Search

Efficient distribution of oxygen (O2) to the tissues in mammals depends on the evolved ability of red blood cell (RBC) hemoglobin (Hb) to sense not only O2 levels, but metabolic cues such as pH, PCO2, and organic phosphates, and then dispense or take up oxygen accordingly. O2 delivery is the product of not only oxygen release from RBCs, but also blood flow, which itself is also governed by vasoactive molecular mediators exported by RBCs. These vascular signals, including ATP and S-nitrosothiols (SNOs) are produced and exported as a function of the oxygen and metabolic milieu, and then fine-tune peripheral metabolism through context-sensitive vasoregulation. Emerging and repurposed RBC-oriented therapeutics can modulate either or both of these allosteric and vasoregulatory activities, with a single molecule or other intervention influencing both arms of O2 transport in some cases. For example, organic phosphate repletion of stored RBCs boosts the negative allosteric effector 2,3 biphosphoglycerate (BPG) as well as the anti-adhesive molecule ATP. In sickle cell disease, aromatic aldehydes such as voxelotor can disfavor sickling by increasing O2 affinity, and in newer generations, these molecules have been coupled to vasoactive nitric oxide (NO)-releasing adducts. Activation of RBC pyruvate kinase also promotes a left shift in oxygen binding by consuming and lowering BPG, while increasing the ATP available for cell health and export on demand. Further translational and clinical investigation of these novel allosteric and/or vasoregulatory approaches to modulating O2 transport are expected to yield new insights and improve the ability to correct or compensate for anemia and other O2 delivery deficits.

Abstract Background Many people suffer from body and breath malodour syndromes. One of these is trimethylaminuria, a condition characterized by excretion in breath and bodily fluids of trimethylamine, a volatile and odorous chemical that has the smell of rotting fish. Trimethylaminuria can be primary, due to mutations in the gene encoding flavin-containing monooxygenase 3, or secondary, due to various causes. To gain a better understanding of problems faced by United Kingdom residents affected by body and breath malodour conditions, we conducted a survey. Methods Two anonymous online surveys, one for adults and one for parents/guardians of affected children, were conducted using the Opinio platform. Participants were invited via a trimethylaminuria advisory website. Questions were a mix of dropdown, checkbox and open-ended responses. Forty-four adults and three parents/guardians participated. The dropdown and checkbox responses were analysed using the Opinio platform. Results All participants reported symptoms of body/breath odour. However, not all answered every question. Twenty-three respondents experienced difficulties in being offered a diagnostic test for trimethylaminuria. Problems encountered included lack of awareness of the disorder by medical professionals and reluctance to recognise symptoms. Of those tested, 52% were diagnosed with trimethylaminuria. The main problems associated with living with body/breath malodours were bullying, harassment and ostracism in either the workplace (90%) or in social settings (88%). All respondents thought their condition had disadvantaged them in their daily lives. Open-ended responses included loss of confidence, stress, exclusion, isolation, loneliness, depression and suicidal thoughts. Respondents thought their lives could be improved by greater awareness and understanding of malodour conditions by medical professionals, employers and the general public, and appreciation that the malodour was due to a medical condition and not their fault. Conclusions Breath and body malodour conditions can cause immense hardship and distress, both mentally and socially, having devastating effects on quality of life. It would be advantageous to establish a standardised pathway from primary care to a specialist unit with access to a robust and reliable test and diagnostic criteria. There is a need to recognise malodour disorders as a disability, giving affected individuals the same rights as those with currently recognised disabilities.

Abstract Here, the authors report that co‐crystallization of fluorophores with matrix‐assisted laser desorption/ionization (MALDI) imaging matrices significantly enhances fluorophore brightness up to 79‐fold, enabling the amplification of innate tissue autofluorescence. This discovery facilitates FluoMALDI, the imaging of the same biological sample by both fluorescence microscopy and MALDI imaging. The approach combines the high spatial resolution and specific labeling capabilities of fluorescence microscopy with the inherently multiplexed, versatile imaging capabilities of MALDI imaging. This new paradigm simplifies registration by avoiding physical changes between fluorescence and MALDI imaging, allowing to image the exact same cells in tissues with both modalities. Matrix‐fluorophore co‐crystallization also facilitates applications with insufficient fluorescence brightness. The authors demonstrate feasibility of FluoMALDI imaging with endogenous and exogenous fluorophores and autofluorescence‐based FluoMALDI of brain and kidney tissue sections. FluoMALDI will advance structural‐functional microscopic imaging in cell biology, biomedicine, and pathology.

Abstract Background In the wake of an epidemic in firearm-related deaths and injuries, youth have become leading voices of concern. This study’s objective was to investigate rural youth’s personal experiences with firearm-related violence, and their attitudes towards firearms and gun violence prevention strategies. Methods Attendees of the 2019 Iowa FFA Leadership Conference were surveyed about personal experiences with firearm-associated deaths and injuries, and their attitudes regarding firearm-related issues. Descriptive (frequencies), bivariate (chi square, Fisher’s exact test) and multivariable logistic regression analyses were performed utilizing Stata 15.1 (StataCorp, College Station, Texas). Results Responses from 1382 FFA members 13–18 years of age were analyzed. About 5% had personally seen someone threatened with a firearm. Over one-third (36%) stated they knew someone who had been killed or injured by gunfire. Of these, over two-thirds knew of someone who had died or was injured unintentionally and 30% knew of someone killed or injured intentionally (e.g. suicide). Nearly all agreed or strongly agreed that the right to use firearms for hunting and shooting sports should be legal (94%), that a firearm safety course should be required to get a hunting license (89%), and that there should be a required background check before purchasing a firearm (89%). Over three-fifths (61%) agreed or strongly agreed that there should be laws requiring safe storage of firearms in homes. Although still high, lesser support for firearm safety policies was seen among males, older youth, participants living on farms or in the country, and youth who hunted, had firearms in their homes, and/or were in homes with unsafe firearm storage. Conclusions The majority of youth in this study supported firearm safety measures including required training, background checks, and safe firearm storage in homes. These findings are consistent with the national youth-led call for firearm safety. Additionally, over one-third of respondents personally knew someone who was killed or injured by a firearm and 5% had seen someone or been personally threatened with firearm violence. Our study did not investigate the effects of firearm violence on participants’ mental health and wellbeing, but future studies addressing this question seem highly justified.

Metabolic homeostasis in animals depends critically on evolved mechanisms by which red blood cell (RBC) hemoglobin (Hb) senses oxygen (O2) need and responds accordingly. The entwined regulation of ATP production and antioxidant systems within the RBC also exploits Hb-based O2-sensitivity to respond to various physiologic and pathophysiologic stresses. O2 offloading, for example, promotes glycolysis in order to generate both 2,3-DPG (a negative allosteric effector of Hb O2 binding) and ATP. Alternatively, generation of the nicotinamide adenine dinucleotide phosphate (NADPH) critical for reducing systems is favored under the oxidizing conditions of O2 abundance. Dynamic control of ATP not only ensures the functional activity of ion pumps and cellular flexibility, but also contributes to the availability of vasoregulatory ATP that can be exported when necessary, for example in hypoxia or upon RBC deformation in microvessels. RBC ATP export in response to hypoxia or deformation dilates blood vessels in order to promote efficient O2 delivery. The ability of RBCs to adapt to the metabolic environment via differential control of these metabolites is impaired in the face of enzymopathies [pyruvate kinase deficiency; glucose-6-phosphate dehydrogenase (G6PD) deficiency], blood banking, diabetes mellitus, COVID-19 or sepsis, and sickle cell disease. The emerging availability of therapies capable of augmenting RBC ATP, including newly established uses of allosteric effectors and metabolite-specific additive solutions for RBC transfusates, raises the prospect of clinical interventions to optimize or correct RBC function via these metabolite delivery mechanisms.

Introduction: Rural areas have higher rates of firearm-related unintentional and suicide deaths. Having access to a firearm greatly increases suicide risk. Safe firearm storage can be a major factor in preventing these tragedies. In this study we evaluated firearm exposure and storage practices in rural adolescents’ homes. Methods: An anonymous survey was administered to a convenience sample of attendees at the 2019 Iowa FFA (formerly Future Farmers of America) Leadership Conference. We performed descriptive, bivariate and multivariable logistic regression analyses. Results: A total of 1,382 adolescents participated; 51% were males and 49% were females. Respondents were 13–18 years old, and 53% lived on a farm, 18% in the country/not on a farm, and 29% in town. Almost all (96%) self-identified as White/Caucasian. In their homes, 84% reported having rifles/shotguns, 58% reported having handguns, and 56% reported having both rifles/shotguns and handguns. Males were significantly more likely than females to report having firearms in their home (P

The Native American Astronomy Outreach Program (NAAOP) at Lowell Observatory is an in-class STEM enrichment program that pairs astronomers with 4th-8th grade teachers at Native-serving schools in northern Arizona. The astronomer works with the teacher to present hands-on astronomy activities to their class with the goal of getting students excited about STEM and STEM careers. Over three school years (2018-2021), a special collaboration with teachers at the Navajo Nation's Kayenta Unified School District was used to develop and implement curriculum units for each grade level with potential for a high impact on students. The curriculum used Project Based Learning to better enable students to see themselves as scientists, and it included cultural and local connections related to the science content to encourage students to see science as relevant to themselves. Although impacted by the COVID-19 pandemic, student surveys suggest that these curriculum units along with the other components of the program had a positive impact on students' interest in STEM.

Statistical inference is a widely-used, powerful tool for learning about natural processes in diverse fields. The statistical software platforms AD Model Builder (ADMB) and Template Model Builder (TMB) are particularly popular in the ecological literature, where they are typically used to perform frequentist inference of complex models. However, both lack capabilities for flexible and efficient Markov chain Monte Carlo (MCMC) integration. Recently, the no-U-turn sampler (NUTS) MCMC algorithm has gained popularity for Bayesian inference through the software Stan because it is efficient for high dimensional, complex hierarchical models. Here, we introduce the R packages adnuts and tmbstan, which provide NUTS sampling in parallel and interactive diagnostics with ShinyStan. The ADMB source code was modified to provide NUTS, while TMB models are linked directly into Stan. We describe the packages, provide case studies demonstrating their use, and contrast performance against Stan. For TMB models, we show how to test the accuracy of the Laplace approximation using NUTS. For complex models, the performance of ADMB and TMB was typically within +/- 50% the speed of Stan. In one TMB case study we found inaccuracies in the Laplace approximation, potentially leading to biased inference. adnuts provides a new method for estimating hierarchical ADMB models which previously were infeasible. TMB users can fit the same model in both frequentist and Bayesian paradigms, including using NUTS to test the validity of the Laplace approximation of the marginal likelihood for arbitrary subsets of parameters. These software developments extend the available statistical methods of the ADMB and TMB user base with no additional effort by the user.

Blue whales (Balaenoptera musculus) were exploited extensively around the world and remain endangered. In the North Pacific their population structure is unclear and current status unknown, with the exception of a well-studied eastern North Pacific (ENP) population. Despite existing abundance estimates for the ENP population, it is difficult to estimate pre-exploitation abundance levels and gauge their recovery because historical catches of the ENP population are difficult to separate from catches of other populations in the North Pacific. We collated previously unreported Soviet catches and combined these with known catches to form the most current estimates of North Pacific blue whale catches. We split these conflated catches using recorded acoustic calls from throughout the North Pacific, the knowledge that the ENP population produces a different call than blue whales in the western North Pacific (WNP). The catches were split by estimating spatiotemporal occurrence of blue whales with generalized additive models fitted to acoustic call patterns, which predict the probability a catch belonged to the ENP population based on the proportion of calls of each population recorded by latitude, longitude, and month. When applied to the conflated historical catches, which totaled 9,773, we estimate that ENP blue whale catches totaled 3,411 (95% range 2,593 to 4,114) from 1905-1971, and amounted to 35% (95% range 27% to 42%) of all catches in the North Pacific. Thus most catches in the North Pacific were for WNP blue whales, totaling 6,362 (95% range 5,659 to 7,180). The uncertainty in the acoustic data influence the results substantially more than uncertainty in catch locations and dates, but the results are fairly insensitive to the ecological assumptions made in the analysis. The results of this study provide information for future studies investigating the recovery of these populations and the impact of continuing and future sources of anthropogenic mortality.

Simulation testing is an important approach to evaluating fishery stock assessment methods. In the last decade, the fisheries stock assessment modeling framework Stock Synthesis (SS3) has become widely used around the world. However, there lacks a generalized and scriptable framework for SS3 simulation testing. Here, we introduce ss3sim, an R package that facilitates reproducible, flexible, and rapid end-to-end simulation testing with SS3. ss3sim requires an existing SS3 model configuration along with plain-text control files describing alternative population dynamics, fishery properties, sampling scenarios, and assessment approaches. ss3sim then generates an underlying 'truth' from a specified operating model, samples from that truth, modifies and runs an estimation model, and synthesizes the results. The simulations can be run in parallel, reducing runtime, and the source code is free to be modified under an open-source MIT license. ss3sim is designed to explore structural differences between the underlying truth and assumptions of an estimation model, or between multiple estimation model configurations. For example, ss3sim can be used to answer questions about model misspecification, retrospective patterns, and the relative importance of different types of fisheries data. We demonstrate the software with an example, discuss how ss3sim complements other simulation software, and outline specific research questions that ss3sim could address.

Introduction: Rural areas have higher rates of firearm-related unintentional and suicide deaths.  Having access to a firearm greatly increases suicide risk. Safe firearm storage can be a major factor in preventing these tragedies. In this study we evaluated firearm exposure and storage practices in rural adolescents’ homes.Methods: An anonymous survey was administered to a convenience sample of attendees at the 2019 Iowa FFA (formerly Future Farmers of America) Leadership Conference. We performed descriptive, bivariate and multivariable logistic regression analyses.Results: A total of 1,382 adolescents participated; 51% were males and 49% were females. Respondents were 13-18 years old, and 53% lived on a farm, 18% in the country/not on a farm, and 29% in town. Almost all (96%) self-identified as White/Caucasian. In their homes, 84% reported having rifles/shotguns, 58% reported having handguns, and 56% reported having both rifles/shotguns and handguns. Males were significantly more likely than females to report having firearms in their home (P

Purpose: Our objective was to investigate rural adolescents' use of firearms and whether they had received firearm training. Methods: 2019 Iowa FFA Leadership Conference attendees were surveyed. Descriptive and comparative analyses were performed. Results: One thousand three hundred and eighty‐two FFA members aged 13‐18 years participated. The vast majority (85%) had fired a rifle/shotgun; 58% reported firing them >20 times. Of those who had fired rifles/shotguns, 32% had done so before 9 years old; 79% before 13 years. Most had also fired a handgun (62%), with 30% having fired handguns >20 times. Of those who had fired handguns, 34% had done so before 11 years old. The average age for first firing rifles/shotguns was 10.1 (SD 2.9) years, and 11.9 (SD 2.8) years for handguns. Males, older teenagers, and those living on farms or in the country had significantly greater percentages that had fired a rifle/shotgun or a handgun. Greater proportions of males had used firearms >20 times and started firing them at younger ages. Over half (55%) reported having gone hunting. Of those, 24% first hunted before 9 years old; 48% before 11 years. Of those who had used a firearm, 61% had completed a firearm safety training course. For hunters, 80% had taken a course. Conclusions: Most participants had used firearms, and many did so at very young ages. Substantial numbers had not received formal training. The authors believe that families should be counseled when it is developmentally appropriate to introduce youth to firearms, and all should take firearm safety training before using them. [ABSTRACT FROM AUTHOR]

The British Columbia longline fishery for Pacific halibut (Hippoglossus stenolepis) has experienced important recent management changes, including the introduction of comprehensive electronic catch monitoring on all vessels; an integrated transferable quota system; a reduction in Pacific halibut quotas; and, beginning in 2016, sharp decreases in quota for yelloweye rockfish (Sebastes ruberrimus, an incidentally caught species). We describe this fishery before integration, after integration, and after the yelloweye rockfish quota reduction using spatial clustering methods to define discrete fishing opportunities. We calculate the relative utilization of these fishing opportunities and their overlap with areas with high encounter rates of yelloweye rockfish during each of the three periods. The spatial footprint (area fished) increased before integration, then decreased after integration. Each period showed shifts in utilization among four large fishing areas. Immediately after the reductions in yelloweye rockfish quota, fishing opportunities with high encounter rates of yelloweye rockfish had significantly lower utilization than areas with low encounter rates, implying rapid avoidance behaviour. La gestion de la peche au fletan du Pacifique (Hippoglossus stenolepis) a la palangre en Colombie-Britannique a recemment connu d'importants changements, dont l'introduction de la surveillance electronique exhaustive des prises sur tous les navires, un systeme de quotas transferables integre, une reduction des quotas de fletans du Pacifique et, depuis 2016, des baisses marquees des quotas de sebastes aux yeux jaunes (Sebastes ruberrimus, une espece pechee accessoirement). Nous decrivons cette peche avant l'integration, apres l'integration et apres la reduction des quotas de sebastes aux yeux jaunes en utilisant des methodes de regroupement spatial pour definir differentes possibilites de peche. Nous calculons l'utilisation relative de ces possibilites de peche et leur chevauchement de zones caracterisees par des taux eleves de rencontres de sebastes aux yeux jaunes durant chacune des trois periodes. L'empreinte spatiale (la superficie visee par la peche) a augmente avant l'integration, puis diminue apres l'integration. Chaque periode a connu des modifications de l'utilisation entre quatre grandes zones de peche. Immediatement apres les reductions des quotas de sebastes a yeux jaunes, les possibilites de peche caracterisees par des taux eleves de rencontres de sebastes a yeux jaunes etaient beaucoup moins utilisees que les zones caracterisees par de faibles taux de rencontres, ce qui indiquerait un comportement d'evitement. [Traduit par la Redaction], Introduction Managing multispecies fisheries with individual transferable quotas (ITQs), coupled with comprehensive monitoring and enforcement, can have positive conservation outcomes for both targeted and incidentally caught species (Costello et al. [...]

In many areas of oncology, we lack sensitive tools to track low-burden disease. Although cell-free DNA (cfDNA) shows promise in detecting cancer mutations, we found that the combination of low tumor fraction (TF) and limited number of DNA fragments restricts low-disease-burden monitoring through the prevailing deep targeted sequencing paradigm. We reasoned that breadth may supplant depth of sequencing to overcome the barrier of cfDNA abundance. Whole-genome sequencing (WGS) of cfDNA allowed ultra-sensitive detection, capitalizing on the cumulative signal of thousands of somatic mutations observed in solid malignancies, with TF detection sensitivity as low as 10.sup.-5. The WGS approach enabled dynamic tumor burden tracking and postoperative residual disease detection, associated with adverse outcome. Thus, we present an orthogonal framework for cfDNA cancer monitoring via genome-wide mutational integration, enabling ultra-sensitive detection, overcoming the limitation of cfDNA abundance and empowering treatment optimization in low-disease-burden oncology care. A new approach for whole-genome sequencing of plasma circulating tumor DNA allows for dynamic monitoring of disease burden and ultra-sensitive detection of minimal residual disease., Author(s): Asaf Zviran [sup.1] [sup.2] , Rafael C. Schulman [sup.1] [sup.2] , Minita Shah [sup.1] , Steven T. K. Hill [sup.1] [sup.2] , Sunil Deochand [sup.1] [sup.2] , Cole C. [...]