How necessary and feasible are reductions of methane emissions from livestock to support stringent temperature goals?

Agriculture is the largest single source of global anthropogenic methane (CH4) emissions, with ruminants the dominant contributor. Livestock CH4 emissions are projected to grow another 30% by 2050 under current policies, yet few countries have set targets or are implementing policies to reduce emissions in absolute terms. The reason for this limited ambition may be linked not only to the underpinning role of livestock for nutrition and livelihoods in many countries but also diverging perspectives on the importance of mitigating these emissions, given the short atmospheric lifetime of CH4. Here, we show that in mitigation pathways that limit warming to 1.5°C, which include cost-effective reductions from all emission sources, the contribution of future livestock CH4 emissions to global warming in 2050 is about one-third of that from future net carbon dioxide emissions. Future livestock CH4 emissions, therefore, significantly constrain the remaining carbon budget and the ability to meet stringent temperature limits. We review options to address livestock CH4 emissions through more efficient production, technological advances and demand-side changes, and their interactions with land-based carbon sequestration. We conclude that bringing livestock into mainstream mitigation policies, while recognizing their unique social, cultural and economic roles, would make an important contribution towards reaching the temperature goal of the Paris Agreement and is vital for a limit of 1.5°C. This article is part of a discussion meeting issue 'Rising methane: is warming feeding warming? (part 1)'.

Natural History of a Mouse Model Overexpressing the Dp71 Dystrophin Isoform.

Dystrophin is a 427 kDa protein that stabilizes muscle cell membranes through interactions with the cytoskeleton and various membrane-associated proteins. Loss of dystrophin as in Duchenne muscular dystrophy (DMD) causes progressive skeletal muscle weakness and cardiac dysfunction. Multiple promoters along the dystrophin gene (DMD) give rise to a number of shorter isoforms. Of interest is Dp71, a 71 kDa isoform implicated in DMD pathology by various animal and patient studies. Strong evidence supporting such a role for Dp71, however, is lacking. Here, we use del52;WT mice to understand how Dp71 overexpression affects skeletal and cardiac muscle phenotypes. Apart from the mouse Dmd gene, del52;WT mice are heterozygous for a full-length, exon 52-deleted human DMD transgene expected to only permit Dp71 expression in muscle. Thus, del52;WT mice overexpress Dp71 through both the human and murine dystrophin genes. We observed elevated Dp71 protein in del52;WT mice, significantly higher than wild-type in the heart but not the tibialis anterior. Moreover, del52;WT mice had generally normal skeletal muscle but impaired cardiac function, exhibiting significant systolic dysfunction as early as 3 months. No histological abnormalities were found in the tibialis anterior and heart. Our results suggest that Dp71 overexpression may have more detrimental effects on the heart than on skeletal muscles, providing insight into the role of Dp71 in DMD pathogenesis.

How much do direct livestock emissions actually contribute to global warming?

Agriculture directly contributes about 10%-12% of current global anthropogenic greenhouse gas emissions, mostly from livestock. However, such percentage estimates are based on global warming potentials (GWPs), which do not measure the actual warming caused by emissions and ignore the fact that methane does not accumulate in the atmosphere in the same way as CO2 . Here, we employ a simple carbon cycle-climate model, historical estimates and future projections of livestock emissions to infer the fraction of actual warming that is attributable to direct livestock non-CO2 emissions now and in future, and to CO2 from pasture conversions, without relying on GWPs. We find that direct livestock non-CO2 emissions caused about 19% of the total modelled warming of 0.81°C from all anthropogenic sources in 2010. CO2 from pasture conversions contributed at least another 0.03°C, bringing the warming directly attributable to livestock to 23% of the total warming in 2010. The significance of direct livestock emissions to future warming depends strongly on global actions to reduce emissions from other sectors. Direct non-CO2 livestock emissions would contribute only about 5% of the warming in 2100 if emissions from other sectors increase unabated, but could constitute as much as 18% (0.27°C) of the warming in 2100 if global CO2 emissions from other sectors are reduced to near or below zero by 2100, consistent with the goal of limiting warming to well below 2°C. These estimates constitute a lower bound since indirect emissions linked to livestock feed production and supply chains were not included. Our estimates demonstrate that expanding the mitigation potential and realizing substantial reductions of direct livestock non-CO2 emissions through demand and supply side measures can make an important contribution to achieve the stringent mitigation goals set out in the Paris Agreement, including by increasing the carbon budget consistent with the 1.5°C goal.

Design of a sensitive uncooled thermal imager based on a liquid crystal Fabry-Perot interferometer.

Microbolometers are the dominant technology for uncooled thermal imaging; however, devices based on a direct retardation measurement of a liquid crystal (LC) transducer pixel have been shown to have comparable sensitivity. In this paper, an approach for increasing LC transducer sensitivity utilizing an etalon structure is considered. A detailed design for an LC resonant cavity between dielectric mirrors is proposed and the performance is evaluated numerically. The measured quantity is the transmission of a visible wavelength through the etalon, which requires no thermal contact with the IR sensor. Numerical and analytical calculations that consider a 470 nm thick LC pixel demonstrate that the change in transmitted intensity with temperature is 26 times greater in the device based on a resonant structure than in a device based on a direct retardation measurement. Finally, the paper discusses how the dielectric mirror materials, dimensions of the resonant cavity structure, and expected process tolerances affect the sensitivity of the device.

Task-anchored grid cell firing is selectively associated with successful path integration-dependent behaviour.

Grid firing fields have been proposed as a neural substrate for spatial localisation in general or for path integration in particular. To distinguish these possibilities, we investigate firing of grid and non-grid cells in the mouse medial entorhinal cortex during a location memory task. We find that grid firing can either be anchored to the task environment, or can encode distance travelled independently of the task reference frame. Anchoring varied between and within sessions, while spatial firing of non-grid cells was either coherent with the grid population, or was stably anchored to the task environment. We took advantage of the variability in task-anchoring to evaluate whether and when encoding of location by grid cells might contribute to behaviour. We find that when reward location is indicated by a visual cue, performance is similar regardless of whether grid cells are task-anchored or not, arguing against a role for grid representations when location cues are available. By contrast, in the absence of the visual cue, performance was enhanced when grid cells were anchored to the task environment. Our results suggest that anchoring of grid cells to task reference frames selectively enhances performance when path integration is required.

Biological and genetic therapies for the treatment of Duchenne muscular dystrophy.

INTRODUCTION: Duchenne muscular dystrophy is a lethal genetic disease which currently has no cure, and poor standard treatment options largely focused on symptom relief. The development of multiple biological and genetic therapies is underway across various stages of clinical progress which could markedly affect how DMD patients are treated in the future. AREAS COVERED: The purpose of this review is to provide an introduction to the different therapeutic modalities currently being studied, as well as a brief description of their progress to date and relative advantages and disadvantages for the treatment of DMD. This review discusses exon skipping therapy, microdystrophin therapy, stop codon readthrough therapy, CRISPR-based gene editing, cell-based therapy, and utrophin upregulation. Secondary therapies addressing nonspecific symptoms of DMD were excluded. EXPERT OPINION: Despite the vast potential held by gene replacement therapy options such as microdystrophin production and utrophin upregulation, safety risks inherent to the adeno-associated virus delivery vector might hamper the clinical viability of these approaches until further improvements can be made. Of the mutation-specific therapies, exon skipping therapy remains the most extensively validated and explored option, and the cell-based CAP-1002 therapy may prove to be a suitable adjunct therapy filling the urgent need for cardiac-specific therapies.

Recent Trends in Antisense Therapies for Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a debilitating and fatal genetic disease affecting 1/5000 boys globally, characterized by progressive muscle breakdown and eventual death, with an average lifespan in the mid-late twenties. While no cure yet exists for DMD, gene and antisense therapies have been heavily explored in recent years to better treat this disease. Four antisense therapies have received conditional FDA approval, and many more exist in varying stages of clinical trials. These upcoming therapies often utilize novel drug chemistries to address limitations of existing therapies, and their development could herald the next generation of antisense therapy. This review article aims to summarize the current state of development for antisense-based therapies for the treatment of Duchenne muscular dystrophy, exploring candidates designed for both exon skipping and gene knockdown.

Safety concerns surrounding AAV and CRISPR therapies in neuromuscular treatment.

Gene therapies, notably those leveraging CRISPR and adeno-associated virus vectors (AAVs), have risen to the forefront of potential treatments for neuromuscular disorders. The recent demise of a Duchenne muscular dystrophy (DMD) patient following a trial utilizing CRISPR transactivation with AAV has cast a spotlight on the potential risks associated with these approaches.1.

Advancing Epidemiology and Genetic Approaches for the Treatment of Spinal and Bulbar Muscular Atrophy: Focus on Prevalence in the Indigenous Population of Western Canada.

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is a debilitating neuromuscular disease characterized by progressive muscular weakness and neuronal degeneration, affecting 1-2 individuals per 100,000 globally. While SBMA is relatively rare, recent studies have shown a significantly higher prevalence of the disease among the indigenous population of Western Canada compared to the general population. The disease is caused by a pathogenic expansion of polyglutamine residues in the androgen receptor protein, which acts as a key transcriptional regulator for numerous genes. SBMA has no cure, and current treatments are primarily supportive and focused on symptom management. Recently, a form of precision medicine known as antisense therapy has gained traction as a promising therapeutic option for numerous neuromuscular diseases. Antisense therapy uses small synthetic oligonucleotides to confer therapeutic benefit by acting on pathogenic mRNA molecules, serving to either degrade pathogenic mRNA transcripts or helping to modulate splicing. Recent studies have explored the suitability of antisense therapy for the treatment of SBMA, primarily focused on gene therapy and antisense-mediated mRNA knockdown approaches. Advancements in understanding the pathogenesis of SBMA and the development of targeted therapies offer hope for improved quality of life for individuals affected by this debilitating condition. Continued research is essential to optimize these genetic approaches, ensuring their safety and efficacy.

Antisense and Gene Therapy Options for Duchenne Muscular Dystrophy Arising from Mutations in the N-Terminal Hotspot.

Duchenne muscular dystrophy (DMD) is a fatal genetic disease affecting children that is caused by a mutation in the gene encoding for dystrophin. In the absence of functional dystrophin, patients experience progressive muscle deterioration, leaving them wheelchair-bound by age 12 and with few patients surviving beyond their third decade of life as the disease advances and causes cardiac and respiratory difficulties. In recent years, an increasing number of antisense and gene therapies have been studied for the treatment of muscular dystrophy; however, few of these therapies focus on treating mutations arising in the N-terminal encoding region of the dystrophin gene. This review summarizes the current state of development of N-terminal antisense and gene therapies for DMD, mainly focusing on exon-skipping therapy for duplications and deletions, as well as microdystrophin therapy.

Spatial representation by ramping activity of neurons in the retrohippocampal cortex.

Neurons in the retrohippocampal cortices play crucial roles in spatial memory. Many retrohippocampal neurons have firing fields that are selectively active at specific locations, with memory for rewarded locations associated with reorganization of these firing fields. Whether this is the sole strategy for representing spatial memories is unclear. Here, we demonstrate that during a spatial memory task retrohippocampal neurons encode location through ramping activity that extends across segments of a linear track approaching and following a reward, with the rewarded location represented by offsets or switches in the slope of the ramping activity. Ramping representations could be maintained independently of trial outcome and cues marking the reward location, indicating that they result from recall of the track structure. When recorded in an open arena, neurons that generated ramping activity during the spatial memory task were more numerous than grid or border cells, with a majority showing spatial firing that did not meet criteria for classification as grid or border representations. Encoding of rewarded locations through offsets and switches in the slope of ramping activity also emerged in recurrent neural network models trained to solve a similar spatial memory task. Impaired performance of model networks following disruption of outputs from ramping neurons is consistent with this coding strategy supporting navigation to recalled locations of behavioral significance. Our results suggest that encoding of learned spaces by retrohippocampal networks employs both discrete firing fields and continuous ramping representations. We hypothesize that retrohippocampal ramping activity mediates readout of learned models for goal-directed navigation.

Telemedicine to a moving ambulance improves outcome after trauma in simulated patients.

BACKGROUND: Rural trauma victims often require prolonged transport by s with limited scopes of practice. We evaluated the impact of telemedicine (TM) to a moving ambulance on outcomes in simulated trauma patients. METHODS: This is an institutional review board approved, prospective double-blind study. Three trauma scenarios (blunt torso trauma, epigastric stab wound, and closed head injury) were created for a human patient simulator. Intermediate emergency medical technicians (EMTs; n = 20) managed the human patient simulator, in a moving ambulance. In the TM group, physicians (n = 12) provided consultation. In the non-TM group, EMTs communicated with medical control by radio, as necessary. We tabulated the fraction of 13 key signs, 5 pathologic processes, and 12 key interventions that were performed. Vital signs and Sao2 (%) were recorded. Data were compared using the Wilcoxon rank-sum test. RESULTS: Lowest Sao2 (84 ± 0.7 vs. 78 ± 0), lowest systolic blood pressure (70 ± 1 vs. 53 ± 1), and highest heart rate (144 ± 0.9 vs. 159 ± 0.5) were significantly improved in the TM group (p < 0.001). Recognition rates for key signs (0.96 ± 0.01 vs. 0.79 ± 0.05), processes (0.98 ± 0.02 vs. 0.75 ± 0.05), and critical interventions (0.92 ± 0.02 vs. 0.49 ± 0.03) were higher in the TM group (p < 0.003). EMTs were successfully guided through needle decompression procedures in 22 of 24 cases (zero in the non-TM group). CONCLUSION: TM to a moving ambulance improved the care of simulated trauma patients. Furthermore, procedurally naïve EMTs were able to perform needle thoracostomy and pericardiocentesis with TM guidance.

Lifetime climate impacts of diet transitions: a novel climate change accounting perspective.

Dietary transitions, such as eliminating meat consumption, have been proposed as one way to reduce the climate impact of the global and regional food systems. However, it should be ensured that replacement diets are indeed nutritious and that climate benefits are accurately accounted for. This study uses New Zealand food consumption as a case study for exploring the cumulative climate impact of adopting the national dietary guidelines and the substitution of meat from hypothetical diets. The new GWP* metric is used as it was designed to better reflect the climate impacts of the release of methane than the de facto standard 100-year Global Warming Potential metric (GWP100). A transition at age 25 to the hypothetical dietary guideline diet reduces cumulative warming associated with diet by 7 to 9% at the 100th year compared with consuming the average New Zealand diet. The reduction in diet-related cumulative warming from the transition to a hypothetical meat-substituted diet varied between 12 and 15%. This is equivalent to reducing an average individual's lifetime warming contribution by 2 to 4%. General improvements are achieved for nutrient intakes by adopting the dietary guidelines compared with the average New Zealand diet; however, the substitution of meat items results in characteristic nutrient differences, and these differences must be considered alongside changes in emission profiles.

The feasibility of using ultrasound and video laryngoscopy in a mobile telemedicine consult.

Emergency healthcare systems in rural communities often have limited access to experienced trauma and emergency physicians. Advanced telecommunication technologies may offer an opportunity to help meet this need. We evaluated healthcare providers' satisfaction with the audio and visual components of an existing telemedicine system, and asked them whether emergency medical services (EMS) personnel could be supported via telemedicine guidance, using video laryngoscopy and ultrasonography, during vulnerable transport periods. Physicians and technologists at a central workstation were linked to a telemedicine-equipped ambulance providing real-time audio and visual communications during patient transport. A scoring system was created for system evaluation using a scale of 1-9. Seven evaluators observed ultrasonography of the carotid vessels and abdominal aorta. Nine evaluators observed an intubation with video laryngoscopy. These observers rated the quality of the images transmitted from the ambulance. Evaluators were asked if this telemedicine system would be suitable for telementoring advanced technical procedures. Mean rating for technical satisfaction with ultrasound was 5.1, the majority of evaluators estimated that they could telementor an abdominal ultrasound examination. The mean rating for technical satisfaction with laryngoscopy was 7.2 with 100% of evaluators estimating they could use the system to telementor intubation. The rating for laryngoscopy was significantly higher than for ultrasound (p = 0.01). Results of this study suggest that telemedicine may provide an advanced support mechanism for rural EMS personnel and patients. Procedures for advanced airway management and ultrasound diagnosis may someday be managed using a remote telepresence.

Process for a Reactive Monomer Alignment Layer for Liquid Crystals Formed on an Azodye Sublayer.

In this work, the detailed studies of surface polymerization stabilizing liquid crystal formed on an azodye sublayer are presented. The surface localized stabilization is obtained by free-radical polymerization of a dilute solution of a bi-functional reactive monomer (RM) in a liquid crystal (LC) solvent. To optimize the process for surface localized stabilization, we investigate the effects of several process parameters including RM concentration in LC hosts, the types of materials (either RM or LC), the photo-initiator (PI) concentration, ultra-violet (UV) polymerization intensity, and the UV curing temperature. The quality of surface localized stabilization is characterized and/or evaluated by optical microscopy, electro-optical behavior (transmission/voltage curve), the life test, and photo-bleaching. Our results show that, by carefully selecting materials, formulating mixtures, and controlling the polymerizing variables, the RM polymerization can be realized either at the surface or through the bulk. Overall, the combination of surface localized stabilization and photo-alignment offers an elegant and dynamic solution for controlling the alignment for LC, which could play a profound role in almost all liquid crystal optical devices.

How much land-based greenhouse gas mitigation can be achieved without compromising food security and environmental goals?

Feeding 9-10 billion people by 2050 and preventing dangerous climate change are two of the greatest challenges facing humanity. Both challenges must be met while reducing the impact of land management on ecosystem services that deliver vital goods and services, and support human health and well-being. Few studies to date have considered the interactions between these challenges. In this study we briefly outline the challenges, review the supply- and demand-side climate mitigation potential available in the Agriculture, Forestry and Other Land Use AFOLU sector and options for delivering food security. We briefly outline some of the synergies and trade-offs afforded by mitigation practices, before presenting an assessment of the mitigation potential possible in the AFOLU sector under possible future scenarios in which demand-side measures codeliver to aid food security. We conclude that while supply-side mitigation measures, such as changes in land management, might either enhance or negatively impact food security, demand-side mitigation measures, such as reduced waste or demand for livestock products, should benefit both food security and greenhouse gas (GHG) mitigation. Demand-side measures offer a greater potential (1.5-15.6 Gt CO2 -eq. yr(-1) ) in meeting both challenges than do supply-side measures (1.5-4.3 Gt CO2 -eq. yr(-1) at carbon prices between 20 and 100 US$ tCO2 -eq. yr(-1) ), but given the enormity of challenges, all options need to be considered. Supply-side measures should be implemented immediately, focussing on those that allow the production of more agricultural product per unit of input. For demand-side measures, given the difficulties in their implementation and lag in their effectiveness, policy should be introduced quickly, and should aim to codeliver to other policy agenda, such as improving environmental quality or improving dietary health. These problems facing humanity in the 21st Century are extremely challenging, and policy that addresses multiple objectives is required now more than ever.

Continuous glucose monitoring considerations for the development of a closed-loop artificial pancreas system.

BACKGROUND: Commercialization of a closed-loop artificial pancreas system that employs continuous subcutaneous insulin infusion and interstitial fluid glucose sensing has been encumbered by state-of-the-art technology. Continuous glucose monitoring (CGM) devices with improved accuracy could significantly advance development efforts. However, the current accuracy of CGM devices might be adequate for closed-loop control. METHODS: The influence that known CGM limitations have on closed-loop control was investigated by integrating sources of sensor inaccuracy with the University of Virginia Padova Diabetes simulator. Non-glucose interference, physiological time lag and sensor error measurements, selected from 83 Enlite™ glucose sensor recordings with the Guardian® REAL-Time system, were used to modulate simulated plasma glucose signals. The effect of sensor accuracy on closed-loop controller performance was evaluated in silico, and contrasted with closed-loop clinical studies during the nocturnal control period. RESULTS: Based on n = 2472 reference points, a mean sensor error of 14% with physiological time lags of 3.28 ± 4.62 min (max 13.2 min) was calculated for simulation. Sensor bias reduced time in target for both simulation and clinical experiments. In simulation, additive error increased time <70 mg/dl and >180 mg/dl by 0.2% and 5.6%, respectively. In-clinic, the greatest low blood glucose index values (max = 5.9) corresponded to sensor performance. CONCLUSION: Sensors have sufficient accuracy for closed-loop control, however, algorithms are necessary to effectively calibrate and detect erroneous calibrations and failing sensors. Clinical closed-loop data suggest that control with a higher target of 140 mg/dl during the nocturnal period could significantly reduce the risk for hypoglycemia.

Expert visual guidance of ultrasound for telemedicine.

Expert visual guidance (EVG) is computer assistance that displays to the examiner how the image plane moves towards (or away from) a desired anatomical location as the ultrasound probe is manipulated over the patient's body. We tested whether EVG by a remote expert could assist inexperienced examiners in acquiring abdominal ultrasound images. The inexperienced examiners were 20 medical students, who were randomly assigned to verbal instruction alone (Group 1) or to EVG (Group 2). The examiners were tested on their ability to visualize the abdominal aorta and the right kidney. Group 2 was more successful in identifying specified anatomy in longitudinal and cross-sectional views of the aorta (95 vs. 75%, P = 0.032) and kidney (98 vs. 88%, P = 0.09). The groups succeeded equally well in obtaining a true cross-sectional view of the aorta. Kidney length was also similar when measured by the two groups. The results demonstrate that an inexperienced ultrasonographer can be significantly assisted by EVG compared to verbal instruction alone. This could be useful for tele-mentoring in rural hospitals as well as for teaching, both in person and at a remote site.