Multiomics Blood-Based Biomarkers Predict Alzheimer's Predementia with High Specificity in a Multicentric Cohort Study.

BACKGROUND: The primary criteria for diagnosing mild cognitive impairment (MCI) due to Alzheimer's Disease (AD) or probable mild AD dementia rely partly on cognitive assessments and the presence of amyloid plaques. Although these criteria exhibit high sensitivity in predicting AD among cognitively impaired patients, their specificity remains limited. Notably, up to 25% of non-demented patients with amyloid plaques may be misdiagnosed with MCI due to AD, when in fact they suffer from a different brain disorder. The introduction of anti-amyloid antibodies complicates this scenario. Physicians must prioritize which amyloid-positive MCI patients receive these treatments, as not all are suitable candidates. Specifically, those with non-AD amyloid pathologies are not primary targets for amyloid-modifying therapies. Consequently, there is an escalating medical necessity for highly specific blood biomarkers that can accurately detect pre-dementia AD, thus optimizing amyloid antibody prescription. OBJECTIVES: The objective of this study was to evaluate a predictive model based on peripheral biomarkers to identify MCI and mild dementia patients who will develop AD dementia symptoms in cognitively impaired population with high specificity. DESIGN: Peripheral biomarkers were identified in a gene transfer-based animal model of AD and then validated during a retrospective multi-center clinical study. SETTING: Participants from 7 retrospective cohorts (US, EU and Australia). PARTICIPANTS: This study followed 345 cognitively impaired individuals over up to 13 years, including 193 with MCI and 152 with mild dementia, starting from their initial visits. The final diagnoses, established during their last assessments, classified 249 participants as AD patients and 96 as having non-AD brain disorders, based on the specific diagnostic criteria for each disorder subtype. Amyloid status, assessed at baseline, was available for 82.9% of the participants, with 61.9% testing positive for amyloid. Both amyloid-positive and negative individuals were represented in each clinical group. Some of the AD patients had co-morbidities such as metabolic disorders, chronic diseases, or cardiovascular pathologies. MEASUREMENTS: We developed targeted mass spectrometry assays for 81 blood-based biomarkers, encompassing 45 proteins and 36 metabolites previously identified in AAV-AD rats. METHODS: We analyzed blood samples from study participants for the 81 biomarkers. The B-HEALED test, a machine learning-based diagnostic tool, was developed to differentiate AD patients, including 123 with Prodromal AD and 126 with mild AD dementia, from 96 individuals with non-AD brain disorders. The model was trained using 70% of the data, selecting relevant biomarkers, calibrating the algorithm, and establishing cutoff values. The remaining 30% served as an external test dataset for blind validation of the predictive accuracy. RESULTS: Integrating a combination of 19 blood biomarkers and participant age, the B-HEALED model successfully distinguished participants that will develop AD dementia symptoms (82 with Prodromal AD and 83 with AD dementia) from non-AD subjects (71 individuals) with a specificity of 93.0% and sensitivity of 65.4% (AUROC=81.9%, p<0.001) during internal validation. When the amyloid status (derived from CSF or PET scans) and the B-HEALED model were applied in association, with individuals being categorized as AD if they tested positive in both tests, we achieved 100% specificity and 52.8% sensitivity. This performance was consistent in blind external validation, underscoring the model's reliability on independent datasets. CONCLUSIONS: The B-HEALED test, utilizing multiomics blood-based biomarkers, demonstrates high predictive specificity in identifying AD patients within the cognitively impaired population, minimizing false positives. When used alongside amyloid screening, it effectively identifies a nearly pure prodromal AD cohort. These results bear significant implications for refining clinical trial inclusion criteria, facilitating drug development and validation, and accurately identifying patients who will benefit the most from disease-modifying AD treatments.

Hypervalent Sulfur Derivatives as Sulfenylating Reagents: Visible-Light-Mediated Direct Thiolation of Activated C(sp2)-H Bonds with Dihalosulfuranes.

In contrast to hypervalent iodine compounds, the chemistry of their sulfur analogues has been considerably less explored. Herein, we report the direct C-H bond thiolation of electron-rich heterocycles, arenes, and 1,3-dicarbonyls by dichlorosulfuranes under mild conditions. Mechanistic studies and density functional theory calculations suggest the radical chain mechanism of the disclosed transformation. The key to success is attributed to a strikingly low S-Cl bond dissociation energy, which enables the generation of radical species upon exposure to daylight.

Evaluation of Hemodynamic Properties After Chimney and Fenestrated Endovascular Aneurysm Repair.

BACKGROUND: Fenestrated (FEVAR) and chimney (ChEVAR) endovascular aortic repair have been applied in anatomically suitable complex aortic aneurysms. However, local hemodynamic changes may occur after repair. This study aimed to compare FEVAR's and ChEVAR's hemodynamic properties, focusing on visceral arteries. METHODS: Preoperative and postoperative computed tomography angiographies have been used to reconstruct patient-based models. Data of 3 patients, for each modality, were analyzed. Following geometric reconstruction, computational fluid dynamics simulations were used to extract near-wall and intravascular hemodynamic indicators, such as pressure drops, velocity, wall shear stress, time averaged wall shear stress, oscillatory shear index, relative residence time, and local normalized helicity. RESULTS: An overall improvement in hemodynamics was detected after repair, with either technique. Preoperatively, a disturbed prothrombotic wall shear stress profile was recorded in several zones of the sac. The local normalized helicity results showed a better organization of the helical structures at postoperative setting, decreasing thrombus formation, with both modalities. Similarly, time averaged wall shear stress increased and oscillatory shear index decreased postoperatively, signaling nondisturbed blood flow. The relative residence time was locally reduced. The flow in visceral arteries tended to be more streamlined in ChEVAR, compared to evident recirculation regions at renal and superior mesenteric artery fenestrations (P = 0.06). CONCLUSIONS: ChEVAR and FEVAR seem to improve hemodynamics toward normal values with a reduction of recirculation zones in the main graft and aortic branches. Visceral artery flow comparison revealed that ChEVAR tended to present lower recirculation regions at parallel grafts' entries while FEVAR showed less intense flow regurgitation in visceral stents.

Nonuniform Current-Driven Formation and Displacement of the Magnetic Compensation Point in Variable-Width Nanoscale Ferrimagnets.

Nano- and microstructures based on ferrimagnets can demonstrate high efficiency and dynamics of current-induced magnetization switching combined with high stability of spin textures such as bubble domains and skyrmions, which are of practical importance for the development of spintronics and spin-orbitronics. This set of features is usually associated with magnetic momentum or angular momentum compensation states. Here, we experimentally show that the compensation state can be realized locally using nonuniform Joule heating. This effect is observed in the variable-width current guide made of the ferrimagnetic W/Co76Tb24/Ru thin films, where the position of a region heated to the compensation temperature depends linearly on the current pulse amplitude. This approach makes it possible to observe the simultaneous coexistence of Co-dominant and Tb-dominant regions, where current pulses induce spin-orbit torques in opposite directions, leading to local magnetization switching. It is found that the position of a Néel domain wall constraining the switched region lies in the vicinity of the coordinate corresponding to the compensation point but does not coincide with it due to high mobility under the action of spin current. Our findings open an alternative approach for engineering of ferrimagnetic nanodevices with advanced properties for future applications in spintronics, spin-orbitronics, and nanoelectronics.

Experimental study on stabilometric complex for terrainkur in overweight people.

Overweight and obesity is a multifactorial, multisystem disease declared a global epidemic by the World Health Organization (WHO) as early as in 1997. At least 30% of the working-age population in Russia is overweight. Only the use of physical activity as an integral (basic) part of obesity treatment and maintenance of the body weight achieved in the course of treatment can achieve durable and long-lasting treatment results as well as significant changes in the body structure (fat/non-fat body weight ratio). Terrainkur (therapeutic walking) is a method of spa treatment that combines climatotherapy and physical therapy. One of the problems in physical activity in obese people is the difficulty they experience in exercising due to the impaired walking pattern caused by imbalances in the muscle chains, including pelvic region, cervical region, which reduces endurance and commitment to physical activity. The study found that the exposure group (Terrainkur) showed lower values of "total fat", "metabolic age", "basic caloric value" compared to initial results and the control group; the exposure group (Terrainkur) showed a decrease in the deviation of the centre of body axis projection from the proper axis, the percentage of non-compliance with the proper fluctuations of the foot underextension. These changes contributed to the elimination of terrainkur restrictions and, as a result, improved the patient compliance during the terrainkur exercises.

One-Step Synthesis of Functionalized Pyrazolo[3,4-b]pyridines via Ring Opening of the Pyrrolinium Ion.

Herein, we report a highly regioselective one-pot synthesis of pyrazolo[3,4-b]pyridines via the reaction of 3-arylidene-1-pyrrolines with aminopyrazoles. The reaction proceeds through the sequential nucleophilic addition/electrophilic substitution/C-N bond cleavage and provides easy access to pyrazolo[3,4-b]pyridine derivatives featuring a primary amino group. Moreover, the reaction can be terminated at the electrophilic substitution stage, thus providing convenient entry to the hardly accessible pyrazolopyrrolopyridine scaffold.

Curcumin and Its Supramolecular Complex with Disodium Glycyrrhizinate as Potential Drugs for the Liver Fluke Infection Caused by Opisthorchis felineus.

Opisthorchiosis is a parasitic liver disease found in mammals that is widespread throughout the world and causes systemic inflammation. Praziquantel remains the drug of choice for the treatment of opisthorchiosis, despite its many adverse effects. An anthelmintic effect is attributed to the main curcuminoid of Curcuma longa L. roots-curcumin (Cur)-along with many other therapeutic properties. To overcome the poor solubility of curcumin in water, a micellar complex of curcumin with the disodium salt of glycyrrhizic acid (Cur:Na2GA, molar ratio 1:1) was prepared via solid-phase mechanical processing. In vitro experiments revealed a noticeable immobilizing effect of curcumin and of Cur:Na2GA on mature and juvenile Opisthorchis felineus individuals. In vivo experiments showed that curcumin (50 mg/kg) had an anthelmintic effect after 30 days of administration to O. felineus-infected hamsters, but the effect was weaker than that of a single administration of praziquantel (400 mg/kg). Cur:Na2GA (50 mg/kg, 30 days), which contains less free curcumin, did not exert this action. The complex, just as free curcumin or better, activated the expression of bile acid synthesis genes (Cyp7A1, Fxr, and Rxra), which was suppressed by O. felineus infection and by praziquantel. Curcumin reduced the rate of inflammatory infiltration, whereas Cur:Na2GA reduced periductal fibrosis. Immunohistochemically, a decrease in liver inflammation markers was found, which is determined by calculating the numbers of tumor-necrosis-factor-positive cells during the curcumin treatment and of kynurenine-3-monooxygenase-positive cells during the Cur:Na2GA treatment. A biochemical blood test revealed a normalizing effect of Cur:Na2GA (comparable to that of curcumin) on lipid metabolism. We believe that the further development and investigation of therapeutics based on curcuminoids in relation Opisthorchis felineus and other trematode infections will be useful for clinical practice and veterinary medicine.

Synthesis and Anticancer Evaluation of Novel 7-Aza-Coumarine-3-Carboxamides.

Herein, we report the design and synthesis of novel 7-aza-coumarine-3-carboxamides via scaffold-hopping strategy and evaluation of their in vitro anticancer activity. Additionally, the improved non-catalytic synthesis of 7-azacoumarin-3-carboxylic acid is reported, which features water as the reaction medium and provides a convenient alternative to the known methods. The anticancer activity of the most potent 7-aza-coumarine-3-carboxamides against the HuTu 80 cell line is equal to that of reference Doxorubicin, while the selectivity towards the normal cell line is 9-14 fold higher.

A traffic signal and loop detector dataset of an urban intersection regulated by a fully actuated signal control system.

Fully actuated signal controls are becoming increasingly popular in modern urban environments, attempting to reduce congestion locally, synchronize flows, or prioritize specific types of vehicles. This trend is expected to grow as more vehicles are expected to communicate via Vehicle-to-Infrastructure (V2I) communication. The presented dataset contains cleaned observations from a fully actuated signal control system with priority for public transportation. Time series data of traffic signals that regulate vehicle, public transportation, bicycle, and pedestrian traffic flows are available, showing where a traffic signal operates in a red or green phase. Also, loop detector data representing the occupancy at several locations at an urban intersection in Zurich, Switzerland is available. The data of all traffic signals and loop detectors corresponds to January and February 2019 and has a resolution of 1 s. Recent advances in transportation science show novel approaches for signalized intersections, but most publications assess their methodology on self-collected or simulated data. Therefore, the presented dataset aims at facilitating the development, calibration, and validation of novel methodological developments for modeling, estimation, forecasting, and other tasks in traffic engineering. Furthermore, it can be used as a real-world benchmark dataset for objectively comparing different methodologies.

N-Benzylethanolammonium Ionic Liquids and Molten Salts in the Synthesis of 68Ga- and Al18F-Labeled Radiopharmaceuticals.

Ionic liquids (ILs), due to their structural features, have unique physical and chemical properties and are environmentally friendly. Every year, the number of studies devoted to the use of ILs in medicine and pharmaceutics is growing. In nuclear medicine, the use of ILs with self-buffering capacity in the synthesis of radiopharmaceuticals is extremely important. This research is devoted to obtaining new ionic buffer agents containing N-benzylethanolammonium (BEA) cations and anions of carboxylic acids. A series of new BEA salts was synthesized and identified by NMR (1H, 13C), IR spectroscopy and elemental and thermal analysis. The crystal structures of BEA hydrogen succinate, hydrogen oxalate and oxalate were determined by x-ray diffraction. Newly synthesized compounds were tested as buffer solutions in 68Ga- and Al18F-radiolabeling reactions with a series of bifunctional chelating agents and clinically relevant peptides used for visualization of malignancies by positron emission tomography. The results obtained confirm the promise of using new buffers in the synthesis of 68Ga- and Al18F-labeled radiopharmaceuticals.

Adaptive physics-informed trajectory reconstruction exploiting driver behavior and car dynamics.

As more and more trajectory data become available, their analysis creates unprecedented opportunities for traffic flow investigations. However, observed physical quantities like speed or acceleration are often measured having unrealistic values. Furthermore, observation devices have different hardware and software specifications leading to heterogeneity in noise levels and limiting the efficiency of trajectory reconstruction methods. Typical strategies prune, smooth, or locally modify vehicle trajectories to infer physically plausible quantities. The filtering strength is usually heuristic. Once the physical quantities reach plausible values, additional improvement is impossible without ground truth data. This paper proposes an adaptive physics-informed trajectory reconstruction framework that iteratively detects the optimal filtering magnitude, minimizing local acceleration variance under stable conditions and ensuring compatibility with feasible vehicle acceleration dynamics and common driver behavior characteristics. Assessment is performed using both synthetic and real-world data. Results show a significant reduction in the speed error and invariability of the framework to different data acquisition devices. The last contribution enables the objective comparison between drivers with different sensing equipment.

Antifragility as a complex system's response to perturbations, volatility, and time.

Antifragility characterizes the benefit of a dynamical system derived from the variability in environmental perturbations. Antifragility carries a precise definition that quantifies a system's output response to input variability. Systems may respond poorly to perturbations (fragile) or benefit from perturbations (antifragile). In this manuscript, we review a range of applications of antifragility theory in technical systems (e.g., traffic control, robotics) and natural systems (e.g., cancer therapy, antibiotics). While there is a broad overlap in methods used to quantify and apply antifragility across disciplines, there is a need for precisely defining the scales at which antifragility operates. Thus, we provide a brief general introduction to the properties of antifragility in applied systems and review relevant literature for both natural and technical systems' antifragility. We frame this review within three scales common to technical systems: intrinsic (input-output nonlinearity), inherited (extrinsic environmental signals), and interventional (feedback control), with associated counterparts in biological systems: ecological (homogeneous systems), evolutionary (heterogeneous systems), and interventional (control). We use the common noun in designing systems that exhibit antifragile behavior across scales and guide the reader along the spectrum of fragility-adaptiveness-resilience-robustness-antifragility, the principles behind it, and its practical implications.

Synthesis and Characterization of Hybrid Materials Derived from Conjugated Copolymers and Reduced Graphene Oxide.

In this study the preparation of hybrid materials based on reduced graphene oxide (rGO) and conjugated copolymers is reported. By tuning the number and arrangement of thiophenes in the main chain (indacenothiophene or indacenothienothiophene) and the nature of the polymer acceptor (difluoro benzothiadiazole or diketopyrrolopyrrole) semiconducting copolymers were synthesized through Stille aromatic coupling and characterized to determine their molecular characteristics. The graphene oxide was synthesized using the Staudenmaier method and was further modified to reduced graphene oxide prior to structural characterization. Various mixtures with different rGO quantities and conjugated copolymers were prepared to determine the optoelectronic, thermal and morphological properties. An increase in the maximum absorbance ranging from 3 to 6 nm for all hybrid materials irrespective of the rGO concentration, when compared to the pristine conjugated copolymers, was estimated through the UV-Vis spectroscopy indicating a differentiation on the optical properties. Through voltammetric experiments the oxidation and reduction potentials were determined and the calculated HOMO and LUMO levels revealed a decrease on the electrochemical energy gap for low rGO concentrations. The study indicates the potential of the hybrid materials consisting of graphene oxide and high band gap conjugated copolymers for applications related to organic solar cells.

Diastereoselective Synthesis of Novel Spiro-Phosphacoumarins and Evaluation of Their Anti-Cancer Activity.

Herein we present the regio- and diastereoselective synthesis of novel pyrrolidine-fused spiro-dihydrophosphacoumarins via intermolecular [3 + 2] cycloaddition reaction. The presented approach is complementary to existing ones and provides an easy entry to the otherwise inaccessible derivatives. Additionally, the unprecedented pathway of the reaction of 4-hydroxycoumarin with azomethine ylides is described. The anti-cancer activity of the obtained compounds was tested in vitro, the most potent compound being 2.6-fold more active against the HuTu 80 cell line than the reference 5-fluorouracil, with a selectivity index > 32.

Enamine-mediated Mannich reaction of cyclic N,O-acetals and amido acetals: the multigram synthesis of pyrrolidine alkaloid precursors.

The cooperative L-proline/Brønsted acid/base promoted reaction of 2-ethoxypyrrolidines or N-substituted 4,4-diethoxybutan-1-amines with methyl(alkyl/aryl)ketones for the synthesis of 2-(acylmethylene)pyrrolidine derivatives is reported. The key features of the developed protocol are gram-scale synthesis of the target compounds, easily available starting materials, operational simplicity and usage of non-expensive reagents.

Formation of Gold Nanoparticle Self-Assembling Films in Various Polymer Matrices for SERS Substrates.

Surface-enhanced Raman spectroscopy (SERS) is regarded as a versatile tool for studying the composition and structure of matter. This work has studied the preparation of a SERS substrate based on a self-assembling plasmonic nanoparticle film (SPF) in a polymer matrix. Several synthesis parameters for the SPF are investigated, including the size of the particles making up the film and the concentration and type of the self-assembling agent. The result of testing systems with different characteristics is discussed using a model substance (pseudoisocyanin iodide). These models can be useful in the study of biology and chemistry. Research results contain the optimal parameters for SPF synthesis, maximizing the SERS signal. The optimal procedure for SPF assembly is determined and used for the synthesis of composite SPFs within different polymer matrices. SPF in a polymer matrix is necessary for the routine use of the SERS substrate for various types of analytes, including solid samples or those sensitive to contamination. Polystyrene, polyvinyl alcohol (PVA), and polyethylene are investigated to obtain a polymer matrix for SPF, and various methods of incorporating SPF into a polymer matrix are being explored. It is found that films with the best signal enhancement and reproducibility were obtained in polystyrene. The minimum detectable concentration for the SERS substrate obtained is equal to 10-10 M. We prepared a SERS substrate with an analytical enhancement factor of 2.7 × 104, allowing an increase in the detection sensitivity of analyte solutions of five orders of magnitude.

Synthesis and Biological Evaluation of Taurine-Derived Diarylmethane and Dibenzoxanthene Derivatives as Possible Cytotoxic and Antimicrobial Agents.

The series of novel taurine-derived diarylmethanes and dibenzoxanthenes was synthesized starting from simple commercially available precursors via modular three-stage approach. All the newly synthesized compounds were screened for in vitro antibacterial and antifungal activity, as well as cytotoxicity towards normal and cancer cell lines. Some of the synthesized compounds exhibited 2-4-fold higher activity against S. aureus, E. faecalis and B. cereus compared with Chloramphenicol. In contrast to Chloramphenicol, the tested compounds also showed bactericidal, rather than bacteriostatic effect, which makes them promising candidates for further studies.

Rigid Ring Versus Flexible Band for Tricuspid Valve Repair in Patients Scheduled for Mitral Valve Surgery: A Prospective Randomised Study.

BACKGROUND: Tricuspid valve repair for functional regurgitation is effectively performed with different annuloplasty devices. However, it remains unclear whether there are advantages associated with rigid rings compared to flexible bands. This prospective randomised study aimed to compare results of using a flexible band ring versus a rigid ring for functional tricuspid regurgitation in patients undergoing mitral valve surgery. METHODS: A single-centre randomised study was designed to allocate patients with functional tricuspid regurgitation undergoing mitral valve surgery to be treated with a flexible band or rigid ring. These patients were analysed by echocardiographic follow-up. The primary outcome was freedom from recurrent tricuspid regurgitation at 12-months follow-up. Secondary outcomes were 30-day mortality, survival, freedom from tricuspid valve reoperation, right ventricular reverse remodelling, and rate of major adverse events. RESULTS: A total of 308 patients were allocated to receive concomitant tricuspid valve annuloplasty with the flexible band or rigid ring. There was no between-group difference in freedom from recurrent tricuspid regurgitation: 97.3% in Rigid group (95% CI, 93.0-98.8) and 96.2% in the Flexible group (95% CI, 92.0-98.5) at 12-months follow-up (log-rank, p=0.261). Early mortality, survival, freedom from tricuspid valve reoperation, and global right ventricle systolic function were also comparable in both groups of patients. However, the flexible band had advantage in restoring regional right ventricle function (Doppler-derived systolic velocities of the annulus [S], tricuspid annular plane systolic excursion) at 12-months follow-up. CONCLUSION: Both the rigid ring and flexible band offered acceptable outcomes for functional tricuspid regurgitation correction without significant differences, as assessed at 12-months follow-up.

Current-Induced Manipulation of the Exchange Bias in a Pt/Co/NiO Structure.

An experimental study of the phenomenon of electric current influence on the value and orientation of the exchange bias field (HEB) in the Pt/Co/NiO structure is carried out. Depending on the direction of the magnetization in a ferromagnet (FM) layer and the current pulse amplitude, the value of the HEB field can be changed repeatedly in the range of ±7.5 mT. A few experiments are performed to separate the contributions from two current-induced effects: (i) an injection of the spin current into an antiferromagnet layer (AFM) and (ii) Joule heating. As a result, we conclude that the modification in the HEB field during current pulse transmission in the Pt/Co/NiO structure is due to heating and the low value of Néel temperature (TN = 162 °C). This fact explains the absence of the exchange bias effect on the spin-orbit torque (SOT)-assisted magnetization switching. The most striking observation to emerge from the experimental data analysis is that depending on the initial spin configuration of the domain structure in the FM layer and the current pulse amplitude, the exchange bias can be changed locally. This opens up prospects for creating exchange-coupled FM/AFM structures with dynamically tuned parameters of the exchange bias, which can be used for the development of magnetic memory, neuromorphic, and logic devices based on magnetic nanosystems.