Cold-induced expression of a truncated adenylyl cyclase 3 acts as rheostat to brown fat function.

Promoting brown adipose tissue (BAT) activity innovatively targets obesity and metabolic disease. While thermogenic activation of BAT is well understood, the rheostatic regulation of BAT to avoid excessive energy dissipation remains ill-defined. Here, we demonstrate that adenylyl cyclase 3 (AC3) is key for BAT function. We identified a cold-inducible promoter that generates a 5' truncated AC3 mRNA isoform (Adcy3-at), whose expression is driven by a cold-induced, truncated isoform of PPARGC1A (PPARGC1A-AT). Male mice lacking Adcy3-at display increased energy expenditure and are resistant to obesity and ensuing metabolic imbalances. Mouse and human AC3-AT are retained in the endoplasmic reticulum, unable to translocate to the plasma membrane and lack enzymatic activity. AC3-AT interacts with AC3 and sequesters it in the endoplasmic reticulum, reducing the pool of adenylyl cyclases available for G-protein-mediated cAMP synthesis. Thus, AC3-AT acts as a cold-induced rheostat in BAT, limiting adverse consequences of cAMP activity during chronic BAT activation.

New grasslands promote pollination but not biological pest control in nearby arable fields in the short term.

Agricultural intensification is a major threat to farmland biodiversity and associated ecosystem services. Semi-natural habitats are integral to the preservation of farmland biodiversity and ecosystem services, however, the extent in which they contribute to specific services is largely unclear. We studied predation rates of ground-dwelling predatory arthropods, and pollination success within old permanent grasslands, newly established grasslands and arable fields near and far from new grasslands. We evaluated whether grassland restoration can enhance pollination and biological control in crop fields. For this purpose, we established new grassland strips within cereal fields, which directly bordered existing permanent grasslands. We evaluated if the distance to these old and new grasslands affects the delivery of the two ecosystem services within crop fields. We found significantly higher seed numbers and seed weight in sentinel plants placed in old grasslands, new grasslands and nearby arable fields compared to distant arable fields. We also found significantly decreasing seed numbers and seed weight in sentinel plants placed in distant arable fields with increasing distance from old grasslands, while pollination success was not affected by distance in nearby arable fields. Contrary, we did not find any significant effects of new grasslands on biological control. Our study showed that 3 years after establishing grasslands arable fields benefited from the proximity of flower-rich new grasslands through increased pollination success though not regarding biological control. This indicates that, on a short term, establishing new grasslands can support beneficial arthropods in providing ecosystem services such as pollination. Predators, in contrast, might take longer to establish effective populations that denote higher predation rates. Our study provides a baseline for future long-term studies to better evaluate pollination and pest control patterns within arable fields. Supplementary Information: The online version contains supplementary material available at 10.1007/s11829-023-10034-5.

Fetal Long QT Syndrome - Challenges in Perinatal Management: A Review and Case Report. Induction of Labor and Vaginal Birth Under Continuous Magnesium Therapy.

Congenital LQTS is an often undetected inherited cardiac channel dysfunction and can be a reason for intrauterine fetal demise. It can present in utero as CTG and ultrasound abnormalities, i. e., bradycardia, ventricular tachycardia, or fetal hydrops. Diagnosis is made by CTG, echocardiography, or fMCG. Intrauterine therapy with a ß blocker and i. v. magnesium should be started. Our objective was to examine the current knowledge about diagnosis and treatment of LQTS and in particular to highlight the opportunity of vaginal birth under continuous intravenous magnesium therapy. Therefore, a thorough MEDLINE and Google Scholar search was conducted. Randomized controlled trials, meta-analyses, prospective and retrospective cohort trials, and case reports were considered. We showed the possibility of vaginal delivery under continuous magnesium therapy in a case of suspected fetal LQTS. A stepwise concept for diagnosis, monitoring, and peripartum management in low, intermediate, and high risk cases of fetal LQTS is presented. If risk is low or intermediate, a vaginal delivery under continuous monitoring is reasonable. Induction of labor at term should be evaluated.

Distance functions of carabids in crop fields depend on functional traits, crop type and adjacent habitat: a synthesis.

Natural pest and weed regulation are essential for agricultural production, but the spatial distribution of natural enemies within crop fields and its drivers are mostly unknown. Using 28 datasets comprising 1204 study sites across eight Western and Central European countries, we performed a quantitative synthesis of carabid richness, activity densities and functional traits in relation to field edges (i.e. distance functions). We show that distance functions of carabids strongly depend on carabid functional traits, crop type and, to a lesser extent, adjacent non-crop habitats. Richness of both carnivores and granivores, and activity densities of small and granivorous species decreased towards field interiors, whereas the densities of large species increased. We found strong distance decays in maize and vegetables whereas richness and densities remained more stable in cereals, oilseed crops and legumes. We conclude that carabid assemblages in agricultural landscapes are driven by the complex interplay of crop types, adjacent non-crop habitats and further landscape parameters with great potential for targeted agroecological management. In particular, our synthesis indicates that a higher edge-interior ratio can counter the distance decay of carabid richness per field and thus likely benefits natural pest and weed regulation, hence contributing to agricultural sustainability.

Stereotactic-guided direct orbital puncture for treatment of orbital arteriovenous fistula.

The patient presented with left-sided chemosis, exophthalmos, and progressive visual loss. Cerebral angiography ed a left orbital arteriovenous malformation and an associated hematoma, with the point of fistulation between the left ophthalmic artery and the anterior section of the inferior ophthalmic vein, with retrograde flow through the superior ophthalmic vein. Transvenous embolization through the anterior facial and angular veins was unsuccessful, with residual shunting. Stereotactic-guided direct venous puncture and Onyx embolization was subsequently performed in the hybrid operating room (OR) to cure the fistula. A subciliary incision allowed for retraction of the orbital contents, creating an optimal trajectory. An endonasal endoscopic approach was performed after the embolization to decompress the orbit. This procedure is shown in video 11-11 neurintsurg;16/4/429/V1F1V1Video 1 .

Supratransmission phenomenon in a Fermi-Pasta-Ulam diatomic lattice.

The nonlinear supratransmission phenomenon in a Fermi-Pasta-Ulam (FPU) diatomic lattice with two forbidden bands is investigated. Using a decoupling ansatz for the motion of the two different sublattices combined with the continuum (quasidiscrete) approximation, we derived analytically the threshold amplitudes of supratransmission occurrence when a sinusoidal driving with frequency in the upper forbidden band (lower forbidden band gap between acoustic and optical modes) is applied at one end. The resulting estimate of the threshold of a lattice with a first heavy particle is different to the one obtained from a lattice with a first light particle, showing the influence of the driven particle and giving also the possibility to have two thresholds on each forbidden gap of a diatomic lattice by switching the order of light (m) and heavy (M) masses. In the lower forbidden band, the dependence of the supratransmission threshold on the mass ratio (µ=m/M) has been evidenced and it appears that for large (small) values of µ, that is µ>60%, the coupling between the two modes must (must not) be considered. Numerical explorations were subsequently performed with an emphasis on the dependence of the threshold on the driving frequency and also on the mass of the driven particle (light or heavy). A good agreement is found between the numerical and analytical thresholds. For the limit case where all the masses are identical, the results of the monoatomic FPU previously found in the literature are recovered.

Echocardiography: conotruncal anomaly: a case of common arterial trunk with intact ventricular septum and hypoplastic left heart complex with unbalanced pulmonary stenoses.

We describe the echocardiographic findings of a common arterial trunk with intact ventricular septum, mitral and left ventricular hypoplasia, atretic left ventricular outlet and bilateral, and unbalanced pulmonary artery stenoses.

Ultrasonic imaging as a means of monitoring gonadal development in lumpfish (Cyclopterus lumpus).

The commercial farming of juvenile lumpfish requires monitoring of gonadal development to achieve synchronized production. Conventional methods such as gonadosomatic index (GSI), sex hormone analyses, gonadal histology, endoscopy, and gene expression analyses are costly, invasive, and often involve sacrificing the fish. We assessed the efficiency of ultrasound as a non-invasive method for monitoring gonadal development in lumpfish. Based on ultrasound observations, we categorized the fish into six stages; F0 to F5 for females and M0 to M5 for males, that represented maturity levels from immature to spent. Importantly, the ultrasound gonadal stages aligned with histological gonadal stages. Additionally, ultrasound stages aligned with profiles of GSI, testosterone (T), 11-ketotestosterone, and 17ß-estradiol throughout gonadal development including the spawning period. Moreover, these parameters exhibited significant positive correlations with each other reflecting their parallel trends during gonadal development. To minimize the frequency of ultrasound usage and fish handling, we established F3 and M3/M4 as arbitrary thresholds for identifying ripe females and males, respectively. By using these thresholds, the need for regular ultrasound monitoring could be reduced during most of the rearing period. Ultrasound proves to be useful and reliable for monitoring gonadal development in lumpfish, enabling synchronized production of juvenile fish.

Diversity-enhanced stability.

We give compelling evidence that diversity, represented by a quenched disorder, can produce a resonant collective transition between two unsteady states in a network of coupled oscillators. The stability of a metastable state is optimized and the mean first-passage time maximized at an intermediate value of diversity. This finding shows that a system can benefit from inherent heterogeneity by allowing it to maximize the transition time from one state to another at the appropriate degree of heterogeneity.

Enhanced signal response in globally coupled networks of bistable oscillators: Effects of mean field density and signal shape.

This paper studies a set of globally coupled bistable oscillators, all subjected to the same weak periodic signal and identical coupling. The effect of mean field density (MFD) on global dynamics is analyzed. The oscillators switch from intra- to interwell motion as MFD increases, clearly demonstrating MFD-enhanced signal amplification. A maximum amplification also occurs at a moderate level of MFD, indicating that the response exhibits a nonmonotonic sensitivity to MFD. The MFD-enhanced response depends mainly on the signal intensity but not on the signal frequency or the network topology. The analytical investigation provides a simplified model to study the mechanism underlying this resonancelike behavior. It is shown that by modifying the bistability nature of the potential energy, the mean field density can promote well-to-well oscillations and larger amplitude motions. Finally, the robustness of this phenomenon to various signal waveforms is examined. It can therefore be used alternatively to efficiently amplify weak signals in practical situations with large network sizes.

Using coupling imperfection to control amplitude death.

Previous studies of nonlinear oscillator networks have shown that amplitude death (AD) occurs after tuning oscillator parameters and coupling properties. Here, we identify regimes where the opposite occurs and show that a local defect (or impurity) in network connectivity leads to AD suppression in situations where identically coupled oscillators cannot. The critical impurity strength value leading to oscillation restoration is an explicit function of network size and system parameters. In contrast to homogeneous coupling, network size plays a crucial role in reducing this critical value. This behavior can be traced back to the steady-state destabilization through a Hopf's bifurcation, which occurs for impurity strengths below this threshold. This effect is illustrated across different mean-field coupled networks and is supported by simulations and theoretical analysis. Since local inhomogeneities are ubiquitous and often unavoidable, such imperfections can be an unexpected source of oscillation control.

Microsurgical Clipping of a Middle Cerebral Artery Aneurysm After Woven Endobridge Embolization Recurrence.

We present the case of a 67-year-old patient with a left middle cerebral artery (MCA) aneurysm treated with a Woven EndoBridge (WEB) device, who experienced neck recurrence after initial complete obliteration. The initial angiogram showed a wide-necked left MCA aneurysm that measured 8 × 7 mm with a 5-mm neck, treated with a WEB device. Post implantation, the initial follow-up angiogram showed complete obliteration. However, subsequent angiogram showed neck recurrence measuring 6.6 × 1.7 mm. The WEB device has become a popular alternative to traditional clipping and coiling procedures, with studies reporting successful treatment of 85%. However, concerns have been raised regarding the device's efficacy in achieving complete aneurysm obliteration, with a lower rate of complete aneurysm occlusion and a higher rate of recurrence compared with surgical clipping. The decision was made to retreat with clipping, and the surgery was successful in completely obliterating the aneurysm. The patient had no residual MCA aneurysm, with both M2 branches patent on postoperative angiogram. Literature review of retreatment options for WEB device failures highlights that the retreatment rate after WEB embolization is approximately 10%. For surgically accessible aneurysms, surgical clipping is an effective retreatment strategy after WEB failure given the compressibility of the device. Video 1 and our literature review provide valuable insights into a rare case of aneurysm recurrence after complete obliteration at initial follow-up after WEB embolization that was successfully treated with surgical clipping.1-8.

Sutimlimab Pharmacokinetics and Pharmacodynamics in Patients with Cold Agglutinin Disease.

Sutimlimab, a humanized monoclonal antibody targeting the classic complement pathway, is approved in the United States, Japan, and the European Union for the treatment of hemolytic anemia in adults with cold agglutinin disease. The objectives of this study were to support dose selection for phase 3 studies, assess dose recommendations, and establish the relationship between sutimlimab exposure and clinical outcome [hemoglobin (Hb) levels]. Clinically meaningful biomarkers were graphically analyzed and the exposure-response relationship was proposed. The pharmacokinetic (PK) characteristics of sutimlimab were best described by a two-compartment model with parallel linear and nonlinear clearance terms. Body weight was a significant covariate for the volume of distribution in the central compartment (Vc) and total body clearance of sutimlimab. Ethnicity (Japanese, non-Japanese) was a covariate on Vc and maximal nonlinear clearance. There were no PK differences between healthy participants and patients. After graphical exposure-response analysis for biomarkers, a pharmacokinetic-pharmacodynamic model was developed by integrating an indirect response/turnover model for Hb with a maximum effect (Emax) model, relating the Hb-elevating effect of sutimlimab to plasma exposure. Renal function and occurrence of blood transfusion were identified as covariates on Hb change from baseline. Simulations showed that Emax was attained with the approved dosing (6.5 g in patients <75 kg and 7.5 g in patients ≥75 kg), independent of covariate characteristics, and provided adequate sutimlimab exposure to maximize effects on Hb, bilirubin, and total complement component C4 levels. A change in Hb from baseline at steady state of 2.2 g/dl was projected, consistent with phase 3 study observations. SIGNIFICANCE STATEMENT: The final validated population pharmacokinetic (PK) and pharmacokinetic/pharmacodynamic (PK/PD) models confirm that the approved dosing regimen for sutimlimab (6.5 g in patients <75 kg and 7.5 g in patients ≥75 kg) is sufficient, without the need for further dose adjustments in populations of patients with cold agglutinin disease.

Third ventricular choroid plexus papilloma: a pure neuroendoscopic approach.

Pure endoscopic technique in resection of intraventricular tumors is an emerging technology. This case demonstrates resection of a multicentric choroid plexus papilloma in a 2-month-old child. This child had two district tumors: one located in the left atrium and another in the third ventricle. Initial microsurgery was performed to resect the left atrial tumor. With the tumor noted to be not very vascular at initial surgery, the third ventricle tumor was resected with a GAAB neuroendoscope and NICO Myriad. A gross-total resection was achieved. At 3 years' follow-up, the child remains tumor free and developing without any functional deficits. The video can be found here: https://stream.cadmore.media/r10.3171/2023.1.FOCVID22145.

Immobilization of per- and polyfluoroalkyl substances (PFAS): Comparison of leaching behavior by three different leaching tests.

The evaluation of PFAS immobilization performance in laboratory experiments, especially the long-term stability, is a challenge. To contribute to the development of adequate experimental procedures, the impact of experimental conditions on the leaching behavior was studied. Three experiments on different scales were compared: batch, saturated column, and variably saturated laboratory lysimeter experiments. The Infinite Sink (IS) test - a batch test with repeated sampling - was applied for PFAS for the first time. Soil from an agricultural field amended with paper-fiber biosolids polluted with various perfluoroalkyl acids (PFAAs; 655 µg/kg ∑18PFAAs) and polyfluorinated precursors (1.4 mg/kg ∑18precursors) was used as the primary material (N-1). Two types of PFAS immobilization agents were tested: treatment with activated carbon-based additives (soil mixtures: R-1 and R-2), and solidification with cement and bentonite (R-3). In all experiments, a chain-length dependent immobilization efficacy is observed. In R-3, the leaching of short-chain PFAAs was enhanced relative to N-1. In column and lysimeter experiments with R-1 and R-2, delayed breakthrough of short-chain PFAAs (C4) occurred (> 90 days; in column experiments at liquid-to-solid ratio (LS) > 30 L/kg) with similar temporal leaching rates suggesting that leaching in these cases was a kinetically controlled process. Observed differences between column and lysimeter experiments may be attributed to varying saturation conditions. In IS experiments, PFAS desorption from N-1, R-1, and R-2 is higher than in the column experiments (N-1: +44 %; R-1: +280 %; R-2: +162 %), desorption of short-chain PFAS occurred predominantly in the initial phase (< 14 days). Our findings demonstrate that sufficient operating times are essential in percolation experiments, e.g., in column experiments >100 days and LS > 30 L/kg. IS experiments may provide a faster estimate for nonpermanent immobilization. The comparison of experimental data from various experiments is beneficial to evaluate PFAS immobilization and to interpret leaching characteristics.

Robotic-guided direct transtemporal embolization of an indirect carotid cavernous fistula.

A middle-aged patient presented with right-sided chemosis, exophthalmos, and progressive visual loss. Digital subtraction angiography revealed a type D carotid-cavernous fistula (CCF). Transarterial embolization through the internal maxillary artery was unsuccessful, and there was no venous access to the CCF. A robotic-guided direct transtemporal embolization of the CCF with Onyx was performed, resulting in successful fistula obliteration and symptom resolution. This is the first reported case of a robotic-guided direct transcranial CCF embolization. We include a technical video that demonstrates this procedure (Supplemental File 1).

Cardiovascular magnetic resonance pulmonary perfusion for guidance of interventional treatment of pulmonary vein stenosis.

BACKGROUND: Pulmonary vein (PV) stenosis represents a rare but serious complication following radiofrequency ablation of atrial fibrillation with a comprehensive diagnosis including morphological stenosis grading together with the assessment of its functional consequences being imperative within the relatively narrow window for therapeutic intervention. The present study determined the clinical utility of a combined, single-session cardiovascular magnetic resonance (CMR) imaging protocol integrating pulmonary perfusion and PV angiographic assessment for pre-procedural planning and follow-up of patients referred for interventional PV stenosis treatment. METHODS: CMR examinations (cine imaging, dynamic pulmonary perfusion, three-dimensional PV angiography) were performed in 32 consecutive patients prior to interventional treatment of PV stenosis and at 1-day and 3-months follow-up. Degree of PV stenosis was visually determined on CMR angiography; visual and quantitative analysis of pulmonary perfusion imaging was done for all five lung lobes. RESULTS: Interventional treatment of PV stenosis achieved an acute procedural success rate of 90%. Agreement between visually evaluated pulmonary perfusion imaging and the presence or absence of a ≥ 70% PV stenosis was nearly perfect (Cohen's kappa, 0.96). ROC analysis demonstrated high discriminatory power of quantitative pulmonary perfusion measurements for the detection of ≥ 70% PV stenosis (AUC for time-to-peak enhancement, 0.96; wash-in rate, 0.93; maximum enhancement, 0.90). Quantitative pulmonary perfusion analysis proved a very large treatment effect attributable to successful PV revascularization already after 1 day. CONCLUSION: Integration of CMR pulmonary perfusion imaging into the clinical work-up of patients with PV stenosis allowed for efficient peri-procedural stratification and follow-up evaluation of revascularization success.