Environmental drivers of increased ecosystem respiration in a warming tundra.

Arctic and alpine tundra ecosystems are large reservoirs of organic carbon1,2. Climate warming may stimulate ecosystem respiration and release carbon into the atmosphere3,4. The magnitude and persistency of this stimulation and the environmental mechanisms that drive its variation remain uncertain5-7. This hampers the accuracy of global land carbon-climate feedback projections7,8. Here we synthesize 136 datasets from 56 open-top chamber in situ warming experiments located at 28 arctic and alpine tundra sites which have been running for less than 1 year up to 25 years. We show that a mean rise of 1.4 °C [confidence interval (CI) 0.9-2.0 °C] in air and 0.4 °C [CI 0.2-0.7 °C] in soil temperature results in an increase in growing season ecosystem respiration by 30% [CI 22-38%] (n = 136). Our findings indicate that the stimulation of ecosystem respiration was due to increases in both plant-related and microbial respiration (n = 9) and continued for at least 25 years (n = 136). The magnitude of the warming effects on respiration was driven by variation in warming-induced changes in local soil conditions, that is, changes in total nitrogen concentration and pH and by context-dependent spatial variation in these conditions, in particular total nitrogen concentration and the carbon:nitrogen ratio. Tundra sites with stronger nitrogen limitations and sites in which warming had stimulated plant and microbial nutrient turnover seemed particularly sensitive in their respiration response to warming. The results highlight the importance of local soil conditions and warming-induced changes therein for future climatic impacts on respiration.

Disease-associated KCNMA1 variants decrease circadian clock robustness in channelopathy mouse models.

KCNMA1 encodes the voltage- and calcium-activated K+ (BK) channel, which regulates suprachiasmatic nucleus (SCN) neuronal firing and circadian behavioral rhythms. Gain-of-function (GOF) and loss-of-function (LOF) alterations in BK channel activity disrupt circadian behavior, but the effect of human disease-associated KCNMA1 channelopathy variants has not been studied on clock function. Here, we assess circadian behavior in two GOF and one LOF mouse lines. Heterozygous Kcnma1N999S/WT and homozygous Kcnma1D434G/D434G mice are validated as GOF models of paroxysmal dyskinesia (PNKD3), but whether circadian rhythm is affected in this hypokinetic locomotor disorder is unknown. Conversely, homozygous LOF Kcnma1H444Q/H444Q mice do not demonstrate PNKD3. We assessed circadian behavior by locomotor wheel running activity. All three mouse models were rhythmic, but Kcnma1N999S/WT and Kcnma1D434G/D434G showed reduced circadian amplitude and decreased wheel activity, corroborating prior studies focused on acute motor coordination. In addition, Kcnma1D434G/D434G mice had a small decrease in period. However, the phase-shifting sensitivity for both GOF mouse lines was abnormal. Both Kcnma1N999S/WT and Kcnma1D434G/D434G mice displayed increased responses to light pulses and took fewer days to re-entrain to a new light:dark cycle. In contrast, the LOF Kcnma1H444Q/H444Q mice showed no difference in any of the circadian parameters tested. The enhanced sensitivity to phase-shifting stimuli in Kcnma1N999S/WT and Kcnma1D434G/D434G mice was similar to other Kcnma1 GOF mice. Together with previous studies, these results suggest that increasing BK channel activity decreases circadian clock robustness, without rhythm ablation.

Incidence of medullary thyroid carcinoma and Hirschsprung disease based on the cosmos database.

PURPOSE: Multiple endocrine neoplasia Type 2A (MEN2A) can occur with Hirschsprung disease (HD) due to mutation in the RET proto-oncogene, with the majority developing medullary thyroid carcinoma (MTC). Given the comorbidity, many parents have contacted us to share concerns and unfortunate experiences about the prevalence rates of MEN2A/MTC in patients with HD. The aim is to determine the prevalence rate of patients with HD and MEN2A or medullary thyroid carcinoma, respectively. METHODS: This is a cross-sectional study of the COSMOS database from January 01, 2017, to March 08, 2023. The database was searched for patients diagnosed with MEN2A, MTC, and HD. IRB exemption was provided (COMIRB #23-0526). RESULTS: The database contained 183,993,122 patients from 198 contributing organizations. The prevalence of HD and MEN2A was 0.00002%, and for HD and MTC was 0.000009%. One in 66 patients (1.5%) with MEN2A also had HD. One in 319 patients (0.3%) in the HD group had MEN2A. One in 839 patients (0.1%) within the HD population had MTC. CONCLUSION: The prevalence of MTC and HD or MEN2A and HD in the study population was low. Considering that almost all MEN2A patients have a positive family history, this data does not support the general genetic testing of HD patients.

BK channel properties correlate with neurobehavioral severity in three KCNMA1-linked channelopathy mouse models.

KCNMA1 forms the pore of BK K+ channels, which regulate neuronal and muscle excitability. Recently, genetic screening identified heterozygous KCNMA1 variants in a subset of patients with debilitating paroxysmal non-kinesigenic dyskinesia, presenting with or without epilepsy (PNKD3). However, the relevance of KCNMA1 mutations and the basis for clinical heterogeneity in PNKD3 has not been established. Here, we evaluate the relative severity of three KCNMA1 patient variants in BK channels, neurons, and mice. In heterologous cells, BKN999S and BKD434G channels displayed gain-of-function (GOF) properties, whereas BKH444Q channels showed loss-of-function (LOF) properties. The relative degree of channel activity was BKN999S > BKD434G>WT > BKH444Q. BK currents and action potential firing were increased, and seizure thresholds decreased, in Kcnma1N999S/WT and Kcnma1D434G/WT transgenic mice but not Kcnma1H444Q/WT mice. In a novel behavioral test for paroxysmal dyskinesia, the more severely affected Kcnma1N999S/WT mice became immobile after stress. This was abrogated by acute dextroamphetamine treatment, consistent with PNKD3-affected individuals. Homozygous Kcnma1D434G/D434G mice showed similar immobility, but in contrast, homozygous Kcnma1H444Q/H444Q mice displayed hyperkinetic behavior. These data establish the relative pathogenic potential of patient alleles as N999S>D434G>H444Q and validate Kcnma1N999S/WT mice as a model for PNKD3 with increased seizure propensity.

So far, only 70 patients around the world have been diagnosed with a newly identified rare syndrome known as KCNMA1-linked channelopathy. The condition is characterised by seizures and abnormal movements which include frequent 'drop attacks', a sudden and debilitating loss of muscle control that causes patients to fall without warning. The disease is associated with mutations in the gene for KCNMA1, a member of a class of proteins important for controlling nerve cell activity and brain function. However, due to the limited number of people affected by the condition, it is difficult to link a particular mutation to the observed symptoms; the basis for the drop attacks therefore remains unknown. Park et al. set out to 'model' KCNMA1-linked channelopathy in the laboratory, in order to determine which mutations in the KCNMA1 gene caused these symptoms. Three groups of mice were each genetically engineered to carry either one of the two most common mutations in the gene for KCNMA1, or a very rare mutation associated with the movement symptoms. Behavioural experiments and studies of nerve cell activity revealed that the mice carrying mutations that made the KCNMA1 protein more active developed seizures more easily and became immobilized, showing the mouse version of drop attacks. Giving these mice the drug dextroamphetamine, which works in some human patients, stopped the immobilizing attacks altogether. These results show for the first time which specific genetic changes cause the main symptoms of KCNMA1-linked channelopathy. Park et al. hope that this knowledge will deepen our understanding of this disease and help develop better treatments.

Potential use of microwave technology in dermatology.

BACKGROUND: Microwaves are used in medicine for diagnostics, and treatment of cancer. Recently, novel microwave devices (Swift®, Emblation Ltd, UK and miraDry®, Miramar Labs Inc., CA) have been cleared by the FDA and Health Canada for various dermatological conditions. OBJECTIVE AND METHODS: To review the dermatological use of microwave-based treatments (plantar warts, corns, actinic keratosis, dermatophytosis, axillary hyperhidrosis, osmidrosis, and hidradenitis suppurativa). Clinical trials, case reports, or in vitro studies for each condition are summarized. RESULTS AND CONCLUSION: Microwaves are a promising alternative therapy for cutaneous warts, actinic keratosis, axillary hyperhidrosis, and osmidrosis, with favorable safety profiles. However, patients with hidradenitis suppurativa have had negative clinical outcomes. Limited treatment of corns showed good pain reduction but did not resolve hyperkeratosis. A preliminary in vitro study indicated that microwave treatment inhibits the growth of T. rubrum. We present the first case of toenail onychomycosis successfully treated with microwaves. Despite the advancements in the use of microwaves, the mechanism of action in non-ablative treatment is not well understood; further research is needed. More high-quality randomized clinical trials with larger groups and long follow-up periods are also required to evaluate the clinical benefits and possible adverse effects of microwaves in treating dermatological conditions.

Transcriptomic and cellular decoding of functional brain connectivity changes reveal regional brain vulnerability to pro- and anti-inflammatory therapies.

BACKGROUND: Systemic inflammation induces acute changes in mood, motivation and cognition that closely resemble those observed in depressed individuals. However, the mechanistic pathways linking peripheral inflammation to depression-like psychopathology via intermediate effects on brain function remain incompletely understood. METHODS: We combined data from 30 patients initiating interferon-α treatment for Hepatitis-C and 20 anti-tumour necrosis factor (TNF) therapy for inflammatory arthritis and used resting-state functional magnetic resonance imaging to investigate acute effects of each treatment on regional global brain connectivity (GBC). We leveraged transcriptomic data from the Allen Human Brain Atlas to uncover potential biological and cellular pathways underpinning regional vulnerability to GBC changes induced by each treatment. RESULTS: Interferon-α and anti-TNF therapies both produced differential small-to-medium sized decreases in regional GBC. However, these were observed within distinct brain regions and the regional patterns of GBC changes induced by each treatment did not correlate suggesting independent underlying processes. Further, the spatial distribution of these differential GBC decreases could be captured by multivariate patterns of constitutive regional expression of genes respectively related to: i) neuroinflammation and glial cells; and ii) glutamatergic neurotransmission and neurons. The extent to which each participant expressed patterns of GBC changes aligning with these patterns of transcriptomic vulnerability also correlated with both acute treatment-induced changes in interleukin-6 (IL-6) and, for Interferon-α, longer-term treatment-associated changes in depressive symptoms. CONCLUSIONS: Together, we present two transcriptomic models separately linking regional vulnerability to the acute effects of interferon-α and anti-TNF treatments on brain function to glial neuroinflammation and glutamatergic neurotransmission. These findings generate hypotheses about two potential brain mechanisms through which bidirectional changes in peripheral inflammation may contribute to the development/resolution of psychopathology.

Transcriptional Profiling of Primate Central Nucleus of the Amygdala Neurons to Understand the Molecular Underpinnings of Early-Life Anxious Temperament.

BACKGROUND: Children exhibiting extreme anxious temperament (AT) are at an increased risk for developing anxiety and depression. Our previous mechanistic and neuroimaging work in young rhesus monkeys linked the central nucleus of the amygdala to AT and its underlying neural circuit. METHODS: Here, we used laser capture microscopy and RNA sequencing in 47 young rhesus monkeys to investigate AT's molecular underpinnings by focusing on neurons from the lateral division of the central nucleus of the amygdala (CeL). RNA sequencing identified numerous AT-related CeL transcripts, and we used immunofluorescence (n = 3) and tract-tracing (n = 2) methods in a different sample of monkeys to examine the expression, distribution, and projection pattern of neurons expressing one of these transcripts. RESULTS: We found 555 AT-related transcripts, 14 of which were confirmed with high statistical confidence (false discovery rate < .10), including protein kinase C delta (PKCδ), a CeL microcircuit cell marker implicated in rodent threat processing. We characterized PKCδ neurons in the rhesus CeL, compared its distribution with that of the mouse, and demonstrated that a subset of these neurons project to the laterodorsal bed nucleus of the stria terminalis. CONCLUSIONS: These findings demonstrate that CeL PKCδ is associated with primate anxiety, provides evidence of a CeL to laterodorsal bed nucleus of the stria terminalis circuit that may be relevant to understanding human anxiety, and points to specific molecules within this circuit that could serve as potential treatment targets for anxiety disorders.

Global plant trait relationships extend to the climatic extremes of the tundra biome.

The majority of variation in six traits critical to the growth, survival and reproduction of plant species is thought to be organised along just two dimensions, corresponding to strategies of plant size and resource acquisition. However, it is unknown whether global plant trait relationships extend to climatic extremes, and if these interspecific relationships are confounded by trait variation within species. We test whether trait relationships extend to the cold extremes of life on Earth using the largest database of tundra plant traits yet compiled. We show that tundra plants demonstrate remarkably similar resource economic traits, but not size traits, compared to global distributions, and exhibit the same two dimensions of trait variation. Three quarters of trait variation occurs among species, mirroring global estimates of interspecific trait variation. Plant trait relationships are thus generalizable to the edge of global trait-space, informing prediction of plant community change in a warming world.

Effects of treadmill running and limb immobilization on knee cartilage degeneration and locomotor joint kinematics in rats following knee meniscal transection.

OBJECTIVE: This study examined the effects of reduced and elevated weight bearing on post-traumatic osteoarthritis (PTOA) development, locomotor joint kinematics, and degree of voluntary activity in rats following medial meniscal transection (MMT). DESIGN: Twenty-one adult rats were subjected to MMT surgery of the left hindlimb and then assigned to one of three groups: (1) regular (i.e., no intervention), (2) hindlimb immobilization, or (3) treadmill running. Sham surgery was performed in four additional rats. Voluntary wheel run time/distance was measured, and 3D hindlimb kinematics were quantified during treadmill locomotion using biplanar radiography. Rats were euthanized 8 weeks after MMT or sham surgery, and the microstructure of the tibial cartilage and subchondral bone was quantified using contrast enhanced micro-CT. RESULTS: All three MMT groups showed signs of PTOA (full-thickness lesions and/or increased cartilage volume) compared to the sham group, however the regular and treadmill-running groups had greater osteophyte formation than the immobilization group. For the immobilization group, increased volume was only observed in the anterior region of the cartilage. The treadmill-running group demonstrated a greater knee varus angle at mid-stance than the sham group, while the immobilization group demonstrated greater reduction in voluntary running than all the other groups at 2 weeks post-surgery. CONCLUSIONS: Elevated weight-bearing via treadmill running at a slow/moderate speed did not accelerate PTOA in MMT rats when compared to regular weight-bearing. Reduced weight-bearing via immobilization may attenuate overall PTOA but still resulted in regional cartilage degeneration. Overall, there were minimal differences in hindlimb kinematics and voluntary running between MMT and sham rats.

Outcomes following stoma formation in patients with spinal cord injury.

AIM: The formation of a diverting stoma of the bowel in patients with spinal cord injury (SCI) is a useful option in managing problems associated with prolonged bowel care, pressure ulcers and neurogenic bowel. This descriptive study examines surgical outcomes and the effect on an individual's health-related quality of life (HrQoL) in this complex group of patients. METHODS: Data were retrospectively collected in all patients with SCI who underwent a diverting stoma at Prince of Wales Hospital, Sydney, between January 2013 and January 2018 via a self-report questionnaire developed specifically for the study. RESULTS: Forty-three individuals were identified of whom 26 responded. 73% were men with a mean age of 45 years. The reasons for stoma formation included sacral pressure ulcer (50%), prolonged bowel care (35%), faecal incontinence (19%), constipation (8%), autonomic dysreflexia (8%), carer difficulties (8%) and haemorrhoids (4%). 76% of patients reported an improvement in HrQoL with 72% scoring their satisfaction with a stoma ≥ 8/10. CONCLUSION: While stoma formation is often seen as a treatment of last resort, our study has shown that it is an effective management option for a number of conditions post-SCI. It can improve HrQoL and has a high level of satisfaction amongst patients. Ideally, patients who could potentially benefit from a stoma should be identified early and receive appropriate education and counselling to help facilitate informed and timely decision-making and reduce adverse bowel related impact on quality of life and adjustment post-SCI.

Traditional plant functional groups explain variation in economic but not size-related traits across the tundra biome.

AIM: Plant functional groups are widely used in community ecology and earth system modelling to describe trait variation within and across plant communities. However, this approach rests on the assumption that functional groups explain a large proportion of trait variation among species. We test whether four commonly used plant functional groups represent variation in six ecologically important plant traits. LOCATION: Tundra biome. TIME PERIOD: Data collected between 1964 and 2016. MAJOR TAXA STUDIED: 295 tundra vascular plant species. METHODS: We compiled a database of six plant traits (plant height, leaf area, specific leaf area, leaf dry matter content, leaf nitrogen, seed mass) for tundra species. We examined the variation in species-level trait expression explained by four traditional functional groups (evergreen shrubs, deciduous shrubs, graminoids, forbs), and whether variation explained was dependent upon the traits included in analysis. We further compared the explanatory power and species composition of functional groups to alternative classifications generated using post hoc clustering of species-level traits. RESULTS: Traditional functional groups explained significant differences in trait expression, particularly amongst traits associated with resource economics, which were consistent across sites and at the biome scale. However, functional groups explained 19% of overall trait variation and poorly represented differences in traits associated with plant size. Post hoc classification of species did not correspond well with traditional functional groups, and explained twice as much variation in species-level trait expression. MAIN CONCLUSIONS: Traditional functional groups only coarsely represent variation in well-measured traits within tundra plant communities, and better explain resource economic traits than size-related traits. We recommend caution when using functional group approaches to predict tundra vegetation change, or ecosystem functions relating to plant size, such as albedo or carbon storage. We argue that alternative classifications or direct use of specific plant traits could provide new insights for ecological prediction and modelling.

Non-Human Leukocyte Antigen Antibody-Mediated Lung Transplant Rejection: The Other Anti-A.

BACKGROUND: Acute rejection of lung allografts is an important contributor to morbidity and mortality in the transplant patient population, resulting in the dysfunction and destruction of the graft by the host's immune system via cellular or antibody-mediated mechanisms. Acute cellular rejection (ACR) is more common and better characterized than antibody-mediated rejection, which to date lacks any widely agreed upon, standardized set of diagnostic criteria. We present a case of AMR attributable to a rare phenomenon, non-human leukocyte antigen (HLA) antibodies. CASE REPORT: A 50-year-old male underwent an uneventful single lung transplant for pulmonary sarcoidosis. Donor and recipient blood type was A positive. No pretransplant donor-specific antibodies were identified. Flow cytometric crossmatch was negative. The postoperative course was significant for a single-unit transfusion of packed red blood cells on postoperative day (POD) 1 and persistent asymptomatic Serratia marcescens in bronchial washes despite ongoing levofloxacin treatment. A surveillance biopsy (POD 34) showed no evidence of rejection. One week later (on POD 41), the patient presented with fever, shortness of breath, and imaging abnormalities of the grafted lung. Inpatient antibiotic escalation to cefepime, ertapenem, and meropenem resolved the positive cultures and fever, but the patient's respiratory function continued to decline, requiring intubation and extracorporeal membrane oxygenation. High-dose steroids and therapeutic plasma exchanges were initiated for suspected acute rejection. During the workup, a newly developed anti-A1 red blood cell antibody was identified. Despite supportive efforts, the patient died on POD 55, 14 days after symptomatic presentation. CONCLUSION: This case highlights the clinical significance of AMR in lung allografts, as well as the need to investigate both HLA and non-HLA antibody sources in pulmonary transplant rejection refractory to treatment.

Creative, strengths-based approaches to knowledge translation within indigenous health research.

OBJECTIVES: Good knowledge translation efforts can lead to significant changes in health status and service delivery. Although there is growing literature around ways to conduct knowledge translation within policy and health service delivery sectors, literature around how to conduct dissemination within indigenous community-based contexts remains scant. STUDY DESIGN: Using creative, strengths-based approaches to not only return results but also to function as tools to address gaps in health knowledge as identified by participants and community members within intergenerational contexts was a central component applied to dissemination and knowledge translation. METHODS: We developed a series of seven key considerations that we applied to the creation of dissemination products from qualitative interviews and focus group discussions from two Manitoba, Canada-specific public health research projects with indigenous communities. RESULTS: Products created (activity sheets, board game, and non-fiction storybooks) considered principles of timeliness, literacy level, feasibility of reproduction, and meeting the stated needs of study participants. CONCLUSIONS: By creating products that seek not only to return study information but also to answer questions and address specific challenges identified by participants, it is possible to continue to engage in research that is meaningful and ethical and strengthens relationships with all stakeholders.

Delayed intestinal perforation secondary to blunt force abdominal trauma in a cat.

CASE SUMMARY: A 7-month-old intact male domestic shorthair cat was presented 4 h after being hit by a car. It had bilateral inguinal hernias and a mesenteric rent that were repaired surgically and a hematoma in the left retroperitoneal space. No other intra-abdominal abnormalities were identified on abdominal surgical exploration. Approximately 72 h after presentation, the cat started vomiting and developed severe abdominal discomfort. A sudden decrease in mentation and elevation of respiratory rate and effort ensued. Abdominal radiographs showed loss of detail in the abdominal cavity, and abdominocentesis confirmed septic peritonitis. The cat was euthanized, and post-mortem evaluation of the bowel revealed two 1 cm perforations of the jejunum. RELEVANCE AND NOVEL INFORMATION: To our knowledge, delayed intestinal perforation secondary to blunt force abdominal trauma has not previously been reported in cats. It has been reported in dogs, but the pathophysiology resulting in perforation is poorly understood. Delayed intestinal injury secondary to blunt force abdominal trauma has been reported in people, especially in children, as a result of motor vehicle accidents.

Prenatal methadone exposure is associated with altered neonatal brain development.

Methadone is used for medication-assisted treatment of heroin addiction during pregnancy. The neurodevelopmental outcome of children with prenatal methadone exposure can be sub-optimal. We tested the hypothesis that brain development is altered among newborn infants whose mothers were prescribed methadone. 20 methadone-exposed neonates born after 37 weeks' postmenstrual age (PMA) and 20 non-exposed controls underwent diffusion MRI at mean PMA of 39+ 2 and 41+ 1 weeks, respectively. An age-optimized Tract-based Spatial Statistics (TBSS) pipeline was used to perform voxel-wise statistical comparison of fractional anisotropy (FA) data between exposed and non-exposed neonates. Methadone-exposed neonates had decreased FA within the centrum semiovale, inferior longitudinal fasciculi (ILF) and the internal and external capsules after adjustment for GA at MRI (p < 0.05, TFCE corrected). Median FA across the white matter skeleton was 12% lower among methadone-exposed infants. Mean head circumference (HC) z-scores were lower in the methadone-exposed group (- 0.52 (0.99) vs 1.15 (0.84), p < 0.001); after adjustment for HC z-scores, differences in FA remained in the anterior and posterior limbs of the internal capsule and the ILF. Polydrug use among cases was common. Prenatal methadone exposure is associated with microstructural alteration in major white matter tracts, which is present at birth and is independent of head growth. Although the findings cannot be attributed to methadone per se, the data indicate that further research to determine optimal management of opioid use disorder during pregnancy is required. Future studies should evaluate childhood outcomes including infant brain development and long-term neurocognitive function.

Ankyrin-G isoform imbalance and interneuronopathy link epilepsy and bipolar disorder.

ANK3, encoding the adaptor protein Ankyrin-G (AnkG), has been implicated in bipolar disorder by genome-wide association studies. ANK3 has multiple alternative first exons, and a bipolar disorder-associated ANK3 variant has been shown to reduce the expression of exon 1b. Here we identify mechanisms through which reduced ANK3 exon 1b isoform expression disrupts neuronal excitation-inhibition balance. We find that parvalbumin (PV) interneurons and principal cells differentially express ANK3 first exon subtypes. PV interneurons express only isoforms containing exon 1b, whereas excitatory principal cells express exon 1e alone or both 1e and 1b. In transgenic mice deficient for exon 1b, PV interneurons lack voltage-gated sodium channels at their axonal initial segments and have increased firing thresholds and diminished action potential dynamic range. These mice exhibit an Ank3 gene dosage-dependent phenotype including behavior changes modeling bipolar disorder, epilepsy and sudden death. Thus ANK3's important association with human bipolar susceptibility may arise from imbalance between AnkG function in interneurons and principal cells and resultant excessive circuit sensitivity and output. AnkG isoform imbalance is a novel molecular endophenotype and potential therapeutic target.