Medium-Chain Triglycerides (MCTs) for the Symptomatic Treatment of Dementia-Related Diseases: A Systematic Review.

Pathomechanisms of dementias involve increasing damage to neuronal energy metabolism, resulting in degeneration-related insulin resistance and glucose hypometabolism. In this case, ketone bodies can provide an alternative energy source. Supplementation with medium-chain triglycerides (MCTs), which can induce ketogenesis, may alleviate brain energy deficits and improve neuronal function. This review aims to determine the effectiveness of MCT as a symptomatic treatment approach. The systematic literature search was conducted in April 2023 following the Cochrane Handbook and PRISMA guidelines. A total of 21 studies were included, comprising eight uncontrolled trials and 13 RCTs investigating the effects of MCT on Alzheimer's disease (AD) and mild cognitive impairment (MCI). A substantial increase in plasma ketone levels and brain metabolic rates was observed. Cognitive assessments showed only occasional or domain-specific performance improvements. The effects on functional abilities or psychological outcomes have been inadequately studied. Besides gastrointestinal side effects, no harmful effects were observed. However, the evidence was severely weakened by heterogeneous and poorly designed study protocols, bias, and conflicts of interest. In conclusion, the ketogenic properties of MCTs may have beneficial effects on brain metabolism in AD and MCI but do not always result in measurable clinical improvement. Current evidence is insufficient to recommend MCT as a comparable symptomatic treatment option.

Iminothioindoxyl Donors with Exceptionally High Cross Section for Protein Vibrational Energy Transfer.

Various protein functions are related to vibrational energy transfer (VET) as an important mechanism. The underlying transfer pathways can be experimentally followed by ultrafast Vis-pump/IR-probe spectroscopy with a donor-sensor pair of non-canonical amino acids (ncAAs) incorporated in a protein. However, so far only one donor ncAA, azulenylalanine (AzAla), exists, which suffers from a comparably low Vis extinction coefficient. Here, we introduce two novel donor ncAAs based on an iminothioindoxyl (ITI) chromophore. The dimethylamino-ITI (DMA-ITI) and julolidine-ITI (J-ITI) moieties overcome the limitation of AzAla with a 50 times higher Vis extinction coefficient. While ITI moieties are known for ultrafast photoswitching, DMA-ITI and J-ITI exclusively form a hot ground state on the sub-ps timescale instead, which is essential for their usage as vibrational energy donor. In VET measurements of donor-sensor dipeptides we investigate the performance of the new donors. We observe 20 times larger signals compared to the established AzAla donor, which opens unprecedented possibilities for the study of VET in proteins.

QDTrack: Quasi-Dense Similarity Learning for Appearance-Only Multiple Object Tracking.

Similarity learning has been recognized as a crucial step for object tracking. However, existing multiple object tracking methods only use sparse ground truth matching as the training objective, while ignoring the majority of the informative regions in images. In this paper, we present Quasi-Dense Similarity Learning, which densely samples hundreds of object regions on a pair of images for contrastive learning. We combine this similarity learning with multiple existing object detectors to build Quasi-Dense Tracking (QDTrack), which does not require displacement regression or motion priors. We find that the resulting distinctive feature space admits a simple nearest neighbor search at inference time for object association. In addition, we show that our similarity learning scheme is not limited to video data, but can learn effective instance similarity even from static input, enabling a competitive tracking performance without training on videos or using tracking supervision. We conduct extensive experiments on a wide variety of popular MOT benchmarks. We find that, despite its simplicity, QDTrack rivals the performance of state-of-the-art tracking methods on all benchmarks and sets a new state-of-the-art on the large-scale BDD100K MOT benchmark, while introducing negligible computational overhead to the detector.

Conserved tyrosine in phytochromes controls the photodynamics through steric demand and hydrogen bonding capabilities.

Using ultrafast spectroscopy and site-specific mutagenesis, we demonstrate the central role of a conserved tyrosine within the chromophore binding pocket in the forward (Pr â†’ Pfr) photoconversion of phytochromes. Taking GAF1 of the knotless phytochrome All2699g1 from Nostoc as representative member of phytochromes, it was found that the mutations have no influence on the early (<30 ps) dynamics associated with conformational changes of the chromophore in the excited state. Conversely, they drastically impact the extended protein-controlled excited state decay (>100 ps). Thus, the steric demand, position and H-bonding capabilities of the identified tyrosine control the chromophore photoisomerization while leaving the excited state chromophore dynamics unaffected. In effect, this residue operates as an isomerization-steric-gate that tunes the excited state lifetime and the photoreaction efficiency by modulating the available space of the chromophore and by stabilizing the primary intermediate Lumi-R. Understanding the role of such a conserved structural element sheds light on a key aspect of phytochrome functionality and provides a basis for rational design of optimized photoreceptors for biotechnological applications.

The Hairdex quality of life instrument-A translation and psychometric validation in patients with alopecia areata.

Background: The German Hairdex quality of life (QoL) instrument is specific to hair and scalp diseases, developed for self-rating and consists of 48 statements divided into five domains: Symptoms, Functioning, Emotions, Self-confidence and Stigmatisation. There was a need of a Swedish reliability tested, validated hair and scalp specific QoL instrument why the German Hairdex was chosen to be translated and reliability tested in a systematic way. Objectives: To make a translation, a reliability test of stability, and validation of the German Hairdex QoL instrument among 100 Swedish patients with a dermatological ICD-10 diagnosis of alopecia areata (AA). Methods: An eight-step method by Gudmundsson was used as a model with a forward and backward translation and with comments from an expert panel. A statistical test-retest (ICC (2,1)) analysis was made, followed by an internal consistency analysis. A comparison between the German and Swedish Hairdex-S constructs by a principal component analysis was performed. Results: The Hairdex-S was very well accepted by patients. The ICC(2,1) test-retest showed a good to excellent correlation of 0.91 (CI [0.85-0.95]). Internal consistency was α = 0.92. Like the original Hairdex, Hairdex-S showed good factorability with a Kaiser-Meyer-Olkin measure of 0.82 and with one component explaining 70% of the variance: original Hairdex instrument (69%). When tested on patients with AA, the domains Functioning and Emotions had the strongest loadings, followed by Stigmatisation and Self-confidence. Younger AA patients at self-assessment and patients who reported to be younger at the onset of AA, scored statistically significantly higher on the Hairdex-S, indicating an overall lower QoL on domains Emotions and Functioning, respectively. Conclusions: The Hairdex-S is very well accepted by AA patients, shows very good psychometric properties, and a very good agreement with the original Hairdex. The Swedish Hairdex instrument can be recommended for evaluation of patients QoL as well as for research purposes.

Mechanistic Elucidation of the Hula-Twist Photoreaction in Hemithioindigo.

The Hula-Twist (HT) photoreaction represents a fundamental photochemical pathway for bond isomerizations and is defined by the coupled motion of a double bond and an adjacent single bond. This photoreaction has been suggested as the defining motion for a plethora of light-responsive chromophores such as retinal within opsins, coumaric acid within photoactive yellow protein, or vitamin D precursors, and stilbenes in solution. However, due to the fleeting character of HT photoproducts a direct experimental observation of this coupled molecular motion was severely hampered until recently. To solve this dilemma, the Dube group has designed a molecular framework able to deliver unambiguous experimental evidence of the HT photoreaction. Using sterically crowded atropisomeric hemithioindigo (HTI) the HT photoproducts are rendered thermally stable and can be observed directly after their formation. However, following the ultrafast excited state process of the HT photoreaction itself has not been achieved so far and thus crucial information for an elementary understanding is still missing. In this work, we present the first ultrafast spectroscopy study of the HT photoreaction in HTI and probe the competition between different excited state processes. Together with extensive excited state calculations a detailed mechanistic picture is developed explaining the significant solvent effects on the HT photoreaction and revealing the intricate interplay between productive isomerizations and unproductive twisted intramolecular charge transfer (TICT) processes. With this study essential insights are thus gained into the mechanism of complex multibond rotations in the excited state, which will be of primary importance for further developments in this field.

Tracking carbon from subduction to outgassing along the Aleutian-Alaska Volcanic Arc.

Subduction transports volatiles between Earth's mantle, crust, and atmosphere, ultimately creating a habitable Earth. We use isotopes to track carbon from subduction to outgassing along the Aleutian-Alaska Arc. We find substantial along-strike variations in the isotopic composition of volcanic gases, explained by different recycling efficiencies of subducting carbon to the atmosphere via arc volcanism and modulated by subduction character. Fast and cool subduction facilitates recycling of ~43 to 61% sediment-derived organic carbon to the atmosphere through degassing of central Aleutian volcanoes, while slow and warm subduction favors forearc sediment removal, leading to recycling of ~6 to 9% altered oceanic crust carbon to the atmosphere through degassing of western Aleutian volcanoes. These results indicate that less carbon is returned to the deep mantle than previously thought and that subducting organic carbon is not a reliable atmospheric carbon sink over subduction time scales.

Coordinating science during an eruption: lessons from the 2020-2021 Kilauea volcanic eruption.

Data collected during well-observed eruptions can lead to dramatic increases in our understanding of volcanic processes. However, the necessary prioritization of public safety and hazard mitigation during a crisis means that scientific opportunities may be sacrificed. Thus, maximizing the scientific gains from eruptions requires improved planning and coordinating science activities among governmental organizations and academia before and during volcanic eruptions. One tool to facilitate this coordination is a Scientific Advisory Committee (SAC). In the USA, the Community Network for Volcanic Eruption Response (CONVERSE) has been developing and testing this concept during workshops and scenario-based activities. The December 2020 eruption of Kilauea volcano, Hawaii, provided an opportunity to test and refine this model in real-time and in a real-world setting. We present here the working model of a SAC developed during this eruption. Successes of the Kilauea SAC (K-SAC) included broadening the pool of scientists involved in eruption response and developing and codifying procedures that may form the basis of operation for future SACs. Challenges encountered by the K-SAC included a process of review and facilitation of research proposals that was too slow to include outside participation in the early parts of the eruption and a decision process that fell on a small number of individuals at the responding volcano observatory. Possible ways to address these challenges include (1) supporting community-building activities between eruptions that make connections among scientists within and outside formal observatories, (2) identifying key science questions and pre-planning science activities, which would facilitate more rapid implementation across a broader scientific group, and (3) continued dialog among observatory scientists, emergency responders, and non-observatory scientists about the role of SACs. The SAC model holds promise to become an integral part of future efforts, leading in the short and longer term to more effective hazard response and greater scientific discovery and understanding.

Beta-Hydroxybutyrate (BHB), Glucose, Insulin, Octanoate (C8), and Decanoate (C10) Responses to a Medium-Chain Triglyceride (MCT) Oil with and without Glucose: A Single-Center Study in Healthy Adults.

MCTs are increasingly being used to promote ketogenesis by patients on ketogenic diet therapy, but also by people with other conditions and by the general public for the perceived potential benefits. However, consumption of carbohydrates with MCTs and untoward gastrointestinal side effects, especially at higher doses, could decrease the sustainability of the ketogenic response. This single-center study investigated the impact of consuming carbohydrate as glucose with MCT oil compared to MCT alone on the BHB response. The effects of MCT oil versus MCT oil plus glucose on blood glucose, insulin response, levels of C8, C10, BHB, and cognitive function were determined, and side effects were monitored. A significant plasma BHB increase with a peak at 60 min was observed in 19 healthy participants (24.4 ± 3.9 years) after consuming MCT oil alone, and a more delayed but slightly higher peak was observed after consuming MCT oil plus glucose. A significant increase in blood glucose and insulin levels occurred only after MCT oil plus glucose intake. The overall mean plasma levels of C8 and C10 were higher with the intake of MCT oil alone. MCT oil plus glucose consumption showed improved scores for the arithmetic and vocabulary subtests.

Monocular Quasi-Dense 3D Object Tracking.

A reliable and accurate 3D tracking framework is essential for predicting future locations of surrounding objects and planning the observer's actions in numerous applications such as autonomous driving. We propose a framework that can effectively associate moving objects over time and estimate their full 3D bounding box information from a sequence of 2D images captured on a moving platform. The object association leverages quasi-dense similarity learning to identify objects in various poses and viewpoints with appearance cues only. After initial 2D association, we further utilize 3D bounding boxes depth-ordering heuristics for robust instance association and motion-based 3D trajectory prediction for re-identification of occluded vehicles. In the end, an LSTM-based object velocity learning module aggregates the long-term trajectory information for more accurate motion extrapolation. Experiments on our proposed simulation data and real-world benchmarks, including KITTI, nuScenes, and Waymo datasets, show that our tracking framework offers robust object association and tracking on urban-driving scenarios. On the Waymo Open benchmark, we establish the first camera-only baseline in the 3D tracking and 3D detection challenges. Our quasi-dense 3D tracking pipeline achieves impressive improvements on the nuScenes 3D tracking benchmark with near five times tracking accuracy of the best vision-only submission among all published methods.

Synthesis of α-Aryl Acrylamides via Lewis-Base-Mediated Aryl/Hydrogen Exchange.

Herein we report a method for the synthesis of α-aryl acrylamides leveraging polar S-to-C aryl migrations induced by a Lewis basic organocatalyst. In contrast to previously reported radical aryl migrations of sulfonyl acrylimides, this polar process enables subsequent elimination, ultimately leading to a formal aryl/hydrogen exchange including SO2 extrusion. This reaction is selective for electron-deficient aromatic groups, while tolerating a variety of substituents on nitrogen and in the ß-position, and it delivers useful building blocks for further transformations, including cycloaddition and cyclisation reactions. The mechanism was investigated in detail using quantum chemical calculations, which unexpectedly revealed the Lewis base to be involved in several decisive steps.

Influence of the PHY domain on the ms-photoconversion dynamics of a knotless phytochrome.

The ability of some knotless phytochromes to photoconvert without the PHY domain allows evaluation of the distinct effect of the PHY domain on their photodynamics. Here, we compare the ms dynamics of the single GAF domain (g1) and the GAF-PHY (g1g2) construct of the knotless phytochrome All2699 from cyanobacterium Nostoc punctiforme. While the spectral signatures and occurrence of the intermediates are mostly unchanged by the domain composition, the presence of the PHY domain slows down the early forward and reverse dynamics involving chromophore and protein binding pocket relaxation. We assign this effect to a more restricted binding pocket imprinted by the PHY domain. The photoproduct formation is also slowed down by the presence of the PHY domain but to a lesser extent than the early dynamics. This indicates a rate limiting step within the GAF and not the PHY domain. We further identify a pH dependence of the biphasic photoproduct formation hinting towards a pKa dependent tuning mechanism. Our findings add to the understanding of the role of the individual domains in the photocycle dynamics and provide a basis for engineering of phytochromes towards biotechnological applications.

Chemerin - exploring a versatile adipokine.

Chemerin is a small chemotactic protein and a key player in initiating the early immune response. As an adipokine, chemerin is also involved in energy homeostasis and the regulation of reproductive functions. Secreted as inactive prochemerin, it relies on proteolytic activation by serine proteases to exert biological activity. Chemerin binds to three distinct G protein-coupled receptors (GPCR), namely chemokine-like receptor 1 (CMKLR1, recently named chemerin1), G protein-coupled receptor 1 (GPR1, recently named chemerin2), and CC-motif chemokine receptor-like 2 (CCRL2). Only CMKLR1 displays conventional G protein signaling, while GPR1 only recruits arrestin in response to ligand stimulation, and no CCRL2-mediated signaling events have been described to date. However, GPR1 undergoes constitutive endocytosis, making this receptor perfectly adapted as decoy receptor. Here, we discuss expression pattern, activation, and receptor binding of chemerin. Moreover, we review the current literature regarding the involvement of chemerin in cancer and several obesity-related diseases, as well as recent developments in therapeutic targeting of the chemerin system.

Towards a Data-Driven Estimation of Resilience in Networked Dynamical Systems: Designing a Versatile Testbed.

Estimating resilience of adaptive, networked dynamical systems remains a challenge. Resilience refers to a system's capacity "to absorb exogenous and/or endogenous disturbances and to reorganize while undergoing change so as to still retain essentially the same functioning, structure, and feedbacks." The majority of approaches to estimate resilience requires exact knowledge of the underlying equations of motion; the few data-driven approaches so far either lack appropriate strategies to verify their suitability or remain subject of considerable debate. We develop a testbed that allows one to modify resilience of a multistable networked dynamical system in a controlled manner. The testbed also enables generation of multivariate time series of system observables to evaluate the suitability of data-driven estimators of resilience. We report first findings for such an estimator.

Volcanic activity and hazard in the East African Rift Zone.

Over the past two decades, multidisciplinary studies have unearthed a rich history of volcanic activity and unrest in the densely-populated East African Rift System, providing new insights into the influence of rift dynamics on magmatism, the characteristics of the volcanic plumbing systems and the foundation for hazard assessments. The raised awareness of volcanic hazards is driving a shift from crisis response to reducing disaster risks, but a lack of institutional and human capacity in sub-Saharan Africa means baseline data are sparse and mitigating geohazards remains challenging.

High 3He/4He in central Panama reveals a distal connection to the Galápagos plume.

It is well established that mantle plumes are the main conduits for upwelling geochemically enriched material from Earth's deep interior. The fashion and extent to which lateral flow processes at shallow depths may disperse enriched mantle material far (>1,000 km) from vertical plume conduits, however, remain poorly constrained. Here, we report He and C isotope data from 65 hydrothermal fluids from the southern Central America Margin (CAM) which reveal strikingly high 3He/4He (up to 8.9RA) in low-temperature (≤50 °C) geothermal springs of central Panama that are not associated with active volcanism. Following radiogenic correction, these data imply a mantle source 3He/4He >10.3RA (and potentially up to 26RA, similar to Galápagos hotspot lavas) markedly greater than the upper mantle range (8 ± 1RA). Lava geochemistry (Pb isotopes, Nb/U, and Ce/Pb) and geophysical constraints show that high 3He/4He values in central Panama are likely derived from the infiltration of a Galápagos plume-like mantle through a slab window that opened ∼8 Mya. Two potential transport mechanisms can explain the connection between the Galápagos plume and the slab window: 1) sublithospheric transport of Galápagos plume material channeled by lithosphere thinning along the Panama Fracture Zone or 2) active upwelling of Galápagos plume material blown by a "mantle wind" toward the CAM. We present a model of global mantle flow that supports the second mechanism, whereby most of the eastward transport of Galápagos plume material occurs in the shallow asthenosphere. These findings underscore the potential for lateral mantle flow to transport mantle geochemical heterogeneities thousands of kilometers away from plume conduits.