Search

The Kenya Agricultural Carbon Project, implemented by the NGO Vi Agroforestry, is breaking new ground in designing and implementing climate finance projects in the agricultural sector. For the first time, while increasing agricultural productivity and enhancing resilience to climate change, smallholder farmers in Africa will receive benefits for greenhouse gas mitigation based on sustainable agricultural land management. The project has developed an activity monitoring system for sustainable agricultural land management (SALM) practices that enables smallholder famers and extension service provider to track and improve farm production. Based on the development of a carbon accounting methodology this system, in combination with a carbon model, is monitoring soil and biomass carbon sequestration consistent with the Verified Carbon Standard. As a result farmers in Africa for the first time can benefit from international voluntary carbon markets. The paper describes the Vi Agroforestry extension approach, outlines the project objectives and activities, and explains the carbon accounting methodology. Project achievements and lessons learned, but also the challenges that still lie ahead are presented. The authors conclude that the project model has great potential for scaling up and provide a potential blueprint for widespread adoption and effective monitoring of sustainable agricultural management in smallholder conditions.

This paper addresses the challenges in community-based management of carbon projects in developing countries. It is based on four years of experience in identifying, developing, implementing, and monitoring mangrove restoration and agroforestry projects in upland and coastal areas of India, Indonesia, and Senegal. While many of the challenges are common to any typical grass-roots development project, we focus on aspects that are more directly related to carbon sequestration activities. To address all of these challenges, the paper proposes some measures that we believe help make implementation and monitoring easier for practitioners in this realm. Our thematic focus of “process”, “participation” and “performance” underscores three key areas we believe merit greater attention in these projects. The process elements are important because of specialized knowledge that is often not familiar to communities such as the process of identifying suitable planting sites and arrangements, and suitable implementation arrangements given stakeholder needs requires significant upfront commitment from all involved. The challenges related to process are highlighted through reference to methodology selection, and the implications it has for site selection through to implementation. The second theme – participation – addresses the peculiar stakeholder interests, interactions and arrangements that arise at all stages of the project. A challenge is meeting all stakeholder expectations and constraints through recognizing that people have different motivations and interests; as examples, active engagement is necessary to find acceptable terms for implementation, revenue sharing, and risk sharing. Again, peculiarities of the carbon market – such as carbon property rights – often create uncertainty that must be handled delicately in such circumstances. The final theme – performance – relates to an ongoing need to accommodate a complex array of monitoring, auditing, validation and quality control requirements over a range of multiple objectives. The challenge in this realm is to implement high-scale projects that are economically viable, but which will stretch the capacity of local community-based systems considering compliance requirements with regards to implementation and carbon accounting standards. Hence the interests and requirements of different stakeholders may not be fully aligned. As an example, many carbon projects now have multiple objectives – carbon, biodiversity, and community welfare – but there are few received protocols for addressing these concurrently. An important insight through all of these dimensions is that no single concept of “community” can be universally applied: the connections among stakeholders and others are never as clear as one assumes them to be.

Abstract Protein kinases of the MARK family phosphorylate tau protein in its repeat domain and thereby regulate its affinity for microtubules and affect the aggregation of tau into Alzheimer paired helical filaments. We are searching for low molecular weight compounds to interfere with the activity of MARK and its pathways. Here we summarize structural features of MARK and cellular pathways of regulation.

Protein kinases of the MARK family phosphorylate tau protein in its repeat domain and thereby regulate its affinity for microtubules and affect the aggregation of tau into Alzheimer paired helical filaments. We are searching for low molecular weight compounds to interfere with the activity of MARK and its pathways. Here we summarize structural features of MARK and cellular pathways of regulation. [ABSTRACT FROM AUTHOR]

The large but shallow (3,558 k m{sup}2{end} , up to 15.3 m deep) lake is eutrophic, with Chironomus plumosus and Potamothrix hammoniensisas dominating macroinvertebrates in the profundal. The extensive well-aerated sublittoral with sandy bottom sediments has a mesotrophic appearance and supports a diverse fauna with several oxyphilous species, including a very abundant population of Dreissena polymorpha. The phytophilous fauna is limited to small sheltered areas only. The average abundance of the "small" animals of macrozoobenthos (without big molluscs) was 2,617 ind. m{sup}- 2{end} , their biomass 12.34 g m{sup}-2{end} (corresponding to 52.2 kJ m{sup}- 2{end} ) in 1964-1994. Thesame figures for big molluscs (mostly Dreissena) were 304 ind. m{sup}-2{end} and 238 g m{sup}-2{end} in 1964-1994, and even 864 ind. m{sup}-2{end} and 687 g m{sup}-2{end} in 1985-1988, at the time of their special mapping. The sublittoral zone revealed the lowest biomass of 11 "small" animals but the highest biomass of big molluscs. The southern, shallower lake regions, more enriched with nutrients and better protected from wind, revealed a significantly higher biomass of "small" macrozoobenthos in the near-shore zone than the cleaner and open northern part, while no positive effect of enrichment was observed neither in the biomass of profundal zoobenthos nor in that of big molluscs. The production of the "small" macrozoobenthos was calculated as 111 and 53 kJ m{sup}-2{end} during two annual cycles in Lake Peipsi s.s., the most productive period being the autumn overtum. Lake Peipsi-Pihkva has the highest abundance and biomass of macrozoobenthos among the large lakes of North Europe. [ABSTRACT FROM AUTHOR]

Macrozoobenthos of the large (3,558 km{sup}2{end} ) Lake Peipsi-Pihkva was monitored at 22-24 sampling spots yearly in. June 1964-1994 aswell as 50 shallow-water profiles in midsummer 1970, 1980, and 1990.No qualitative changes were observed in the bottom fauna, except forthe introduction of a Baikalian gammarid species, Gmelinoides fasciatus. The average total biomass in June (without big molluscs) revealed considerable annual fluctuations, with an insignificant general tendency of increase. The increase was significant in the biomass of several Mollusca (including the highly abundant big clam Dreissena polymorpha), Asellus, Gammaridae, and Hirudinea but not in the most abundant animal groups Chironomidae and Oligochaeta. The low biomass of Ephemeroptera and Hydrachnellae decreased significantly. The mid-summer samples taken from the shallow-water zone in three different years revealed the highest biomass in 1980 and the lowest in 1990 (the latterbeing probably related to the high water level). A gradual decrease in the biomass of the Ephemeroptera and Hydrachnellae as well as the Oligochaeta, Pisidiidae and Bithynia tentaculata occur-red in the shallow-water zone, while the Gammaridae increased on the account of theintroduced species. No coincidence was found with the neighbouring Lake Vortsjarv when comparing the annual fluctuations of biomass. A general tendency to a slow increase in total biomass and a decrease in the biomass of the most vulnerable groups Ephemeroptera and Hydrachnellae, probably due to progressing eutrophication, were common for both lakes. [ABSTRACT FROM AUTHOR]

Lake Peipsi-Pihkva (3555 km{sup}2{end} , mean depth 8.3 m), consisting of three parts, (L. Peipsi, L. Pihkva, L. Lammijarv) is located onthe border of Estonia and Russia. L. Peipsi belongs to unstratified eutrophic lakes with mesotrophic features, L. Lammijarv has some dyseutrophic features, while L. Pihkva is strongly eutrophic. The total annual nutrient load is 15.57 tons N km{sup}-2{end} and 327 kgP km{sup}-2{end} with 74 percent of N and 39 percent of P originating from agriculture. The mean concentrations of total N and P in the lake are 876 mg m{sup}-3{end} -3 and 46 mg m{sup}-3{end} , respectively, both being the highest in L. Pihkva and the lowest in the northern part of L. Peipsi. Average pH is 8.14 and Secchi disk transparency 1.63 m. Diatoms and blue-green algae prevail in phytoplankton biomass. The blue-greens Gloeotrichia echinulata and Aphanizomenon flos-aquae dominatein summer causing the water-blooms. The concentration of Chla was the lowest in the northern part of L. Peipsi (mean 14.7 mg m{sup}-3{end} ) and the highest in the southern part of L. Pihkva (mean 47.9 mg m{sup}-3{end} , median 16.3 mg m{sup}-3{end} ). An increase of Chla and decrease of Secchi depth could be noticed in 1983-1988, while in 1988-1994 the tendency was opposite. The long-term average primary production is 0.8 g C m{sup}-2{end} d{sup}-1{end} . Zooplankton is remarkably rich in species, the average biomass in the vegetative period being 2-3 g m{sup}-3{end} and production 22 g C m{sup}- 2{end}. The role of rotifers in production is 53 percent followed by that of cladocerans (30 percent), copepods (16 percent) and Dreissena polymorpha larvae (1 percent). The total count of bacteria is 1-9 million cells perml. Chironomus plumosus and Potamothrix hammoniensis are dominating in the profundal. The average abundance of macrozoobenthos (without big molluscs) 2617 ind. m{sup}-2{end} , and their biomass 12.34 g m{sup}-2{end} are considered to be the highest among the large lakes of Nort [ABSTRACT FROM AUTHOR]

Background and Purpose: Patients suffering from ischaemic heart disease and heart failure are at high risk of recurrent ventricular arrhythmias (VAs), eventually leading to sudden cardiac death. While high-voltage shocks delivered by an implantable defibrillator may prevent sudden cardiac death, these interventions themselves impair quality of life and raise both morbidity and mortality, which accentuates the need for developing novel defibrillation techniques., Experimental Approach: Photopharmacology allows for reversible control of biological processes by light. When relying on synthetic and externally applied chromophores, it renders genetic modification of target cells dispensable and may hence be advantageous over optogenetic approaches. Here, the photochromic ligand azobupivacaine 2 (AB2) was probed as a modulator of cardiac electrophysiology in an ex vivo intact mouse heart model., Key Results: By reversibly blocking voltage-gated Na + and K + channels, photoswitching of AB2 modulated both the ventricular effective refractory period and the conduction velocity in native heart tissue. Moreover, photoswitching of AB2 was able to convert VA into sinus rhythm., Conclusion and Implications: The present study provides the first proof of concept that AB2 enables gradual control of cardiac electrophysiology by light. AB2 may hence open the door to the development of an optical defibrillator based on photopharmacology., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

The retina extracts chromatic information present in an animal's environment. How this information is processed in the retina is not well understood. In the mouse, chromatic information is not collected equally throughout the retina. Green and UV signals are primarily detected in the dorsal and ventral retina, respectively. However, at the output of the retina, chromatic tuning is more mixed throughout the retina. This suggests that lateral processing by inhibitory amacrine cells shapes chromatic information at the retinal output. We systematically surveyed the chromatic responses of dendritic processes of the 40+ GABAergic amacrine cell types. We identified 25 functional types with distinct chromatic and achromatic properties. We used pharmacology and a biologically inspired deep learning model to explore how inhibition and excitation shape the properties of functional types. Our data suggest that amacrine cells balance the biased spectral tuning of excitation, thereby supporting diversity of chromatic information at the retinal output., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: In the treatment of hepatocellular carcinoma (HCC) with transarterial radioembolization (TARE), identifying reliable biomarkers for predicting survival outcomes remains a critical challenge. We aimed to address this gap by investigating the significance of serum cytokines associated with inflammation as potential biomarkers for the selection of patients for TARE., Methods: Our retrospective study involved 161 patients diagnosed with HCC who underwent Y90 radioembolization at our medical center between 2010 and 2020. Serum samples from a subset of 78 patients were retrospectively analyzed to determine the concentrations of pro-inflammatory cytokines. The results from the prospective SORAMIC trial were used for independent validation., Results: With a median overall survival of 36 weeks (range 4-436), our study showed the strongest correlation between 12-week survival and IL-8 levels before treatment (p < 0.001), while other relevant interleukins, interferon-α2, INF-γ, TNF-α and MCP-1 were not associated with survival. IL-8 levels below the cut-off of 190 pg/mL were significantly associated with increased 12-week and 24-week survival, with hazard ratios of 19.01 (95% CI: 2.29-157.89) and 2.57 (95% CI: 1.05-6.31), respectively (p = 0.006 and p = 0.039, respectively). In the adjusted multivariate analysis, the 190 pg/mL cut-off for IL-8 remained independently associated with 12- (p = 0.011) and 24-week survival (p = 0.039). Similarly, the SORAMIC population showed a strong association between IL-8 levels and 36-week survival (p = 0.03)., Conclusion: Our study emphasizes the pivotal role of IL-8 as a valuable parameter, demonstrating its potential for predicting treatment outcomes and assessing liver function in patients with HCC undergoing TARE. The robustness of these findings warrants further validation., (© 2024. The Author(s).)

Background: Simulation-based training is gaining importance in urologic residents training., Objectives: This prospective study evaluated the influence of the Endo Workshop of the German Society of Residents in Urology e. V. (GeSRU) on surgical confidence., Materials and Methods: GeSRU Endo Workshop 2022 included 1 h simulation-based training sessions on stone removal using ureteroscopy (URS) and transurethral resection of the bladder (TURB). Using an online questionnaire, surgical confidence was assessed before and after the workshop. Surgical assessment relied on the global rating scale (GRS)., Results: Overall, 40 residents participated: 25 (62.5%) men and 15 (37.5%) women. In URS assessment, men vs. women achieved an average of 26.6 vs. 26.1/35 points on the GRS (p = 0.7) and completed the task in 8.1 ± 1.9 vs. 9.9 ± 0.4 min (p < 0.001). In TURB assessment, men vs. women achieved an average of 26.0 vs. 27.3/35 points on the GRS (p = 0.3) and required 7.6 ± 1.9 vs. 7.7 ± 2.2 min (p = 0.9), respectively. Among participants who answered the baseline survey and the evaluation (n = 33), 16 (80%) men vs. 3 (23%) women had surgical confidence to perform URS before (p = 0.01), and 19 (95%) men vs. 7 (54%) women after the workshop (p = 0.03). Regarding the performance of TURB, 10 (50%) men vs. 7 (54%) women reported surgical confidence before (p = 0.1), and 15 (75%) men vs. 10 (77%) women after the workshop (p = 1.0). An increase in surgical confidence to perform URS and TURB was reported by 9 (45%) and 10 (50%) men and 9 (69%) and 8 (62%) women, respectively., Conclusions: Endourologic simulation-based training increases surgical confidence of both female and male residents. Despite comparable surgical outcomes, women approach URS with lower surgical confidence compared to their male counterparts., (© 2024. The Author(s).)

The use of correlated states and measurements promises improvements in the accuracy of frequency metrology and the stability of atomic clocks. However, developing strategies robust against dominant noise processes remains challenging. We address the issue of decoherence due to spontaneous decay and show that Greenberger-Horne-Zeilinger (GHZ) states, in conjunction with a correlated measurement and nonlinear estimation strategy, achieve gains of up to 2.25 decibel, comparable to fundamental bounds for up to about 80 atoms in the presence of decoherence. This result is unexpected because GHZ states do not provide any enhancement under dephasing due to white frequency noise compared to the standard quantum limit of uncorrelated states. The gain arises from a veto signal, which allows for the detection and mitigation of errors caused by spontaneous emission events. Through comprehensive Monte Carlo simulations of atomic clocks, we demonstrate the robustness of the GHZ protocol.

Many complications associated with type 2 diabetes mellitus (T2DM) are closely linked with the generation of reactive species or free radicals leading to oxidative/nitrosative stress. The aim of this study was to investigate the effect of combined administration of metformin with propionate on the degree of oxidative/nitrosative damage in the brain of rats with an experimental model of T2DM. Male Wistar rats were divided into control (healthy rats); rats with T2DM and no further therapy; rats with T2DM that received: metformin, propionate, propionate + metformin. Ventromedial hypothalamus samples were analyzed by transmission electron microscopy, gas-liquid chromatography, Western blotting, RT-PCR and electron paramagnetic resonance. Combined treatment resulted in normalization of the neuronal NOS levels and reduction of mRNA level of induced nitric oxide synthase (NOS) and superoxide radicals compared to untreated T2DM rats. A decrease was also observed in the level of 8-oxyguanine with normalization of fatty acids distribution. The combined treatment partially mitigated ultrastructural alterations resulting from oxidative/nitrosative damage in neurons' mitochondria in T2DM. Thus, we demonstrated a positive effect of the combined use of metformin and propionate on all indicators of oxidative/nitrosative stress in T2DM., (© 2024. The Author(s).)

Background: The significance of computed tomography (CT)-based volume measurement of the inferior vena cava (IVC) in the treatment and prognosis of trauma patients is not yet fully understood. The conflicting results that have been reported may be attributable to differences in injury severity and the use of different measurement methods, including IVC index and volumetry. The purpose of this study was to determine the relationship between IVC volume and red blood cell (RBC) transfusion and mortality in intubated trauma patients who were stable enough for initial CT imaging., Methods: A retrospective analysis was conducted on all consecutive trauma patients who underwent emergency tracheal intubation and mechanical ventilation before initial whole-body CT imaging at a level-1 trauma center over a 12-year period (2008-2019). The IVC volume was determined on initial trauma CT and included in multivariable models with demographic and diagnostic data. Associations of overall RBC transfusion, massive transfusion, 24-h mortality, and 30-day mortality were assessed using logistic regression analyses and Cox proportional hazard models., Results: A total of 438 patients (75.3% male) with a median age of 50 years, and a median injury severity score (ISS) of 26 points were included in the analysis. Most of the patients (97.5%) had suffered from blunt trauma mechanisms. Median IVC volume was 36.25 cm 3 , and RBC transfusion and massive transfusion were performed in 197 and 90 patients, respectively. The 24-h and 30-day mortality rates were 7.3% and 23.3%, respectively. VCI volume was found to be independently associated with the necessity of RBC transfusion and 24-h mortality (OR 0.98, 95% CI 0.96-0.99, p = 0.01 and HR 0.96, 95% CI 0.93-0.99, p = 0.025, respectively), while associations with massive transfusion and 30-day mortality were not statistically significant in multivariable analyses., Conclusion: Initial IVC volume may serve as a predictor of patients at risk for overall RBC transfusion requirements and 24-h mortality, suggesting the possibility of its diagnostic efficacy in short-term outcomes. Further studies are needed to confirm these findings., (© 2024. The Author(s).)

In an acute contact test with bees the compound of interest is dissolved in a carrier solvent (frequently acetone) and then a droplet of the solution is placed on the dorsal thorax of the bee. The volume of the droplet is standardised to 1 µL for honeybees and to 2 µL for bumblebees. In practice the same droplet volume is used for bees with very different sizes. In this research the effect of the droplet volume was evaluated with acute contact tests with dimethoate for the alfalfa leafcutter bee, the red mason bee, the honeybee and the bumblebee. The results were analysed with a ToxicoKinetic ToxicoDynamic (TKTD) model to separate kinetic from dynamic effects. This allows to compare the sensitivity of the bee based on the effect threshold and not on the time, species and test dependent LD 50 s. The analysis of the test results indicates that the magnitude of the response of the bees increased with increasing droplet size. The results also showed that the manifestation of effects over time is slower for the red mason bee and the bumblebee compared to the honeybee and the alfalfa leafcutter bee. This implies that the result of a 2 day test with a fixed dosing volume results in different response for a bumblebee compared to the alfalfa leafcutter bee, not because of different sensitivities of the bees involved but due to the difference of relative dosed surface ratio. So comparing the sensitivity of bee species, based on standardised tests is biased and amplifies the sensitivity for the smaller bee species., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

In this research article, we report on the strengthening of a non-classical hydrogen bond (C-H⋅⋅⋅O) by introducing electron withdrawing groups at the carbon atom. The approach is demonstrated on the example of derivatives of the physiological E-selectin ligand sialyl Lewis x (1, sLe x ). Its affinity is mainly due to a beneficial entropy term, which is predominantly caused by the pre-organization of sLe x in its binding conformation. We have shown, that among the elements responsible for the pre-organization, the stabilization by a non-classical hydrogen bond between the H-C5 of l-fucose and the ring oxygen O5 of the neighboring d-galactose moiety is essential and yields 7.4 kJ mol -1 . This effect could be further strengthened by replacing l-fucose by 6,6,6-trifluoro-l-fucose leading to an improved non-classical H-bond of 14.9 kJ mol -1 , i.e., an improved pre-organization in the bioactive conformation. For a series of glycomimetics of sLe x (1), this outcome could be confirmed by high field NMR-shifts of the H-C5 Fuc , by X-ray diffraction analysis of glycomimetics co-crystallized with E-selectin as well as by isothermal titration calorimetry. Furthermore, the electron-withdrawing character of the CF 3 -group beneficially influences the pharmacokinetic properties of sLe x mimetics. Thus, acid-stability, a prerequisite for gastrointestinal stability, could be substantially improved., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

"True" cobras (genus Naja ) are among the venomous snakes most frequently involved in snakebite accidents in Africa and Asia. The Cape cobra ( Naja nivea ) is one of the African cobras of highest medical importance, but much remains to be learned about its venom. Here, we used a shotgun proteomics approach to better understand the qualitative composition of N. nivea venom and tested its cytotoxicity and protease activity as well as its effect on intracellular Ca 2+ release and NO synthesis. We identified 156 venom components representing 17 protein families, with the dominant ones being three-finger toxins, mostly of the short-chain type. Two-thirds of the three-finger toxin entries identified were assigned as cytotoxins, while the remainder were categorized as neurotoxins, including short-chain, long-chain, and ancestral three-finger toxins. We also identified snake venom metalloproteinases and members of CRISP, l-amino acid oxidase, and other families. Protease activity and its effect on intracellular Ca 2+ release and NO synthesis were low. Phospholipase A 2 activity was surprisingly high, despite this toxin family being marginally recovered in the analyzed venom. Cytotoxicity was relevant only at higher venom concentrations, with macrophage and neuroblastoma cell lines showing the lowest viability. These results are in line with the predominantly neurotoxic envenomation symptoms caused by Cape cobra bites. The present overview of the qualitatively complex and functionally intriguing venom of N. nivea may provide insights into the pathobiochemistry of this species' venom.

Objectives: The aim of this systematic review was to evaluate whether platelet-rich-fibrin (PRF) is effective in preventing postoperative bleeding after dental extractions in patients on anticoagulation or antiplatelet therapy compared to stitches alone and different hemostatic agents., Materials and Methods: This systematic review was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The protocol was registered at the International Prospective Register of Systematic Reviews (PROSPERO) (registration number CRD42024562289). Two authors independently performed searches in several databases, including PubMed, EMBASE, Cochrane Library, and SCOPUS., Results: In total, 789 studies were identified, of which 11 met the inclusion criteria after full-text screening. Four studies evaluated the efficiency of PRF in patients on antiplatelet therapy, and seven studies analyzed its hemostatic effect in patients on anticoagulants. All studies showed sufficient hemostasis when PRF was used, but due to heterogeneity meta-analysis was not possible., Conclusions: Despite the use of different protocols and control groups, PRF treatment seems to be superior to only stitches and inferior to chitosan dressings concerning the time of hemostasis. Additionally, PRF seems to be beneficial in terms of faster wound healing and less postoperative pain., Clinical Relevance: PRF is known to enhance soft tissue healing and reduce postoperative pain. As a fully autologous platelet concentrate, it can support hemostasis after dental extractions in patients on antiplatelet or anticoagulation therapy. This systematic review aims to provide an update of the existing literature on PRF and its hemostatic capacity in patients with blood thinning medication., (© 2024. The Author(s).)

Introduction: Recent data show that magnesium supplementation decreases systolic and diastolic blood pressure values depending on the blood pressure levels and improves metabolic parameters in cardiovascular disease., Materials and Methods: In this context, we conducted a prospective, randomized, double-blind study on serum and ionized magnesium, systolic and diastolic blood pressure values, interleukin-6, vitamin D, and metabolic profile in 27 patients (13 male/14 female, age: 60.2 ± 12.5 years) with metabolic syndrome. All patients received 400 mg of oral magnesium supplementation daily. Parameters were measured before and after 6 and 12 weeks of treatment. 27 patients served as controls without additional magnesium treatment (10 male/17 female, age: 64.6 ± 13.2 years)., Results: There was no significant change in serum magnesium after 6 and 12 weeks of magnesium supplementation and in controls. Ionized magnesium significantly increased from 0.56 ± 0.05 to up to 0.63 ± 0.08 mmol/L (mean ± SD) (p < 0.01). The ionized Ca ++ /Mg ++ ratio was significantly increased at baseline in about 32% of all patients; after 12 weeks of magnesium supplementation, the Ca ++ /Mg ++ ratio decreased significantly from 2.32 ± 0.22 to 2.04 ± 0.24 at the end of the study (mean ± SD, p < 0.05). In the magnesium-treated group, there was a significant decrease in systolic and diastolic blood pressure values after 12 weeks (systolic: 134.6 ± 6.8 to 126.3 ± 5.6 mmHg, diastolic: 84.1 ± 3.9 to 79.4 ± 1.6 mmHg) (mean ± SD) (p < 0.01). Additional magnesium supplementation decreased interleukin-6 values significantly from 4.94 ± 3.30 to 4.53 ± 6.89 pg/mL after 6 weeks to 3.01 ± 1.32 pg/mL after 12 weeks (mean ± SD) (p < 0.01). In the control group, interleukin-6 was 3.73 ± 4.36 pg/mL before the start of the supplementation, 4.87 ± 4.35 pg/mL after 6 weeks, and 4.41 ± 3.15 pg/mL after 12 weeks (means ± SD) (n.s.). In patients receiving magnesium supplementation, vitamin D levels significantly improved from 17.93 ± 8.96 to 24.41 ± 10.20 ng/mL (mean ± SD) (p < 0.05). HbA1c and serum cholesterol values improved under magnesium therapy, but the improvement did not reach significance. For statistical analysis, Mann-Whitney-U-Test was used., Conclusion: Using supplementation with 400 mg magnesium for 12 weeks in patients with metabolic syndrome, ionized magnesium concentrations significantly increased, while serum magnesium did not change significantly. Both systolic and diastolic blood pressure values decreased significantly in the magnesium-treated group. Magnesium supplementation also significantly decreased interleukin-6 levels and increased vitamin D in patients. HbA1c and cholesterol levels improved with magnesium supplementation, but the improvement did not reach significance. The anti-inflammatory effects of magnesium as well as anti-arteriosclerotic effects of magnesium therapy are beneficial for patients with metabolic syndrome at high risk of cardiovascular disease and mortality.

We characterized 15 H5N1 HPAI viruses from different small- and medium-scale poultry flocks across Bangladesh during 2018-2021 based on their complete genome sequences. The antigenic relatedness of H5N1 HPAI viruses from different timepoints was analysed. During 2020-2021, 42.11% of the flocks tested positive for at least one of the respiratory infections, with 15.79% showing influenza A virus, of which 8.77% tested positive for HPAIV H5N1. Co-infections with two to four pathogens were detected in 15.8% of flocks. Phylogeny and gene constellation analyses based on complete genome sequences of 15 HPAI viruses revealed the continuing circulation of H5 clade 2.3.2.1a genotype G2 viruses. In the HA protein of the study isolates, functionally meaningful mutations caused the loss of an N-linked glycosylation site (T156A), a modified antigenic site A (S141P), and a mutation in the receptor binding pocket (E193R/K). Consequently, antigenic analysis revealed a significant loss of cross-reactivity between viruses from different host species and periods. Most viruses displayed oseltamivir resistance markers at positions V96, I97, S227, and N275 (N1 numbering) of the NA protein. In addition, for the PB2, M1, and NS1 proteins, significant mutations were noticed that have been associated with polymerase activity and increased virulence for mammals in all study isolates. These results highlight the need for intensified genomic surveillance of HPAI circulating in poultry in Bangladesh and for establishing appropriate control measures to decrease the circulation of these viruses in poultry in the country.

Abstract: Immune thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening autoimmune disorder caused by a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS13) deficiency. Caplacizumab, an anti-von Willebrand factor nanobody, is approved for iTTP treatment, reducing the need for therapeutic plasma exchange (TPE) and improving platelet count recovery and survival. We conducted a retrospective study on 42 acute iTTP cases in Austria and Germany, treated with a modified regimen aimed at avoiding TPE if platelet count increased after the first caplacizumab dose. Baseline characteristics and patient outcomes were compared with a control group of 59 patients with iTTP receiving frontline treatment with TPE, caplacizumab, and immunosuppression. The main outcome was the time to platelet count normalization. Secondary outcomes included clinical response, exacerbation, refractory iTTP, iTTP-related deaths, and the time to platelet count doubling. The median time to platelet count normalization was similar between the 2 cohorts (3 and 4 days; P = .31). There were no significant differences in clinical response, exacerbations, refractoriness, iTTP-related deaths, or time to platelet count doubling, reflecting the short-term treatment response. Four patients did not respond to the first caplacizumab dose, and TPE was subsequently initiated. Cytomegalovirus infection, HIV/hepatitis B virus coinfection, an ovarian teratoma with associated antiplatelet antibodies, and multiple platelet transfusions before the correct diagnosis may have impeded the immediate treatment response in these patients. In conclusion, caplacizumab and immunosuppression alone, without TPE, rapidly controlled thrombotic microangiopathy and achieved a sustained clinical response in iTTP. Our study provides a basis for TPE-free iTTP management in experienced centers via shared decision-making between patients and treating physicians., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Within the last decades industrial swine herds in Europe grown significantly, creating an optimized reservoir for swine influenza A viruses (swIAV) to become enzootic, particularly in piglet producing herds among newborn, partly immunologically naïve piglets. To date, the only specific control measure to protect piglets from swIAV is the vaccination of sows, which provides passive immunity through maternally derived antibodies in colostrum of vaccinated sows. Interruption of infection chains through management practices have had limited success. This study focused on weaned piglets in five enzootically swIAV infected swine herds in North-West and North-East Germany and aimed to better understand swIAV infection patterns to improve piglet protection and reduce zoonotic risks. Participating farms fulfilled the following inclusion criteria: sow herd with ≥ 400 sows (actual size 600-1850 sows), piglets not vaccinated against influenza A virus and a history of recurrent respiratory problems associated with continuing influenza A virus infection. Influenza vaccination was performed in all sow herds, except for one, which discontinued vaccination during the study., Results: First swIAV detections in weaned piglets occurred at 4 weeks of age in the nursery and continued to be detected in piglets up to 10 weeks of age showing enzootic swIAV infections in all herds over the entire nursery period. This included simultaneous circulation of two subtypes in a herd and co-infection with two subtypes in individual animals. Evidence for prolonged (at least 13 days) shedding was obtained in one piglet based on two consecutive swIAV positive samplings. Possible re-infection was suspected in twelve piglets based on three samplings, the second of which was swIAV negative in contrast to the first and third sampling which were swIAV positive. However, swIAV was not detected in nasal swabs from either suckling piglets or sows in the first week after farrowing., Conclusions: Predominantly, weaned piglets were infected. There was no evidence of transmission from sow to piglet based on swIAV negative nasal swabs from sows and suckling piglets. Prolonged virus shedding by individual piglets as well as the co-circulation of different swIAV subtypes in a group or even individuals emphasize the potential of swIAV to increase genetic (and potentially phenotypic) variation and the need to continue close monitoring. Understanding the dynamics of swIAV infections in enzootically infected herds has the overall goal of improving protection to reduce economic losses due to swIAV-related disease and consequently to advance animal health and well-being., (© 2024. The Author(s).)

While natural terpenoid cyclases generate complex terpenoid structures via cationic mechanisms, alternative radical cyclization pathways are underexplored. The metal-catalysed H-atom transfer reaction (M-HAT) offers an attractive means for hydrofunctionalizing olefins, providing access to terpenoid-like structures. Artificial metalloenzymes offer a promising strategy for introducing M-HAT reactivity into a protein scaffold. Here we report our efforts towards engineering an artificial radical cyclase (ARCase), resulting from anchoring a biotinylated [Co(Schiff-base)] cofactor within an engineered chimeric streptavidin. After two rounds of directed evolution, a double mutant catalyses a radical cyclization to afford bicyclic products with a cis-5-6-fused ring structure and up to 97% enantiomeric excess. The involvement of a histidine ligation to the Co cofactor is confirmed by crystallography. A time course experiment reveals a cascade reaction catalysed by the ARCase, combining a radical cyclization with a conjugate reduction. The ARCase exhibits tolerance towards variations in the dienone substrate, highlighting its potential to access terpenoid scaffolds., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background:  This review discusses the quantitative assessment of tissue composition in the human body (body composition, BC) using radiological methods. Such analyses are gaining importance, in particular, for oncological and metabolic problems. The aim is to present the different methods and definitions in this field to a radiological readership in order to facilitate application and dissemination of BC methods. The main focus is on radiological cross-sectional imaging., Methods:  The review is based on a recent literature search in the US National Library of Medicine catalog (pubmed.gov) using appropriate search terms (body composition, obesity, sarcopenia, osteopenia in conjunction with imaging and radiology, respectively), as well as our own work and experience, particularly with MRI- and CT-based analyses of abdominal fat compartments and muscle groups., Results and Conclusion:  Key post-processing methods such as segmentation of tomographic datasets are now well established and used in numerous clinical disciplines, including bariatric surgery. Validated reference values are required for a reliable assessment of radiological measures, such as fatty liver or muscle. Artificial intelligence approaches (deep learning) already enable the automated segmentation of different tissues and compartments so that the extensive datasets can be processed in a time-efficient manner - in the case of so-called opportunistic screening, even retrospectively from diagnostic examinations. The availability of analysis tools and suitable datasets for AI training is considered a limitation., Key Points:   · Radiological imaging methods are increasingly used to determine body composition (BC).. · BC parameters are usually quantitative and well reproducible.. · CT image data from routine clinical examinations can be used retrospectively for BC analysis.. · Prospectively, MRI examinations can be used to determine organ-specific BC parameters.. · Automated and in-depth analysis methods (deep learning or radiomics) appear to become important in the future.., Citation Format: · Linder N, Denecke T, Busse H. Body composition analysis by radiological imaging - methods, applications, and prospects. Fortschr Röntgenstr 2024; 196: 1046 - 1054., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Snakebite primarily impacts rural communities of Africa, Asia, and Latin America. The sharp-nosed viper (Deinagkistrodon acutus) is among the snakes of highest medical importance in Asia. Despite various studies on its venom using modern venomics techniques, a comprehensive understanding of composition and function of this species' venom remains lacking. We combined proteogenomics with extensive bioactivity profiling to present the first genome-level catalogue of D. acutus venom proteins and their exochemistry. Our analysis identified an unusually simple venom containing 45 components from 20 distinct protein families. Relative toxin abundances indicate that C-type lectin and C-type lectin-related protein (CTL), snake venom metalloproteinase (svMP), snake venom serine protease (svSP), and phospholipase A 2 (PLA 2 ) constitute 90 % of the venom. Bioassays targeting key aspects of viperid envenomation showed considerable concentration-dependent cytotoxicity, particularly in kidney and lung cells, and potent protease and PLA 2 activity. Factor Xa and thrombin activities were minor, and no plasmin activity was observed. Effects on haemolysis, intracellular calcium (Ca 2+ ) release, and nitric oxide (NO) synthesis were negligible. Our analysis provides the first holistic genome-based overview of the toxin arsenal of D. acutus, predicting the molecular and functional basis of its life-threatening effects, and opens novel avenues for treating envenomation by this highly dangerous snake., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Conclusive evidence on the benefits of automated insulin delivery (AID) systems on person-reported outcomes (PROs) is missing., Methods: In this systematic review and meta-analysis, four databases (PubMed, PsycINFO, Cochrane, and GoogleScholar) were searched from inception up to August 7th, 2024. All types of studies were included if studies reported on PROs in people with diabetes using an AID system. All types of control groups in randomised controlled trials (RCT) were included. Summary data were extracted by three reviewers. Main outcomes focused on diabetes distress, fear of hypoglycaemia and quality of life. Meta-analyses were conducted for RCTs and observational studies separately. When five or more studies could be pooled, random-effects meta-analysis was used, otherwise common-effects meta-analysis was used. Risk of bias was evaluated with Cochrane tools. This study was registered with PROSPERO, CRD42022352502., Findings: A total of 62 studies (n = 9253) were included reporting on 45 different questionnaires. Twenty-seven studies were RCTs and 25 were observational studies. RCT meta-analyses showed reduced diabetes distress (standardised mean difference [95% CI]: -0.159 [-0.309, -0.010], I 2  = 23.0%), reduced fear of hypoglycaemia (-0.339 [-0.566, -0.111], I 2  = 42.6%), and improved hypoglycaemia unawareness (-0.231 [-0.424, -0.037], I 2  = 0.0%), quality of life in adults (0.347 [0.134, 0.560], I 2  = 0.0%) and children/adolescents (0.249 [0.050, 0.448], I 2  = 0.0%). Observational meta-analyses corroborated improvements in diabetes distress (-0.217 [-0.403, -0.031], I 2  = 68.5%), fear of hypoglycaemia (-0.445 [-0.540, -0.349], I 2  = 0.0%), hypoglycaemia unawareness (-0.212 [-0.419, -0.004], I 2  = 0.0%), and showed improved sleep quality (-0.158 [-0.255, -0.061], I 2  = 0.0%)., Interpretation: We found low to moderate effect sizes indicating that AID therapy is associated with reduced burden and improved well-being in people with diabetes. Evidence comes from both RCTs and observational studies. However, for some PROs only a limited number of studies could be pooled with a large heterogeneity in questionnaires used. More research is needed with a more uniformed assessment of PROs to demonstrate the added value of AID therapy on psychosocial outcomes., Funding: None., Competing Interests: T.R. reports honoraria for lectures from Berlin-Chemie AG. N.H. reports Advisory Board member fees from Abbott Diabetes Care and Insulet as well as honoraria for lectures from Berlin Chemie AG, Becton Dickenson, Sanofi Germany, Roche Diabetes Care, and Dexcom Germany. C.G. reports no conflict of interest. B.K. reports Advisory Board member fees from Abbott Diabetes Care, Embecta, Roche Diabetes Care, Novo Nordisk, Berlin Chemie AG, and Dexcom Germany as well as honoraria for lectures from Sanofi Germany, Novo Nordisk, Abbott Diabetes Care, Roche Diabetes Care, Berlin Chemie AG, Embecta, Dexcom, and Feen. In addition, he reports support for travel and fees for scientific meetings from Sanofi, Roche Diabetes Care and Berlin Chemie AG as well as unpaid obligations as workshop leader and member of working groups of the German Diabetes Association. T.H. reports consulting fees from Eli Lilly, NovoNordisk, Sanofi, Boehringer Ingelheim, and Abbott Diabetes Care as well as honoraria for lectures from Abbott Diabetes Care, Sanofi, and Eli Lilly. D.E. reports Advisory Board member fees from Dexcom Germany and Roche Diabetes Care as well as honoraria for lectures from Berlin Chemie AG, Sanofi-Aventis, Dexcom Germany, Boehringer Ingelheim, and Roche Diabetes Care., (© 2024 The Author(s).)

CAR T-cell products targeting lineage-specific cell-of-origin antigens, thereby eliminating both tumor and healthy counterpart cells, are currently clinically approved therapeutics in B- and plasma-cell malignancies. While they represent a major clinical improvement, they are still limited in terms of efficacy by e.g. single, sometimes low-expressed antigen targeting, and in terms of safety by e.g., lack of on-off activity. Successful cell-of-origin non-discriminative targeting of heterogeneous hematopoietic stem and progenitor cell malignancies, such as acute myeloid leukemia (AML), will require antigen-versatile targeting and off-switching of effectors in order to then allow rescue by hematopoietic stem cell transplantation (HSCT), preventing permanent myeloablation. To address this, we developed adaptor-CAR (AdFITC-CAR) T-cells targeting fluoresceinated AML antigen-binding diabody adaptors. This platform enables the use of adaptors matching the AML-antigen-expression profile and conditional activity modulation. Combining adaptors significantly improved lysis of AML cells in vitro. In therapeutic xenogeneic mouse models, AdFITC-CAR T-cells co-administered with single diabody adaptors were as efficient as direct CAR T-cells, and combinatorial use of adaptors further enhanced therapeutic efficacy against both, cell lines and primary AML. Collectively, this study provides proof-of-concept that AdFITC-CAR T-cells and combinations of adaptors can efficiently enhance immune-targeting of AML., (© 2024. The Author(s).)

The kidney is the main organ that senses changes in systemic O 2 pressure by hypoxia-PHD-HIFa (HPH) signaling, resulting in adaptive target gene activation, including erythropoietin (EPO). The non-essential transition metal cadmium (Cd) is nephrotoxic and disrupts the renal HPH pathway, which may promote Cd-associated chronic renal disease (CKD). A deeper molecular understanding of Cd interference with renal HPH signaling is missing, and no data with renal cell lines are available. In rat kidney NRK-52E cells, which model the proximal tubule, and murine fibroblastoid atypical interstitial kidney (FAIK3-5) cells, which mimic renal EPO-producing cells, the chemical hypoxia mimetic dimethyloxalylglycine (DMOG; 1 mmol/l) or hypoxia (1% O 2 ) activated HPH signaling. Cd 2+ (2.5-20 µmol/l for ≤ 24 h) preferentially induced necrosis (trypan blue uptake) of FAIK3-5 cells at high Cd whereas NRK-52E cells specially developed apoptosis (PARP-1 cleavage) at all Cd concentrations. Cd (12.5 µmol/l) abolished HIFa stabilization and prevented upregulation of target genes (quantitative real-time polymerase chain reaction and immunoblotting) induced by DMOG or hypoxia in both cell lines, which was caused by the formation of insoluble HIFa aggregates. Strikingly, hypoxic preconditioning (1% O 2 for 18 h) reduced apoptosis of FAIK3-5 and NRK-52E cells at low Cd concentrations and decreased insoluble HIFa proteins. Hence, drugs mimicking hypoxic preconditioning could reduce CKD induced by chronic low Cd exposure., (© 2024. The Author(s).)

Pluripotent mouse embryonic stem cells (ESCs) can differentiate to all germ layers and serve as an in vitro model of embryonic development. To better understand the differentiation paths traversed by ESCs committing to different lineages, we track individual differentiating ESCs by timelapse imaging followed by multiplexed high-dimensional Imaging Mass Cytometry (IMC) protein quantification. This links continuous live single-cell molecular NANOG and cellular dynamics quantification over 5-6 generations to protein expression of 37 different molecular regulators in the same single cells at the observation endpoints. Using this unique data set including kinship history and live lineage marker detection, we show that NANOG downregulation occurs generations prior to, but is not sufficient for neuroectoderm marker Sox1 upregulation. We identify a developmental cell type co-expressing both the canonical Sox1 neuroectoderm and FoxA2 endoderm markers in vitro and confirm the presence of such a population in the post-implantation embryo. RNASeq reveals cells co-expressing SOX1 and FOXA2 to have a unique cell state characterized by expression of both endoderm as well as neuroectoderm genes suggesting lineage potential towards both germ layers., (© 2024. The Author(s).)

Predicting thermodynamic equilibrium properties is essential to develop chemical and energy conversion processes in the absence of experimental data. For the modeling of thermodynamic properties, statistical associating fluid theory (SAFT)-based equations of state, such as perturbed-chain polar (PCP)-SAFT, have been proven powerful and found broad application. The PCP-SAFT parameters can be predicted by group-contribution (GC) methods. However, their application to the dipole term is substantially limited: current GC methods neglect the dipole term or only allow for a single dipolar group per substance to avoid handling the molecular dipole moment's symmetry effects. Still, substances with multiple dipolar groups are highly relevant, and their description substantially improves by including the dipole term in SAFT models. To overcome these limitations, this work proposes a vector-addition-based (Vector-)GC method for the dipole term of PCP-SAFT that accounts for molecular symmetry. The Vector-GC employs information on the substance's molecular 3D structure to predict the molecular dipole moment through a vector addition of bond contributions. Combining the proposed sum rule for dipole moments with established sum rules for the remaining parameters yields a consistent GC method for PCP-SAFT for dipolar substances. The prediction capabilities of the Vector-GC method are analyzed against experimental data for two substance classes: nonassociating oxygenated and halogenated substances. We demonstrate that the Vector-GC method improves vapor pressure and liquid density predictions compared to neglecting the dipole term. Moreover, we show that the Vector-GC method enables differentiation between cis- and trans-isomers. The Vector-GC method, hence, substantially increases the predictive capabilities and applicability domain of GC methods. All parameters are provided as JSON and CSV files, and the Vector-GC method is available through an open-source python package. Additionally, the developed regression framework for GC methods for PCP-SAFT is openly available. The regression framework can be employed to regress the Vector-GC method to other substance classes and is easily adaptable to other sum rules for PCP-SAFT., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

National public health emergency operations centers (PHEOCs) serve as hubs for coordinating information and resources for effective emergency management. In the International Health Regulations (IHR 2005) Monitoring and Evaluation Framework, a simulation exercise is 1 of 4 components that can be used to test the functionality of a country's emergency response capabilities in a simulated situation. To test the functionality of PHEOCs in World Health Organization African Region member states, a regional functional exercise simulating an Ebola virus disease outbreak was conducted. The public health actions taken in response to the simulated outbreak were evaluated against the exercise objectives. Thematic analysis was conducted to summarize key strengths and areas for improvement. From December 6 to 7, 2022, more than 1,000 representatives from 36 of the 47 African Region member states participated in the exercise from their respective PHEOCs. Approximately 95% of the 461 participants polled agreed with the positive responses to the postexercise survey. More than half of the PHEOC participants were able to test their existing emergency preparedness and response plans and became familiar with the expected roles to be fulfilled during an event. Of the participants who responded to the survey, over 90% reported that the exercise helped them understand their roles during emergency management. The exercise met its objectives and provided an opportunity to test the functionality of PHEOCs using realistic scenarios, and it helped participants understand existing response systems and procedures. However, the exercise also revealed areas for improvement in terms of the timing and preparation of participants. We recommend conducting functional exercises at the regional and national levels at least once a year, early or midyear, to allow many stakeholders to take part in the exercise. Moreover, there is a need to train country-level evaluators and controllers in designing and conducting functional exercises.

Background: Texture analysis derived from computed tomography (CT) may provide clinically relevant imaging biomarkers associated with tumor histopathology. Perihilar cholangiocarcinoma is a malignant disease with an overall poor prognosis., Aims: The present study sought to elucidate possible associations between texture features derived from CT images with grading, tumor markers, and survival in extrahepatic, perihilar cholangiocarcinomas tumors., Methods: This retrospective study included 22 patients (10 females, 45%) with a mean age of 71.8 ± 8.7 years. Texture analysis was performed using the free available Mazda software. All tumors were histopathologically confirmed. Survival and clinical parameters were used as primary study outcomes., Results: In discrimination analysis, "S(1,1)SumVarnc" was statistically significantly different between patients with long-term survival and nonlong-term survival (mean 275.8 ± 32.6 vs. 239.7 ± 26.0, p = 0.01). The first-order parameter "skewness" was associated with the tumor marker "carcinoembryonic antigen" (CEA) (r = -0.7, p = 0.01). A statistically significant correlation of the texture parameter "S(5,0)SumVarnc" with tumor grading was identified (r = -0.6, p < 0.01). Several other texture features correlated with tumor markers CA-19-9 and AFP, as well as with T and N stage of tumors., Conclusion: Several texture features derived from CT images were associated with tumor characteristics and survival in patients with perihilar cholangiocarcinomas. CT texture features could be used as valuable novel imaging markers in clinical routine., (© 2024 The Author(s). Cancer Reports published by Wiley Periodicals LLC.)