malformations and consider the current state of the art for evaluating trilobite malformations. Finally, the Deiss collection history and its ongoing contributions to Paleozoic fossils are presented. [ABSTRACT FROM AUTHOR]

Background: The Nyakaza-Move-for-Health intervention program was developed in response to the alarming rise in non-communicable diseases (NCDs) globally, in sub-Saharan Africa and South Africa. The rise in NCDs is attributed to the low levels of participation in physical activity (PA) among adolescents. Therefore, this study aimed to design a culturally tailored PA intervention for adolescents, guided by the Intervention Mapping (IM) protocol. The intervention program aims to address the multifaceted determinants of physical activity behavior, promote healthy lifestyles and improve adolescent fitness levels. Methods: The Intervention Mapping protocol was applied to design the intervention program. The IM has 6 steps: (1) Needs assessment, (2) developing a logic model of the problem (LMP), (3) Formulating program outcomes and objectives, (4) Program design and production, (5) Generating implementation plan, and (6) Generating intervention evaluation plan. Participants included (n = 48) adolescent learners recruited from 8 (n = 8) participating schools. Adolescent learners participated in focus group discussions (FGD) to identify personal, interpersonal and environmental determinants of physical inactivity. Twenty-six (n = 26) key informant stakeholders participated in a stakeholder engagement workshop (SEW) to determine the motivators and constraints in implementing physical activity interventions. Results: The Nyakaza intervention program's process development involved extensive stakeholder engagement, capacity development training, and integration of community feedback into the design. The intervention included a social marketing campaign and structured after-school physical activity sessions based on the Health Belief Model (HBM) and Transtheoretical Model (TTM). Implementation and evaluation plans were created, emphasizing real-time monitoring and adaptations. Strategies to enhance parental and community support were developed to address participation barriers. Although not tested in this study, these plans laid a robust foundation for fostering sustainable behavior change and improving physical activity among adolescents in resource-constrained settings. Conclusion: The Nyakaza-Move-for-Health intervention demonstrates a promising framework for promoting adolescent physical activity and addressing Non-Communicable Diseases in a culturally relevant manner. The systematic approach, grounded in the intervention mapping protocol, ensured a robust and replicable intervention design. Future research should focus on long-term follow-up, integrating objective physical activity measures, and expanding the program to include nutrition education. Addressing identified barriers, such as parental involvement, is crucial for enhancing the intervention's effectiveness and sustainability. [ABSTRACT FROM AUTHOR]

The global energy budget is pivotal to understanding planetary evolution and climate behaviors. Assessing the energy budget of giant planets, particularly those with large seasonal cycles, however, remains a challenge without long-term observations. Evolution models of Saturn cannot explain its estimated Bond albedo and internal heat flux, mainly because previous estimates were based on limited observations. Here, we analyze the long-term observations recorded by the Cassini spacecraft and find notably higher Bond albedo (0.41 ± 0.02) and internal heat flux (2.84 ± 0.20 Wm−2) values than previous estimates. Furthermore, Saturn's global energy budget is not in a steady state and exhibits significant dynamical imbalances. The global radiant energy deficit at the top of the atmosphere, indicative of the planetary cooling of Saturn, reveals remarkable seasonal fluctuations with a magnitude of 16.0 ± 4.2%. Further analysis of the energy budget of the upper atmosphere including the internal heat suggests seasonal energy imbalances at both global and hemispheric scales, contributing to the development of giant convective storms on Saturn. Similar seasonal variabilities of planetary cooling and energy imbalance exist in other giant planets within and beyond the Solar System, a prospect currently overlooked in existing evolutional and atmospheric models. Global energy budgets of planets are important to understand their climate system. Here, the authors show long-term multi-instrument observations from Cassini spacecraft, which reveals dynamical imbalances of Saturn's global energy budget. [ABSTRACT FROM AUTHOR]

The reaction of indigo with two equivalents of the electrophile ethyl bromoacetate with caesium carbonate as a base result in the formation of structurally complex polyheterocyclics, including a fused spiroimidazole and a spiro[1,3]oxazino derivative, together with a biindigoid-type derivative, through a convenient one-pot reaction. Further assessment of the reaction using five equivalents of the electrophile gave rise to other molecules incorporating the 2-(7,13,14-trioxo-6,7,13,14-tetrahydropyrazino[1,2-a:4,3-a′]diindol-6-yl) scaffold. The reaction of ethyl bromoacetate with the less reactive indirubin resulted in the synthesis of three derivatives of a new class of polyheterocyclic system via a cascade process, although yields were low. These compounds were derived from the parent indolo[1,2-b]pyrrolo[4,3,2-de]isoquinoline skeleton. Despite the modest yields of the reactions, they represent quick cascade routes to a variety of heterocycles from cheap starting materials, with these structures otherwise being difficult to synthesise in a traditional stepwise manner. These outcomes also contribute significantly to the detailed understanding of the indigo/indirubin cascade reaction pathways initiated by base-catalysed N-alkylation. [ABSTRACT FROM AUTHOR]

Extracellularly released molecular inflammasome assemblies -ASC specks- cross-seed Aβ amyloid in Alzheimer's disease. Here we show that ASC governs the extent of inflammation-induced amyloid A (AA) amyloidosis, a systemic disease caused by the aggregation and peripheral deposition of the acute-phase reactant serum amyloid A (SAA) in chronic inflammatory conditions. Using super-resolution microscopy, we found that ASC colocalized tightly with SAA in human AA amyloidosis. Recombinant ASC specks accelerated SAA fibril formation and mass spectrometry after limited proteolysis showed that ASC interacts with SAA via its pyrin domain (PYD). In a murine model of inflammatory AA amyloidosis, splenic amyloid load was conspicuously decreased in Pycard−/− mice which lack ASC. Treatment with anti-ASCPYD antibodies decreased amyloid loads in wild-type mice suffering from AA amyloidosis. The prevalence of natural anti-ASC IgG (−logEC50 ≥ 2) in 19,334 hospital patients was <0.01%, suggesting that anti-ASC antibody treatment modalities would not be confounded by natural autoimmunity. These findings expand the role played by ASC and IL-1 independent inflammasome employments to extraneural proteinopathies and suggest that anti-ASC immunotherapy may contribute to resolving such diseases. Synopsis: ASC scaffolds and cross-seeds Aβ amyloid and is considered an actionable target against Alzheimer's disease. This study investigated the role of ASC in amyloid A (AA) amyloidosis, a systemic disease in which serum amyloid A (SAA) aggregates invade internal organs due to chronic inflammation. ASC and SAA were found to colocalize in inflammatory amyloidosis in humans and mice. ASC interacts with SAA via its pyrin domain (PYD) and was found to accelerate SAA/AA fibril formation in a dose-dependent manner. Ablation of Pycard (Asc) was found to reduce amyloid deposition in mice. Immunotherapy with an anti-ASC antibody targeting the PYD diminished SAA-derived amyloid deposition and its sequelae in vivo. A large-scale human anti-ASC autoantibody screening of 23,450 plasma samples from 19,334 patients revealed rare immunoreactivity towards ASC, indicating high tolerance for employing anti-ASC modalities in inflammatory diseases. ASC scaffolds and cross-seeds Aβ amyloid and is considered an actionable target against Alzheimer's disease. This study investigated the role of ASC in amyloid A (AA) amyloidosis, a systemic disease in which serum amyloid A (SAA) aggregates invade internal organs due to chronic inflammation. [ABSTRACT FROM AUTHOR]

There is a lack of information on effective burn prevention strategies. The objective of this study was to examine a safe fireplace program, as a method of burn prevention, in a resource-limited setting. We conducted a qualitative, phenomenological study at a community health and development program for a rural population in Kenya. Semistructured, in-depth interviews were conducted with a purposive sample of community health workers involved with the safe fireplace program. Data were reviewed iteratively and coded independently by two researchers using NVivo 12. The study included five participants. Reflections from participants fell into three main domains: (1) effective methods of education, (2) strategies to incorporate stakeholders, and (3) implementation challenges. The results of this study emphasize the importance of community engagement in implementing a successful burn injury prevention program in a resource-limited setting. The participants involved in this study reported that rather than focusing on resources outside the community, effective methods of education and strategies for incorporating stakeholders depended on involving peers and community leaders. The challenges to the program were similarly specific to community concerns about resources and maintenance. These findings provide information to guide future community health programs in creating successful models for burn prevention strategies in resource-limited areas. [ABSTRACT FROM AUTHOR]

Regional citrate anticoagulation (RCA) is a preferred method for continuous renal replacement therapy (CRRT) due to its benefits of extended filter lifespan and reduced bleeding complications. However, RCA can cause metabolic side effects such as alkalosis, acidosis, hypotension, and electrolyte imbalances. Optimal anticoagulation requires careful adjustment of citrate infusion based on blood flow rate. Citrate accumulation can occur in certain conditions, leading to adverse effects. Strategies for adapting citrate anticoagulation include adjusting the dose based on the patient's condition. The Cori cycle has been proposed as an alternative pathway for citrate metabolism outside the liver mitochondria. Establishing thresholds for citrate initiation is important, and lactate levels can be used as an indicator of impaired citrate metabolism. The proposed hypothesis of an alternative inducible citrate metabolism pathway requires further research, including an animal model, to validate its effectiveness. Overall, RCA is a viable option for patients with liver failure, and further research is needed to optimize its application and improve anticoagulation strategies in various clinical contexts. [Extracted from the article]

Spontaneous activity in dorsal root ganglion (DRG) neurons is a key driver of neuropathic pain in patients suffering from this largely untreated disease. While many intracellular signalling mechanisms have been examined in preclinical models that drive spontaneous activity, none have been tested directly on spontaneously active human nociceptors. Using cultured DRG neurons recovered during thoracic vertebrectomy surgeries, we showed that inhibition of mitogen-activated protein kinase interacting kinase (MNK) with tomivosertib (eFT508, 25 nM) reversibly suppresses spontaneous activity in human sensory neurons that are likely nociceptors based on size and action potential characteristics associated with painful dermatomes within minutes of treatment. Tomivosertib treatment also decreased action potential amplitude and produced alterations in the magnitude of after hyperpolarizing currents, suggesting modification of Na+ and K+ channel activity as a consequence of drug treatment. Parallel to the effects on electrophysiology, eFT508 treatment led to a profound loss of eIF4E serine 209 phosphorylation in primary sensory neurons, a specific substrate of MNK, within 2 min of drug treatment. Our results create a compelling case for the future testing of MNK inhibitors in clinical trials for neuropathic pain. [ABSTRACT FROM AUTHOR]

Research on romantic conflict has persuasively documented that the way partners communicate with one another during disagreements is a driving factor in predicting how they perceive the conflicts in their relationships. The current research added to this literature by differentiating couples who resolve conflicts more, versus less, successfully. Specifically, the current work examined how couples' behavioral trajectories across the course of conflict related to their perceptions of conflict resolution. To this end, we coded warmth and dominance behaviors exhibited by 173 couple members (346 individuals) over the course of an eight-minute conflict discussion. We examined how participants', and their partners', perceptions of conflict resolution were related to their interpersonal behaviors. In line with predictions, less average interpersonal warmth was associated with worse perceptions of resolution, and declining warmth over time was also associated with worse perceptions of resolution. Dominance behaviors were not associated with conflict resolution perceptions. [ABSTRACT FROM AUTHOR]

A gastrocnemius contracture is a common problem that results in decreased ankle dorsiflexion that contributes to an array of foot and ankle ailments. A common surgical treatment for this condition is a gastrocnemius recession (GR). Many adaptations of the original procedure have been described. Misinterpretations of proper GR procedures have potentially caused confusion when selecting a treatment. This paper proposes to identify errors between the use of GR and gastrocnemius-soleus recession (GSR) procedure techniques in the current literature. A systematic literature review was performed in June 2021, using the PubMed database and select orthopedic texts. Only studies that met the established criteria and either correctly or incorrectly described a GR or GSR procedure were included. After applying exclusion criteria, 108 publications were included. These articles and texts were reviewed for surgical technique and terminology errors in accordance with established parameters. The articles were classified as either: "Correct" or "Incorrect." Of the 108 publications and texts included, 18 articles incorrectly described either a GR or a GSR (16.67%). Ninety articles correctly described either a GR or a GSR (83.33%). The literature supports the use of a GR to treat a gastrocnemius contracture. Inaccurate articles create confusion as to what exactly a GR entails. Sources of ambiguity included terminology, inconsistent anatomical zone definition, and technique selection. Due to this confusion, it is suspected that patient outcomes can be impacted. Postoperative outcomes of GSR patients are worse than GR patients. Further investigation is necessary to determine if performing the incorrect procedure negatively affects patient outcomes. [ABSTRACT FROM AUTHOR]

Regardless of the type, extracorporeal membrane oxygenation (ECMO) requires the use of large intravascular cannulas and results in multiple abnormalities including non-physiologic blood flow, hemodynamic perturbation, rapid changes in blood oxygen and carbon dioxide levels, coagulation abnormalities, and a significant systemic inflammatory response. Among other sequelae, neurologic complications are an important source of mortality and long-term morbidity. The frequency of neurologic complications varies and is likely underreported due to the high mortality rate. Neurologic complications in patients supported by ECMO include ischemic and hemorrhagic stroke, hypoxic brain injury, intracranial hemorrhage, and brain death. In addition to the disease process that necessitates ECMO, cannulation strategies and physiologic disturbances influence neurologic outcomes in this high-risk population. For example, the overall documented rate of neurologic complications in the venovenous ECMO population is lower, but a higher rate of intracranial hemorrhage exists. Meanwhile, in the venoarterial ECMO population, ischemia and global hypoperfusion seem to compose a higher percentage of neurologic complications. In what follows, the literature is reviewed to discuss the pathophysiology, incidence, risk factors, and outcomes related to short-term neurologic complications in patients supported by ECMO. [ABSTRACT FROM AUTHOR]

RNA methylation plays a central regulatory role in plant biology and is a relatively new target for plant improvement efforts. In nearly all cases, perturbation of the RNA methylation machinery results in deleterious phenotypes. However, a recent landmark paper reported that transcriptome‐wide use of the human RNA demethylase FTO substantially increased the yield of rice and potatoes. Here, we have performed the first independent replication of those results and demonstrated broader transferability of the trait, finding increased flower and fruit count in the model species Arabidopsis thaliana. We also performed RNA‐seq of our FTO‐transgenic plants, which we analyzed in conjunction with previously published datasets to detect several previously unrecognized patterns in the functional and structural classification of the upregulated and downregulated genes. From these, we present mechanistic hypotheses to explain these surprising results with the goal of spurring more widespread interest in this promising new approach to plant engineering. [ABSTRACT FROM AUTHOR]

Background: Precursor plasma cell disorders such as monoclonal gammopathy of undetermined significance (MGUS) always precede the development of active malignancies such as multiple myeloma (MM). There is a need for novel biomarkers to identify those patients with such precursor plasma cell disorders who rapidly progress to MM. Plasma‐derived extracellular vesicles (EVs) may serve as a reservoir of potential biomarkers that can shed light on the pathogenesis and disease biology of MM. Methods: This study isolated small EVs (SEVs) and large EVs (LEVs) from the platelet‐poor peripheral blood plasma of MGUS (n = 9) and MM (n = 12) patients using the size exclusion chromatography‐based method and evaluated their proteome using a label‐free proteomics workflow. Results: In total, 2055 proteins were identified in SEVs, while 2794 proteins were identified in LEVs. The transferrin receptor (or CD71) protein was upregulated in both populations of EVs derived from MM patients compared to MGUS patients and was of prognostic significance. Similarly, three isoforms of serum amyloid A (SAA) protein, SAA1, SAA2, and SAA4, were also highly upregulated in SEVs within MM patients relative to MGUS patients. Finally, CD40 expression was also higher in the LEVs derived from MM patients than in MGUS patients. Conclusions: This study demonstrates the feasibility of successfully isolating both SEVs and LEVs from the peripheral blood of patients with plasma cell disorders and quantifying protein biomarkers within these EVs that could be of prognostic and diagnostic interest. [ABSTRACT FROM AUTHOR]

Internally displaced persons (IDPs) are at high risk for COVID-19 transmission because of congested and unsanitary living conditions. COVID-19 vaccination is essential to build population immunity and prevent severe disease among this population. We determined the prevalence and factors associated with intention to accept COVID-19 vaccine among IDPs in Northeast Nigeria. This cross-sectional study, conducted during July–December 2022, included 1,537 unvaccinated IDPs from 18 IDPs camps. We performed a complex sample survey analysis and described participants' characteristics and vaccination intention with weighted descriptive statistics. We fitted weighted logistic regression models and computed adjusted odds ratios with 95% confidence intervals to identify factors associated with intention to accept COVID-19 vaccine. Of 1,537 IDPs, 55.4% were 18–39 years old, 82.6% were females, and 88.6% had no formal education. Among them, 63.5% (95% CI: 59.0–68.1) expressed intention to accept COVID-19 vaccine. Among the IDPs who intended to reject vaccine, 42.8% provided no reason, 35.3% had COVID-19 misconceptions, 9.5% reported vaccine safety concerns, and 7.4% felt no need. IDPs who perceived COVID-19 as severe (Adjusted Odds Ratio (AOR) = 2.31, [95% CI: 1.35–3.96]), perceived COVID-19 vaccine as effective (AOR = 4.28, [95% CI: 2.46–7.44]) and resided in official camps (AOR = 3.29, [95% CI: 1.94–5.56]) were more likely to accept COVID-19 vaccine. However, IDPs who resided 2 kilometers or farther from the nearest health facility (AOR = 0.34, [95% CI: 0.20–0.58]) were less likely to accept vaccine. Intention to accept COVID-19 vaccine among the IDPs was suboptimal. To improve vaccination acceptance among this population, health education and risk communication should be intensified to counter misinformation, strengthen vaccine confidence, and shape perception of COVID-19 severity, focusing on IDPs in unofficial camps. Appropriate interventions to deliver vaccines to remote households should be ramped up. [ABSTRACT FROM AUTHOR]

Past research on interspecies communication has shown that animals can be trained to use Augmentative Interspecies Communication (AIC) devices, such as soundboards, to make simple requests of their caretakers. The recent uptake in AIC devices by hundreds of pet owners around the world offers a novel opportunity to investigate whether AIC is possible with owner-trained family dogs. To answer this question, we carried out two studies to test pet dogs' ability to recognise and respond appropriately to food-related, play-related, and outside-related words on their soundboards. One study was conducted by researchers, and the other by citizen scientists who followed the same procedure. Further, we investigated whether these behaviours depended on the identity of the person presenting the word (unfamiliar person or dog's owner) and the mode of its presentation (spoken or produced by a pressed button). We find that dogs produced contextually appropriate behaviours for both play-related and outside-related words regardless of the identity of the person producing them and the mode in which they were produced. Therefore, pet dogs can be successfully taught by their owners to associate words recorded onto soundboard buttons to their outcomes in the real world, and they respond appropriately to these words even when they are presented in the absence of any other cues, such as the owner's body language. [ABSTRACT FROM AUTHOR]

Many accretion-powered pulsars rotate in magnetocentrifugal disequilibrium, spinning up or down secularly over multiyear intervals. The magnetic dipole moment μ of such systems cannot be inferred uniquely from the time-averaged aperiodic X-ray flux 〈 L (t)〉 and pulse period 〈 P (t)〉, because the radiative efficiency of the accretion is unknown and degenerate with the mass accretion rate. Here, we circumvent the degeneracy by tracking the fluctuations in the unaveraged time series L (t) and P (t) using an unscented Kalman filter, whereupon μ can be estimated uniquely, up to the uncertainties in the mass, radius, and distance of the star. The analysis is performed on Rossi X-ray Timing Explorer observations for 24 X-ray transients in the Small Magellanic Cloud, which have been monitored regularly for ∼16 yr. As well as independent estimates of μ, the analysis yields time-resolved histories of the mass accretion rate and the Maxwell stress at the disk–magnetosphere boundary for each star, and hence auto- and cross-correlations involving the latter two state variables. The inferred fluctuation statistics convey important information about the complex accretion physics at the disk–magnetosphere boundary. [ABSTRACT FROM AUTHOR]

Novel chimeric antigen receptor (CAR) T-cell approaches are needed to improve therapeutic efficacy in solid tumors. High-risk neuroblastoma is an aggressive pediatric solid tumor that expresses cell-surface GPC2 and GD2 with a tumor microenvironment infiltrated by CD16a-expressing innate immune cells. Here we engineer T-cells to express a GPC2-directed CAR and simultaneously secrete a bispecific innate immune cell engager (BiCE) targeting both GD2 and CD16a. In vitro, GPC2.CAR-GD2.BiCE T-cells induce GPC2-dependent cytotoxicity and secrete GD2.BiCE that promotes GD2-dependent activation of antitumor innate immunity. In vivo, GPC2.CAR-GD2.BiCE T-cells locally deliver GD2.BiCE and increase intratumor retention of NK-cells. In mice bearing neuroblastoma patient-derived xenografts and reconstituted with human CD16a-expressing immune cells, GD2.BiCEs enhance GPC2.CAR antitumor efficacy. A CAR.BiCE strategy should be considered for tumor histologies where antigen escape limits CAR efficacy, especially for solid tumors like neuroblastoma that are infiltrated by innate immune cells. GPC2 and GD2 have been described as immunotherapeutic targets in neuroblastoma. Here the authors engineer T cells to simultaneously express a GPC2-directed CAR and a bispecific innate immune cell engager targeting GD2 and CD16a, showing antitumor activity in neuroblastoma preclinical models. [ABSTRACT FROM AUTHOR]

Objective: Tobacco use and obesity are leading causes of preventable death in the U.S. E-cigarette use is on the rise; however, obesity prevalence among e-cigarette users is unknown. The present study characterized obesity prevalence among e-cigarette and tobacco users in a national sample of U.S. adults. Method: Data were obtained from the 2018 Behavioral Risk Factor Surveillance System. Approximately 249,726 participants provided data on e-cigarette and tobacco use, height, weight, and demographics, and were categorized as follows: Ever vaped, ever smoked; Ever vaped, never smoked; Never vaped, ever smoked; Never vaped, never smoked. Results: Obesity prevalence (BMI ≥30 kg/m2) differed significantly across groups: 33.0% (ever vaped, ever smoked); 27.7% (ever vaped, never smoked); 33.1% (never vaped, ever smoked); 32.1% (never vaped, never smoked), p <.001. Groups also differed demographically. Logistic regressions adjusted for demographics revealed subjects in the never vaped, ever smoked group were significantly more likely to have obesity relative to those in the never vaped, never smoked group (p < 0.001) with vaping status having no main effect. Secondary analyses using never smokers as the reference found current smokers were less likely to have obesity and former smokers were more likely to have obesity, p <.001. Discussion: The present study is the first to characterize U.S. obesity prevalence among e-cigarette and tobacco users. Obesity prevalence was lower in the ever vaped, never smoked group; however, this finding appears to be attributable to demographic variables. As e-cigarette use becomes more common, future research should examine the development and maintenance of obesity among users. [ABSTRACT FROM AUTHOR]

Background Host-response biomarkers to differentiate bacterial from viral etiology in children with respiratory infections have shown high accuracies, but are understudied in Mycoplasma pneumoniae (Mp) infections. Methods We compared BV scores (0–34 indicating viral etiology, and 66–100 indicating bacterial etiology), tumor necrosis factor–related apoptosis-inducing ligand (TRAIL; pg/mL), interferon-γ inducible protein 10 (IP-10; pg/mL), and C-reactive protein (CRP; mg/L) serum levels between Mp -positive (Mp +) and Mp -negative (Mp −) community-acquired pneumonia (CAP) patients. We performed receiver operating characteristic (ROC) curve analyses for clinical features and biomarkers. Results Of 80 CAP patients (median age, 6.3 years; 57.5% male), 26 had Mp +CAP. In Mp +CAP patients, compared to Mp −CAP patients, BV scores were lower (14.0 [3.0–27.8] vs 54.0 [12.0–84.8]; P =.0008), TRAIL levels were higher (86.5 [67.4–123.0] vs 65.5 [42.5–103.9]; P =.025), CRP levels were lower (12.9 [4.0–22.3] vs 36.7 [13.0–132.8]; P =.0019), and IP-10 levels were comparable (366.0 [150.2–603.8] vs 331.0 [154.3–878.8]; P =.73) (all median [interquartile range]). ROC analyses yielded a comparable discriminatory accuracy for the combination of age, fever duration, and duration of respiratory symptoms, with either procalcitonin or BV score (area under the ROC curve, 0.87 vs 0.86; P =.94). Conclusions Children with Mp +CAP have atypically low, viral levels of the BV score, underscoring the complementary role of microbiological testing. [ABSTRACT FROM AUTHOR]

High volume hemofiltration (HVHF) could remove from plasma inflammatory mediators involved in sepsis-associated acute kidney injury (SA-AKI). The IVOIRE trial did not show improvements of outcome and organ dysfunction using HVHF. The aim of this study was to evaluate in vitro the biological effects of plasma of patients treated by HVHF or standard volume hemofiltration (SVHF). We evaluated leukocyte adhesion, apoptosis and functional alterations of endothelial cells (EC) and tubular epithelial cells (TEC). In vitro data were correlated with plasma levels of TNF-α, Fas-Ligand (FasL), CD40-Ligand (CD40L), von Willebrand Factor (vWF) and endothelial-derived microparticles. An experimental model of in vitro hemofiltration using LPS-activated blood was established to assess cytokine mass adsorption during HVHF or SVHF. Plasma concentrations of TNF-ɑ, FasL, CD40L and von Willebrand Factor (vWF) were elevated at the start (d1h0) of both HVHF and SVHF, significantly decreased after 6 h (d1h6), remained stable after 12 h (d1h12) and then newly increased at 48 h (d3h0). Plasma levels of all these molecules were similar between HVHF- and SVHF-treated patients at all time points considered. In addition, the levels of endothelial microparticles remained always elevated, suggesting the presence of a persistent microvascular injury. Plasma from septic patients induced leukocyte adhesion on EC and TEC through up-regulation of adhesion receptors. Moreover, on EC, septic plasma induced a cytotoxic and anti-angiogenic effect. On TEC, septic plasma exerted a direct pro-apoptotic effect via Fas up-regulation and caspase activation, loss of polarity, altered expression of megalin and tight junction molecules with an impaired ability to internalize albumin. The inhibition of plasma-induced cell injury was concomitant to the decrease of TNF-α, Fas-Ligand and CD40-Ligand levels. The protective effect of both HVHF and SVHF was time-limited, since a further increase of circulating mediators and plasma-induced cell injury was observed after 48 h (d3h0). No significant difference of EC/TEC damage were observed using HVHF- or SVHF-treated plasma. The in vitro hemofiltration model confirmed the absence of a significant modulation of cytokine adsorption between HVHF and SVHF. In comparison to SVHF, HVHF did not increase inflammatory cytokine clearance and did not reverse the detrimental effects of septic plasma-induced EC and TEC injury. Further studies using adsorptive membranes are needed to evaluate the potential role of high dose convective therapies in the limitation of the harmful activity of plasma soluble factors involved in SA-AKI. Trial registration IVOIRE randomized clinical trial; ClinicalTrials.gov (NCT00241228) (18/10/2005). [ABSTRACT FROM AUTHOR]

Canada thistle is a pervasive perennial weed, causing challenges to agricultural and natural ecosystems globally. Although research has focused on the phenology, genetics, and control of Canada thistle, little is known about the rhizosphere microbiome and the role plant–microbe interactions play in invasion success. This study investigated the rhizosphere microbiome of Canada thistle across diverse climates, soils, and crops in the U.S. northern Great Plains. Soil and rhizosphere samples were collected and bacterial 16S and fungal ITS2 sequencing were performed to characterize the core microbiome and identify potential factors contributing to invasion success. Amplicon sequencing revealed a stable core microbiome that was detected in the Canada thistle rhizosphere across all locations. The core microbiome was dominated by the bacterial phyla Actinobacteriota and Proteobacteria and fungal phyla Ascomycota and Basidiomycota. Differential abundance analysis showed rhizosphere fungal communities were enriched in pathogen-containing genera with a 1.7-fold greater abundance of Fusaria and a 2.6-fold greater abundance of Gibberella compared to bulk soil. Predictive functional profiling showed rhizosphere communities were enriched (p < 0.05, FDR corrected) in plant pathogen fungal guilds which represented 19% of the fungal community. The rhizosphere microbiome was similar in composition across environments, highlighting the stable association between Canada thistle and specific microbial taxa. This study characterized the core microbiome of Canada thistle, and the findings highlight plant–microbe interactions shaping invasive behavior. These findings are important for understanding the ecological impacts of plant invasion and soil-microbe ecological processes. [ABSTRACT FROM AUTHOR]

Diversifying wheat (Triticum aestivum L.)-based cropping systems is important for the sustainability of dryland agriculture. Research has focused on the agronomic benefits of increased crop diversity in semi-arid environments, but less is known about the impacts of increased crop diversity on the soil microbial community. This work compared soil health parameters between a continuous wheat crop sequence to a diverse sequence that included pea (Pisum sativum L.), proso millet (Panicum miliaceum L.), safflower (Carthamus tinctorius, L.), and spring wheat. Respiration was higher (p <.005) in the diverse sequence while activity of N-acetyl-β-d-glucosaminidase was lower (p <.05) with a mean rate of 26.3 and 16.3 mg ρ-nitrophenol kg−1 soil h−1 for the continuous wheat and diverse sequences, respectively. The mean net nitrogen mineralized during the growing season was 33.2 ± 2.5 kg ha−1 and was not different between treatments (p >.05). No difference was observed in bacterial alpha diversity, while fungal community diversity was 52% lower in the diverse rotation. The results of this work suggest that specific crops in a rotation may impact microbial processes related to nitrogen mineralization and that the soil fungal community may be more sensitive to changes in crop sequence than the soil bacterial community. [ABSTRACT FROM AUTHOR]

Chromone‐based compounds have established cytotoxic, antiproliferative, antimetastatic, and antiangiogenic effects on various cancer cell types via modulating different molecular targets. Herein, 17 novel chromone‐2‐carboxamide derivatives were synthesized and evaluated for their in vitro anticancer activity against 15 human cancer cell lines. Among the tested cell lines, MDA‐MB‐231, the triple‐negative breast cancer cell line, was found to be the most sensitive, where the N‐(2‐furylmethylene) (15) and the α‐methylated N‐benzyl (17) derivatives demonstrated the highest growth inhibition with GI50 values of 14.8 and 17.1 μM, respectively. In vitro mechanistic studies confirmed the significant roles of compounds 15 and 17 in the induction of apoptosis and suppression of EGFR, FGFR3, and VEGF protein levels in MDA‐MB‐231 cancer cells. Moreover, compound 15 exerted cell cycle arrest at both the G0‐G1 and G2‐M phases. The in vivo efficacy of compound 15 as an antitumor agent was further investigated in female mice bearing Solid Ehrlich Carcinoma. Notably, administration of compound 15 resulted in a marked decrease in both tumor weight and volume, accompanied by improvements in biochemical, hematological, histological, and immunohistochemical parameters that verified the repression of both angiogenesis and inflammation as additional Anticancer mechanisms. Moreover, the binding interactions of compounds 15 and 17 within the binding sites of all three target receptors (EGFR, FGFR3, and VEGF) were clearly illustrated using molecular docking. [ABSTRACT FROM AUTHOR]

Cities in South America face many of the urban water supply challenges experienced globally including increasingly extreme future hydroclimatic conditions and rapid population growth. These challenges are further exacerbated by historical socioeconomic inequity, informal land occupation, and poor water services management. In recent years, decision support tools that aid in structuring water supply management and infrastructure pathway policies that remain robust under deeply uncertain future scenarios have been developed. However, within the context of developing countries, failing to acknowledge the complex social and institutional dynamics and stark differences in residents' experiences of climate extremes may lead to uneven adaptation capacities across socioeconomic strata. Toward this end, our study extends the deeply uncertain pathways framework by applying multiobjective optimization, disaggregated service area-level assessments of performance and vulnerability across time, and exploratory visual analytics in the Federal District of Brazil (FDB). We highlight the performance and robustness disparities between two water supply service areas in the FDB that differ in socioeconomic standing to reveal the impacts of deeply uncertain future hydroclimatic and socioeconomic scenarios on vulnerable populations. We further show that historical inequity renders poorer residents significantly more vulnerable to deeply uncertain future conditions without urgent and significant infrastructure investments. Overall, the outcomes of our study are largely applicable to urban water utilities in regions with high levels of historical regional inequity seeking to develop water management and infrastructure planning policies that are robust, adaptive, and equitable. [ABSTRACT FROM AUTHOR]

The term 'priming exercise' has recently been introduced to describe exercise stimuli prescribed to enhance performance within 1–48 hours of that stimulus. Despite evidence of these activities being utilised in competitive settings, the reasoning underpinning the application of priming exercise is not yet clear. Therefore, this study aimed to explore practitioners' perceptions about using priming exercise as a pre-competition strategy to improve performance. Semi-structured interviews were conducted with 28 practitioners involved in prescribing training programs to elite Australian athletes. Reflexive thematic analysis revealed six organising themes (i.e. 'limited and inapplicable research findings', 'consideration of athletes' training age', risk-return of priming session outcomes', 'logistical concerns', 'buy-in' and 'priming exercise prescription') later grouped into a global theme, representing the 'challenges of applying priming exercise'. The findings highlight contextual factors influencing practitioners' use of priming exercise and, based on these considerations, draw attention to the apparent uncertainty about whether these stimuli can be prescribed effectively to improve competition performance in sports. In addition to gaining insight into applied priming strategies, the present findings may be used to inform externally valid and relevant study designs that subsequently guide practice. [ABSTRACT FROM AUTHOR]

Environmental fate and toxicity testing typically requires knowledge of the water solubility of the test substances. Determining the solubility of aromatic diisocyanates in water poses great challenges because of their hydrophobic nature and water-reactivity. The reactive dissolution process is dynamic and the establishment of a steady-state equilibrium cannot readily be observed. In preparation of experimental work, computer simulation was used to derive and evaluate criteria that enable distinguishing homogeneous (i.e., substances would be fully dissolved in water) from heterogeneous (i.e., a separate organic phase would be present) conditions. The simulation utilized available kinetic information and models representing the main physical and chemical processes taking place. It was found that the transition to heterogeneous conditions (i.e., the exceedance of the solubility limit with increasing loading) can be identified by observing either a rapid decline in ultimate yield of the diamine hydrolysis product from near-stoichiometric to much lower values, or a decrease in rate of formation of the diamine hydrolysis product relative to its ultimate yield. The latter criterion is expected to be the more powerful indicator. These criteria can be used in future work to define and interpret an experimental program for determining solubility limits for aromatic diisocyanates or other poorly-soluble, water-reactive substances. [ABSTRACT FROM AUTHOR]

Combinatorial antiretroviral therapy (cART) has transformed HIV infection from a death sentence to a controllable chronic disease, but cannot eliminate the virus. Latent HIV-1 reservoirs are the major obstacles to cure HIV-1 infection. Previously, we engineered exosomal Tat (Exo-Tat) to reactivate latent HIV-1 from the reservoir of resting CD4+ T cells. Here, we present an HIV-1 eradication platform, which uses our previously described Exo-Tat to activate latent virus from resting CD4+ T cells guided by the specific binding domain of CD4 in interleukin 16 (IL16), attached to the N-terminus of exosome surface protein lysosome-associated membrane protein 2 variant B (Lamp2B). Cells with HIV-1 surface protein gp120 expressed on the cell membranes are then targeted for immune cytolysis by a BiTE molecule CD4-αCD3, which colocalizes the gp120 surface protein of HIV-1 and the CD3 of cytotoxic T lymphocytes. Using primary blood cells obtained from antiretroviral treated individuals, we find that this combined approach led to a significant reduction in replication-competent HIV-1 in infected CD4+ T cells in a clonal in vitro cell system. Furthermore, adeno-associated virus serotype DJ (AAV-DJ) was used to deliver Exo-Tat, IL16lamp2b and CD4-αCD3 genes by constructing them in one AAV-DJ vector (the plasmid was named pEliminator). The coculture of T cells from HIV-1 patients with Huh-7 cells infected with AAV-Eliminator viruses led to the clearance of HIV-1 reservoir cells in the in vitro experiment, which could have implications for reducing the viral reservoir in vivo, indicating that Eliminator AAV viruses have the potential to be developed into therapeutic biologics to cure HIV-1 infection. [ABSTRACT FROM AUTHOR]

The article presents a novel statistical framework for COVID-19 transmission monitoring and control, which was developed and deployed at The Ohio State University main campus in Columbus during the Autumn term of 2020. Our approach effectively handles prevalence data with interval censoring and explicitly incorporates changes in transmission dynamics and human behaviour. To illustrate the methodology's usefulness, we apply it to both synthetic and actual student SARS-CoV-2 testing data collected at the OSU Columbus campus in late 2020. [ABSTRACT FROM AUTHOR]

Development of optimal therapeutics for disease states that can be associated with increased membrane cholesterol requires better molecular understanding of lipid modulation of the drug target. Type 1 cholecystokinin receptor (CCK1R) agonist actions are affected by increased membrane cholesterol, enhancing ligand binding and reducing calcium signaling, while agonist actions of the closely related CCK2R are not. In this work, we identified a set of chimeric human CCK1R/CCK2R mutations that exchange the cholesterol sensitivity of these 2 receptors, providing powerful tools when expressed in CHO and HEK-293 model cell lines to explore mechanisms. Static, low energy, high-resolution structures of the mutant CCK1R constructs, stabilized in complex with G protein, were not substantially different, suggesting that alterations to receptor dynamics were key to altered function. We reveal that cholesterol-dependent dynamic changes in the conformation of the helical bundle of CCK receptors affects both ligand binding at the extracellular surface and G protein coupling at the cytosolic surface, as well as their interrelationships involved in stimulus-response coupling. This provides an ideal setting for potential allosteric modulators to correct the negative impact of membrane cholesterol on CCK1R. A previous study in PLOS Biology solved the cryo-EM structure of the cholecystokinin type 1 receptor (CCK1R) to gain insights into the mechanisms governing G protein selectivity. This Update Article provides a structural and biophysical characterization of the effects of cholesterol on ligand binding and G protein coupling at the receptor. [ABSTRACT FROM AUTHOR]

The sequencing platform and workflow strongly influence microbial community analyses through potential errors at each step. Effective diagnostics and experimental controls are needed to validate data and improve reproducibility. This cross-laboratory study evaluates sources of variability and error at three main steps of a standardized amplicon sequencing workflow (DNA extraction, polymerase chain reaction [PCR], and sequencing) using Oxford Nanopore MinION to analyze agricultural soils and a simple mock community. Variability in sequence results occurs at each step in the workflow with PCR errors and differences in library size greatly influencing diversity estimates. Common bioinformatic diagnostics and the mock community are ineffective at detecting PCR abnormalities. This work outlines several diagnostic checks and techniques to account for sequencing depth and ensure accuracy and reproducibility in soil community analyses. These diagnostics and the inclusion of a reference soil can help ensure data validity and facilitate the comparison of multiple sequencing runs within and between laboratories.A soil bacterial amplicon sequencing study using the Nanopore MinION platform suggests that common diagnostics are insufficient to detect irregular community results and recommends further diagnostics and the use of a reference soil as a mock community. [ABSTRACT FROM AUTHOR]

Targeting allosteric sites of M1 muscarinic acetylcholine receptors (M1 receptors) is a promising strategy to treat neurocognitive disorders, such as Alzheimer's disease and schizophrenia. Indeed, the last two decades have seen an impressive body of work focussing on the design and development of positive allosteric modulators (PAMs) for the M1 receptor. This has led to the identification of a structurally diverse range of highly selective M1 PAMs. In preclinical models, M1 PAMs have shown rescue of cognitive deficits and improvement of endpoints predictive of symptom domains of schizophrenia. Yet, to date only a few M1 PAMs have reached early‐stage clinical trials, with many of them failing to progress further due to on‐target mediated cholinergic adverse effects that have plagued the development of this class of ligand. This review covers the recent preclinical and clinical studies in the field of M1 receptor drug discovery for the treatment of Alzheimer's disease and schizophrenia, with a specific focus on M1 PAM, highlighting both the undoubted potential but also key challenges for the successful translation of M1 PAMs from bench‐side to bedside. LINKED ARTICLES: This article is part of a themed issue Therapeutic Targeting of G Protein‐Coupled Receptors: hot topics from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists 2021 Virtual Annual Scientific Meeting. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.14/issuetoc [ABSTRACT FROM AUTHOR]

Objective: The pleated sea squirt Styela plicata (subphylum Tunicata), an invasive marine invertebrate in coastal waters of southeastern North Carolina, was investigated as an alternative protein source to fish meal (FM) in the diet of juvenile Black Sea Bass Centropristis striata. Methods: Six different isoproteic and isolipidic diets were formulated to replace 0.0, 8.3, 16.7, 25.0, 33.3, and 41.6% of FM protein with tunicate meal (TM) protein by supplementing 0, 5, 10, 15, 20, and 25% TM in the diets. The experimental system consisted of eighteen 75‐L tanks supported by a recirculating seawater system in an indoor, climate‐controlled laboratory. Juveniles (average weight = 7.1 g) were stocked at a density of 15 fish/tank (N = 3 tanks/treatment) and were fed the test diets daily to apparent satiation for 55 days. Result: Replacement of FM protein with TM protein caused slight declines in dietary amino acid concentrations (notably arginine, methionine, and tryptophan) at higher replacement levels. At terminal sampling, no significant differences in survival (87–96%), percent body weight gain (157–228%), feed conversion ratio (1.50–1.71), or proximate composition were observed among dietary treatment groups. However, significant positive linear trends were found between incremental levels of TM and final fish weight, body weight gain, and specific growth rate. Whole‐body fatty acid composition reflected dietary levels. Conclusion: Results indicate that TM protein can be used to replace at least 41.6% of the FM protein in the diet for juvenile Black Sea Bass without adverse effects on survival, growth, feed utilization, or whole‐body proximate composition. Impact statementSea squirts (subphylum Tunicata) are suspension‐feeding marine invertebrates. They foul shellfish cages, lines, and the shellfish directly, thus increasing the resource competition experienced by the shellfish. The use of tunicates in aquaculture feed is a possible way to reduce reliance on expensive and unsustainable fish meal protein in aquafeeds. The use of tunicate meal in aquafeeds could be another new cost‐effective alternative protein source with which to develop sustainable feed for aquaculture while reducing the fouling problem in marine shellfish aquaculture. [ABSTRACT FROM AUTHOR]

Purpose: Frailty is common in critically ill patients but the timing and optimal method of frailty ascertainment, trajectory and relationship with care processes remain uncertain. We sought to elucidate the trajectory and care processes of frailty in critically ill patients as measured by the Clinical Frailty Scale (CFS) and Frailty Index (FI). Methods: This is a multi-centre prospective cohort study enrolling patients ≥ 50 years old receiving life support > 24 h. Frailty severity was assessed with a CFS, and a FI based on the elements of a comprehensive geriatric assessment (CGA) at intensive care unit (ICU) admission, hospital discharge and 6 months. For the primary outcome of frailty prevalence, it was a priori dichotomously defined as a CFS ≥ 5 or FI ≥ 0.2. Processes of care, adverse events were collected during ICU and ward stays while outcomes were determined for ICU, hospital, and 6 months. Results: In 687 patients, whose age (mean ± standard deviation) was 68.8 ± 9.2 years, frailty prevalence was higher when measured with the FI (CFS, FI %): ICU admission (29.8, 44.8), hospital discharge (54.6, 67.9), 6 months (34.1, 42.6). Compared to ICU admission, aggregate frailty severity increased to hospital discharge but improved by 6 months; individually, CFS and FI were higher in 45.3% and 50.6% patients, respectively at 6 months. Compared to hospital discharge, 18.7% (CFS) and 20% (FI) were higher at 6 months. Mortality was higher in frail patients. Processes of care and adverse events were similar except for worse ICU/ward mobility and more frequent delirium in frail patients. Conclusions: Frailty severity was dynamic, can be measured during recovery from critical illness using the CFS and FI which were both associated with worse outcomes. Although the CFS is a global measure, a CGA FI based may have advantages of being able to measure frailty levels, identify deficits, and potential targets for intervention. [ABSTRACT FROM AUTHOR]

The APOE4 allele is recognized as a significant genetic risk factor to Alzheimer's disease (AD) and influences longevity. Nonetheless, some APOE4 carriers exhibit resistance to AD even in advanced age. Humanin, a mitochondrial‐derived peptide comprising 24 amino acids, has variants linked to cognitive resilience and longevity. Our research uncovered a unique humanin variant, P3S, specifically enriched in centenarians with the APOE4 allele. Through in silico analyses and subsequent experimental validation, we demonstrated a strong affinity between humanin P3S and APOE4. Utilizing an APOE4‐centric mouse model of amyloidosis (APP/PS1/APOE4), we observed that humanin P3S significantly attenuated brain amyloid‐beta accumulation compared to the wild‐type humanin. Transcriptomic assessments of mice treated with humanin P3S highlighted its potential mechanism involving the enhancement of amyloid beta phagocytosis. Additionally, in vitro studies corroborated humanin P3S's efficacy in promoting amyloid‐beta clearance. Notably, in the temporal cortex of APOE4 carriers, humanin expression is correlated with genes associated with phagocytosis. Our findings suggest a role of the rare humanin variant P3S, especially prevalent among individuals of Ashkenazi descent, in mitigating amyloid beta pathology and facilitating phagocytosis in APOE4‐linked amyloidosis, underscoring its significance in longevity and cognitive health among APOE4 carriers. [ABSTRACT FROM AUTHOR]

Aim: Study the association between neighbourhood risk and behaviour in extreme preterm (EPT) children. We hypothesised that EPT children living in high‐risk neighbourhoods have increased risk of clinical range behaviour problems at age 30–36 months. Methods: Retrospective analyses of Child Behavior Checklist (CBCL)scores for 739 EPTs born 2005–2016. Addresses were geocoded to identify census block groups and create high versus low‐risk groups. Regression analyses assessed the impact of neighbourhood risk on behaviour. Results: Children from high‐risk (N = 272, 39%) and low‐risk (N = 417, 61%) neighbourhoods were compared. In adjusted analyses, odds of clinical range scores remained greater in high‐risk neighbourhoods for Emotionally Reactive (OR: 4.32, CI: 1.13, 16.51), Somatic Complaints (2.30, CI 1.11,4.79), Withdrawn (OR: 2.56, CI: 1.21, 5,42), Aggressive Behaviour (OR: 4.12, CI: 1.45, 11.68), Internalising (OR: 1.96, CI: 1.17, 3.28), and Total score (OR: 1.86, OR: CI: 1.13, 3.07). Cognitive delay was higher in high‐risk neighbourhoods and a risk factor for Attention Problems (2.10,1.08, 4.09). Breast milk was protective for Emotionally Reactive (OR: 0.22, CI: 0.06, 0.85) and Sleep Problems (OR: 0.47, CI:0.24, 0.94). Conclusion: Neighbourhood risk provided an independent contribution to preterm adverse behaviour outcomes with cognitive delay an additional independent risk factor. Breast milk at discharge was protective. [ABSTRACT FROM AUTHOR]

Botulinum neurotoxins are some of the most potent natural toxins known; they cause flaccid paralysis by inhibiting synaptic vesicle release. Some serotypes, notably serotype A and B, can cause persistent paralysis lasting for several months. Because of their potency and persistence, botulinum neurotoxins are now used to manage several clinical conditions, and there is interest in expanding their clinical applications using engineered toxins with novel substrate specificities. It will also be beneficial to engineer toxins with tunable persistence. We have investigated the potential use of small-molecule proteolysis-targeting chimeras (PROTACs) to vary the persistence of modified recombinant botulinum neurotoxins. We also describe a complementary approach that has potential relevance for botulism treatment. This second approach uses a camelid heavy chain antibody directed against botulinum neurotoxin that is modified to bind the PROTAC. These strategies provide proof of principle for the use of two different approaches to fine tune the persistence of botulinum neurotoxins by selectively targeting their catalytic light chains for proteasomal degradation. [ABSTRACT FROM AUTHOR]

Tributary valleys along the Pigeon River in southwestern Michigan USA possess many previously defined criteria for sapping valleys. Direct observations of seasonal variations in groundwater levels, hydraulic gradients and water temperatures confirm that perennial springs and their streams are present in these small valleys. Estimated spring‐fed stream discharges are low and variable, but continuous. Direct observations, grain‐size distributions and bedload transport estimates indicate that significant transport of fine to medium sand occurs in all seasons. We present a process‐form model for small‐scale sapping processes. Stream terraces and paleo‐meander scarps are being modified by sapping, and elongated valleys are likely being lengthened headward by groundwater sapping. Sapping processes have been occurring for at least the past ~4,500 years after Pigeon River adjusted to a fall in base level from the Nipissing high stand to the modern level of Lake Michigan. Sapping processes are currently producing a variety of small‐scale landforms dependent on four main factors: 1) hydraulic gradients and spring discharges, 2) available grain size of material being eroded, 3) transport rate of sand bedload by spring‐fed streams and finally 4) time available for groundwater sapping process to occur. [ABSTRACT FROM AUTHOR]

Northern peatlands are a globally significant source of methane (CH4), and emissions are projected to increase due to warming and permafrost loss. Understanding the microbial mechanisms behind patterns in CH4 production in peatlands will be key to predicting annual emissions changes, with stable carbon isotopes (δ13C‐CH4) being a powerful tool for characterizing these drivers. Given that δ13C‐CH4 is used in top‐down atmospheric inversion models to partition sources, our ability to model CH4 production pathways and associated δ13C‐CH4 values is critical. We sought to characterize the role of environmental conditions, including hydrologic and vegetation patterns associated with permafrost thaw, on δ13C‐CH4 values from high‐latitude peatlands. We measured porewater and emitted CH4 stable isotopes, pH, and vegetation composition from five boreal‐Arctic peatlands. Porewater δ13C‐CH4 was strongly associated with peatland type, with δ13C enriched values obtained from more minerotrophic fens (−61.2 ± 9.1‰) compared to permafrost‐free bogs (−74.1 ± 9.4‰) and raised permafrost bogs (−81.6 ± 11.5‰). Variation in porewater δ13C‐CH4 was best explained by sedge cover, CH4 concentration, and the interactive effect of peatland type and pH (r2 = 0.50, p < 0.001). Emitted δ13C‐CH4 varied greatly but was positively correlated with porewater δ13C‐CH4. We calculated a mixed atmospheric δ13C‐CH4 value for northern peatlands of −65.3 ± 7‰ and show that this value is more sensitive to landscape drying than wetting under permafrost thaw scenarios. Our results suggest northern peatland δ13C‐CH4 values are likely to shift in the future which has important implications for source partitioning in atmospheric inversion models. Plain Language Summary: Peatlands are abundant across the boreal‐Arctic landscape and are important sources of methane, a powerful greenhouse gas. The amount of methane emitted into the atmosphere depends on multiple factors including the organic material being decomposed and the microbial processes ("pathways") that produce methane. The different pathways of methane production leave distinct fingerprints ("stable carbon isotopes") on methane that provide information on how that methane was formed and help to trace methane in the atmosphere back to its ground source. We looked at how stable carbon isotopes change across five northern peatland locations and wanted to know what controls those changes. We found that stable carbon isotopes differ between bogs and fens and are further controlled by soil pH and the abundance of sedge vegetation present. We used this information to test how stable carbon isotopes from northern peatlands might change as the landscape becomes wetter or drier due to the impacts of climate change. We found that peatland stable carbon isotopes are most sensitive to potential landscape drying opposed to wetting which has important implications for improving methane emission models. Key Points: Porewater δ13C‐CH4 values of northern bogs and fens differ from each other and correlate with emitted δ13C‐CH4 valuesIn addition to peatland type, vascular plant cover, pH, and CH4 concentration help explain variation in porewater δ13C‐CH4 valuesThe δ13C‐CH4 value for northern peatlands is more sensitive to landscape drying than wetting under permafrost thaw scenarios [ABSTRACT FROM AUTHOR]

Vehicle bills are used by many state legislatures, including the South Dakota Legislature. These bills serve as empty shells to be amended with substantive text later in the legislative session. Critics charge that such vehicles allow legislators to meet the filing deadline with an essentially meaningless bill that gets amended late in the session, thereby depriving the public and opposition legislators from adequately investigating and debating the newly amended bill. This article examines how, and to what extent, the South Dakota Legislature has used vehicle bills over the past decade. In so doing, the article may provide some insight into how the use of these vehicle bills can affect the legislative process and its advancement of republican and democratic values. [ABSTRACT FROM AUTHOR]

In this study, we delved into the comparative analysis of gene expression data across RNA-Seq and NanoString platforms. While RNA-Seq covered 19,671 genes and NanoString targeted 773 genes associated with immune responses to viruses, our primary focus was on the 754 genes found in both platforms. Our experiment involved 16 different infection conditions, with samples derived from 3D airway organ-tissue equivalents subjected to three virus types, influenza A virus (IAV), human metapneumovirus (MPV), and parainfluenza virus 3 (PIV3). Post-infection measurements, after UV (inactive virus) and Non-UV (active virus) treatments, were recorded at 24-h and 72-h intervals. Including untreated and Mock-infected OTEs as control groups enabled differentiating changes induced by the virus from those arising due to procedural elements. Through a series of methodological approaches (including Spearman correlation, Distance correlation, Bland-Altman analysis, Generalized Linear Models Huber regression, the Magnitude-Altitude Score (MAS) algorithm and Gene Ontology analysis) the study meticulously contrasted RNA-Seq and NanoString datasets. The Magnitude-Altitude Score algorithm, which integrates both the amplitude of gene expression changes (magnitude) and their statistical relevance (altitude), offers a comprehensive tool for prioritizing genes based on their differential expression profiles in specific viral infection conditions. We observed a strong congruence between the platforms, especially in identifying key antiviral defense genes. Both platforms consistently highlighted genes including ISG15, MX1, RSAD2, and members of the OAS family (OAS1, OAS2, OAS3). The IFIT proteins (IFIT1, IFIT2, IFIT3) were emphasized for their crucial role in counteracting viral replication by both platforms. Additionally, CXCL10 and CXCL11 were pinpointed, shedding light on the organ tissue equivalent's innate immune response to viral infections. While both platforms provided invaluable insights into the genetic landscape of organoids under viral infection, the NanoString platform often presented a more detailed picture in situations where RNA-Seq signals were more subtle. The combined data from both platforms emphasize their joint value in advancing our understanding of viral impacts on lung organoids. [ABSTRACT FROM AUTHOR]