Direct Proximity Research Articles

Kinetic Control over Social and Narcissistic Self-Sorting from Multicomponent Mixtures in Seed-Initiated Supramolecular Polymerization by Fine-Tuning of Steric Effects.

Supramolecular polymers offer an intriguing possibility to transfer molecular properties from the nano- to the mesoscale. Towards this achievement, seed-initiated supramolecular polymerization has emerged as a powerful tool, as it prevents unlimited growth and enables size control of the assembly outcome. However, the potential application of the seeding method in the context of complex supramolecular systems is hitherto unclear. Herein we demonstrate that minute differences in molecular design in direct proximity to intermolecular recognition sites govern the molecular packing and in turn dictate the efficacy of seeded polymerization processes. We introduce a stepwise increase in steric demand in the central amino acid residue of a diamide system, which gradually increases the rotational displacement within the aggregated state. This fine-tuning of the molecular packing directly affects the propensity of the different aggregates to act as seeds for the other supramolecular synthons. In turn this allows us to selectively target specific trapped monomer states in binary mixtures for social or narcissistic seeded polymerization.

Kinetic Control over Social and Narcissistic Self‐Sorting from Multicomponent Mixtures in Seed‐Initiated Supramolecular Polymerization by Fine‐Tuning of Steric Effects

Supramolecular polymers offer an intriguing possibility to transfer molecular properties from the nano‐ to the mesoscale. Towards this achievement, seed‐initiated supramolecular polymerization has emerged as a powerful tool, as it prevents unlimited growth and enables size control of the assembly outcome. However, the potential application of the seeding method in the context of complex supramolecular systems is hitherto unclear. Herein we demonstrate that minute differences in molecular design in direct proximity to intermolecular recognition sites govern the molecular packing and in turn dictate the efficacy of seeded polymerization processes. We introduce a stepwise increase in steric demand in the central amino acid residue of a diamide system, which gradually increases the rotational displacement within the aggregated state. This fine‐tuning of the molecular packing directly affects the propensity of the different aggregates to act as seeds for the other supramolecular synthons. In turn this allows us to selectively target specific trapped monomer states in binary mixtures for social or narcissistic seeded polymerization.

Eco-Thrax: Anthrax Narratives and Unstable Ground

Abstract Numerous articles predicting pandemic futures identify threats tied directly to a warming planet. One notable example is the threat of once-stable pathogens held in ice shelves being released into the world. Bacillus anthracis, or anthrax, presents as the key bacterial threat emerging from melting permafrost. Such a threat reads like a fictitious horror brought into direct proximity with the real. Exploring perceptions of microbes across time and the resonance of specific tropes in television and eco-horror in the context of anthrax reveals an unstable theoretical and ecological landscape characterized by shifting human/biological relationships. Untangling this relationship more than 20 years after the last great anthrax-related challenge – the “Amerithrax” incident – and in recognition of the impact of COVID-19 on contemporary environmental humanities, it becomes possible to think of contagion as more than an epidemiological threat. Instead, contagion, as related to anthrax, can be identified as a window across time and place, one which assists in rethinking relationships to ecologies and environments. Two theoretical frameworks, the “outbreak narrative” as proposed by Priscilla Wald and the “hijacker model” introduced by Hannah Landecker, are deployed as lenses to introduce and think differently anthrax’s contemporary condition.

Unveiling the Intricate Link Between Anaerobe Niche and Alzheimer Disease Pathogenesis.

Dysbiosis within microbiomes has been increasingly implicated in many systemic illnesses, such as cardiovascular disease, metabolic syndrome, respiratory infections, and Alzheimer disease (Ad). The correlation between Ad and microbial dysbiosis has been repeatedly shown, yet the etiologic cause of microbial dysbiosis remains elusive. From a neuropathology perspective, abnormal (often age-related) changes in the brain, associated structures, and bodily lumens tend toward an accumulation of oxygen-depleted pathologic structures, which are anaerobically selective niches. These anaerobic environments may promote progressive change in the microbial community proximal to the brain and thus deserve further investigation. In this review, we identify and explore what is known about the anaerobic niche near or associated with the brain and the anaerobes that it is harbors. We identify the anaerobe stakeholders within microbiome communities and the impacts on the neurodegenerative processes associated with Ad. Chronic oral dysbiosis in anaerobic dental pockets and the composition of the gut microbiota from fecal stool are the 2 largest anaerobic niche sources of bacterial transference to the brain. At the blood-brain barrier, cerebral atherosclerotic plaques are predominated by anaerobic species intimately associated with the brain vasculature. Focal cerebritis/brain abscess and corpora amylacea may also establish chronic anaerobic niches in direct proximity to brain parenchyma. In exploring the anaerobic niche proximal to the brain, we identify research opportunities to explore potential sources of microbial dysbiosis associated with Ad.

Multi-Sensory Tool Holder for Process Force Monitoring and Chatter Detection in Milling.

Sensor-based monitoring of process and tool condition in milling is a key technology for improving productivity and workpiece quality, as well as enabling automation of machine tools. However, industrial implementation of such monitoring systems remains a difficult task, since they require high sensitivity and minimal impact on CNC machines and cutting conditions. This paper presents a novel multi-sensory tool holder for measurement of process forces and vibrations in direct proximity to the cutting tool. In particular, the sensor system has an integrated temperature sensor, a triaxial accelerometer and strain gauges for measurement of axial force and bending moment. It is equipped with a self-sufficient electric generator and wireless data transmission, allowing for a tool holder design without interfering contours. Milling and drilling experiments with varying cutting parameters are conducted. The measurement data are analyzed, pre-processed and verified with reference signals. Furthermore, the suitability of all integrated sensors for detection of dynamic instabilities (chatter) is investigated, showing that bending moment and tangential acceleration signals are the most sensitive regarding this monitoring task.

Cooperative, Close and Remote Steric Effects on the Structural and Optical Properties of Copper(I) Bis‐Phenanthroline Complexes

AbstractThe synthesis as well as the structural, optical and computational characterization of seven new highly hindered homoleptic copper(I) phenanthroline complexes (namely C1–C7) is reported along with the comparison with the benchmark derivatives. Despite limited steric hindrance in direct proximity of the copper(I) coordination site, X‐ray structures show that the higher hindered derivatives of the series display a more optimal tetrahedral geometry with minimal D2 symmetry distortion. A novel remote control of the geometry, with steric hindrance away from the coordination site, leads to a favorable arrangement as demonstrated by structural and computational data. In addition, electrochemical and steady‐state and time‐resolved photophysical studies are presented which further support the beneficial effects on the ground‐state redox and excited‐state properties when both remote and close steric effects are exploited. Indeed, both an increase of the photoluminescence quantum yield and a prolongation of the excited state lifetime is observed for the highly‐substituted derivative C6 compared to benchmark counterparts on account of the reduced excited‐state flattening distortions imparted by the additional steric constraints.

Ab initio calculations of nonlinear susceptibility and multiphonon mixing processes in a 2DEG-piezoelectric heterostructure

Solid-state elastic-wave phonons are a promising platform for a wide range of quantum information applications including facilitating quantum transduction from microwave to optical electromagnetic fields, long-lived quantum memories, in addition to potentially acting as qubits themselves. An outstanding challenge and enabling capability in harnessing phonons for quantum information processing is achieving sufficiently strong nonlinear interactions between them. To this end, we propose a general architecture for generating strong quantum phononic nonlinearity using piezoelectric-semiconductor heterostructures consisting of a piezoelectric acoustic material hosting phononic modes that is in direct proximity to a two-dimensional electron gas (2DEG). Each phonon in the piezoelectric material carries an electric field, which extends into the 2DEG. The fields induce polarization of 2DEG electrons, which in turn interact with other piezoelectric phononic electric fields. The net result is coupling between the electric fields associated with the various phonon modes. We derive, from first principles, the nonlinear phononic susceptibility of a piezo-2DEG system and provide a prescription to calculate all orders of the susceptibility in a perturbative expansion. We show that many nonlinear processes are strongly favored at high electron mobility, motivating the use of the 2DEG to mediate the nonlinearities. We derive the first, second, and third-order susceptibilities and calculate them for the case of a lithium niobate surface acoustic wave interacting with a GaAs-AlGaAs heterostructure 2DEG. We show that, for this system, the strong third-order phononic nonlinearities generated could enable single-phonon Kerr shift in an acoustic cavity that exceeds realistic cavity linewidths, potentially leading to a new class of acoustic qubit. We further show that the strong second-order nonlinearity could be used to produce a high-gain, traveling-wave parametric amplifier to amplify—and ultimately detect—the outputs of the acoustic cavity qubits. Assuming favorable losses in such a system, the combination of these capabilities, combined with the ability to efficiently transduce phonons from microwave electromagnetic fields in transmission lines, thus hold promise for creating all-acoustic quantum information processors. Published by the American Physical Society 2024

ESORES-Trial: Surgery as needed versus surgery on principle in patients with postneoadjuvant clinical complete tumor response of esophageal cancer.

TPS4185 Background: A substantial fraction of patients with esophageal cancer (EC) shows post-neoadjuvant pathological complete response (pCR). Principal esophagectomy after neoadjuvant treatment is the standard of care for all patients. Active surveillance (AS) and surgery as needed may be a treatment alternative for patients with clinical complete response (cCR). Methods: ESORES is a multicenter randomized controlled parallel-group non-inferiority trial. Patients are randomized either to surgery on principle and subsequent follow-up (Arm B) or clinical response evaluation (CRE) and surgery as needed (Arm A). CRE consists of esophagogastroscopy with deep biopsies (EGD), endoscopic ultrasound (EUS) and fine-needle aspiration (FNA) of suspicious lymph nodes, and F18-FDG-PET CT. In case of residual tumor (non-CR) after CRE, treatment is surgery. Patients with cCR will proceed with AS and surgery only if local regrowth occurs. AS comprises EGD, EUS-FNA and CT-Thorax/Abdomen at 3/6/9/12/18/24 months and yearly thereafter. A sample size of 670 patients is needed to demonstrate non-inferiority of Arm A vs. Arm B with regard to overall survival (OS) at a one-sided significance level of 5%, choosing a hazard ratio of 1.325 as non-inferiority margin which corresponds to a difference in 3-year OS rates of 8%. Superiority with regard to quality of life will be evaluated hierarchically only after non-inferiority with respect to OS has been shown. Key inclusion criteria: histologically verified EC, TNM stage ycT0-3 ycN0 ycM0, completion of neoadjuvant chemotherapy (nCT) or chemoradiation (nCRT) (irrespective of specific protocol), no visible lymphatic or distant metastasis in routine postneoadjuvant CT. Key exclusion criteria: postneoadjuvant dysphagia and/or esophageal obstruction, tumors of the cervical esophagus, tumors with direct proximity to the membranous part of the central airways (if regrowth is suspected to evoke locally irresectable ryT4b-stage), TNM stage cT4/ycT4 and/or cM1/ycM1, tumor progression during/after nCT/nCRT, and nCRT with >50 Gy radiation dose. Primary endpoints (hierarchically tested): 1) OS, 2) EORTC QLQ C30 global quality of life subscale. Secondary endpoints: Efficacy: long term tumor control, disease free survival, distant metastasis/local recurrence/regional recurrence; quality of life: EORTC QLQ C30, QLQ OES18, fear of progression: FoP-Q-12, surgery-free survival time in Arm A, patients’ satisfaction: EORTC OUT-PATSAT7; economic impact: days and costs of hospitalization; Safety: Interventional Safety: 3-Year-Comprehensive Complication Index, Oncological Safety (diagnostic accuracy of CRE, resection status (R0/R1/R2), irresectable regrowth during AS). Enrollment of patients started on January 30th, 2024. Clinical trial information: DRKS00032613 .

Adipose tissue as a linchpin of organismal ageing.

Ageing is a conserved biological process, modulated by intrinsic and extrinsic factors, that leads to changes in life expectancy. In humans, ageing is characterized by greatly increased prevalence of cardiometabolic disease, type 2 diabetes and disorders associated with impaired immune surveillance. Adipose tissue displays species-conserved, temporal changes with ageing, including redistribution from peripheral to central depots, loss of thermogenic capacity and expansion within the bone marrow. Adipose tissue is localized to discrete depots, and also diffusely distributed within multiple organs and tissues in direct proximity to specialized cells. Thus, through their potent endocrine properties, adipocytes are capable of modulating tissue and organ function throughout the body. In addition to adipocytes, multipotent progenitor/stem cells in adipose tissue play a crucial role in maintenance and repair of tissues throughout the lifetime. Adipose tissue may therefore be a central driver for organismal ageing and age-associated diseases. Here we review the features of adipose tissue during ageing, and discuss potential mechanisms by which these changes affect whole-body metabolism, immunity and longevity. We also explore the potential of adipose tissue-targeted therapies to ameliorate age-associated disease burdens.

Abstract 6932: Single-cell multiomics profiling reveals heterogeneous transcriptional programs and microenvironment in desmoplastic small round cell tumors

Abstract Background: Desmoplastic Small Round Cell Tumor (DSRCT) is a rare, aggressive sarcoma primarily affecting young males. Despite being driven by the unique oncogenic transcription factor (TF) EWSR1-WT1, and a monotonous morphology, DSRCT cells display a polyphenotypic differentiation of unknown etiology. Methods: To explore DSRCT heterogeneity, we characterized a series of patient samples by single-cell, spatial, and bulk multi-omics. We integrated patients’ data with bulk RNA-sequencing, ChIP-sequencing, and ATAC-sequencing data generated in a DSRCT cell line model upon EWSR1-WT1 transcriptional silencing. Results: Single-cell RNA-sequencing (scRNA-seq) on 11 patient samples identified recurrent subpopulations of DSRCT tumor cells, including lineage-, metabolism-, and pseudostate-related clusters. These subpopulations showed overlapping gene modules and lacked copy number variation diversity, suggesting transcriptional plasticity as a potential source of tumor heterogeneity. We first investigated whether cell-intrinsic mechanisms may drive DSRCT intra-tumor heterogeneity. Using an in-house-developed assay, we found limited variability in EWSR1-WT1 transcript expression. Preclinical modeling defined an EWSR1-WT1 regulon, used as a surrogate for EWSR1-WT1 TF activity. Integration with scRNA-seq data showed that high EWSR1-WT1 activity was associated with lineage-related states, while glycolytic and profibrotic states correlated with low EWSR1-WT1 activity. Single-cell ATAC-seq with scRNA-seq (Multiome) on one patient sample identified TF motifs related to developmental processes - e.g., SOX, FOX, and GATA - as the most differentially enriched across clusters. Interestingly, EGR1 regulon activity showed an inverse correlation with EWSR1-WT1 and Androgen Receptor regulons’ activity, in line with preclinical data, where ATAC-seq showed increased accessibility of EGR1 upon EWSR1-WT1 silencing. We next investigated cell-extrinsic factors by spatial transcriptomics in six patient samples. Glycolytic and profibrotic subpopulations localized within hypoxic niches at the tumor periphery, in direct proximity to cancer-associated fibroblasts (CAFs), which promoted tumor growth in vitro, as assessed in DSRCT cells/CAFs co-culture assays. Finally focusing on inter-tumor heterogeneity, the prognostic evaluation of scRNA-seq-derived signatures revealed that a tumor cell epithelial signature correlated with improved patient survival in a cohort of 29 DSRCT samples profiled with bulk RNA-sequencing. Conclusion: DSRCT heterogeneity is driven by combined cell-intrinsic and -extrinsic mechanisms, including EWSR1-WT1 DNA-binding activity and interaction with CAFs. Gene signatures associated with specific DSRCT subpopulations correlated with prognosis, highlighting the clinical relevance of our findings. Citation Format: Clémence Henon, Julien Vibert, Thomas Eychenne, Nadège Gruel, Léo Colmet-Daage, Carine Ngo, Marlène Garrido, Nicolas Dorvault, Maria Eugenia Marques Da Costa, Antonin Marchais, Asuka Kawachi, Madison Lenormand, Clémence Astier, Roman Chabanon, Benjamin Verret, Rastislav Bahleda, Axel Le Cesne, Fatima Mechta-Grigoriou, Charles Honoré, Matthieu Faron, Olivier Delattre, Joshua J Waterfall, Sarah Watson, Sophie Postel-Vinay. Single-cell multiomics profiling reveals heterogeneous transcriptional programs and microenvironment in desmoplastic small round cell tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6932.

Russia's Weaponized Migration: Analysing its Impact on Finnish-Russian Border Security

ObjectivesThis study aims to understand the frameworks of Russia's hybrid maneuvers , specifically the strategic use of migration, on Finland's security, as well as that of the European Union (EU) and the North Atlantic Treaty Organization (NATO). The focus is on examining how migration is used by Russia as a geopolitical tool to influence the security landscape of these regions.MethodsEmploying a case study methodology, the analysis draws upon a diverse range of data sources and scholarly literature. It scrutinises Russia's tactical approaches towards Finland and other countries situated on NATO's eastern flank, shedding light on the broader implications for regional stability and security.ResultsThe findings underscore Russia's deployment of migration as a geopolitical lever, exerting significant pressure on national security frameworks. In response, Finland has strengthened its defence mechanisms and sought to enhance international cooperation to effectively counteract these challenges.ConclusionsAfter joining NATO, Finland plays a key role in ensuring the security of the northern flank. Due to its location, this country is compelled to respond in real time to all possible threats that come with the direct proximity of the Russian Federation. Consequently, Finland is, in a sense, a frontline state and other countries should draw from its experience.

The Combination of Hvsr and Masw Methods with Landsat 8 Imagery to Assess the Changing Shoreline along the Coastal Area of Central Bengkulu

The Central Bengkulu Regency possesses a coastline measuring 21.8 km, situated in direct proximity to the Indian Ocean. The heightened wave and ocean current dynamics possess the capacity to induce detrimental effects in the form of coastal abrasion along the coastline. This study conducted an examination of the rate of shoreline changes resulting from coastal abrasion in Central Bengkulu Regency, Bengkulu, Indonesia. Horizontal-to-vertical spectral ratio (HVSR) analysis, multichannel analysis of surface waves (MASW), and Landsat-8 remote sensing were all used in the current investigation. The project gets started with conducting field investigations and measurements of geophysical techniques, including the collection of Landsat-8 satellite imagery spanning the period from 1990 to 2020. Additionally, an examination was conducted on the rate at which the shoreline undergoes changes in velocity. In order to determine the increase in change that occurs along coastlines over a period of several decades, a study was carried out during which Landsat-8 satellite images were analyzed. This study investigates the application of the HVSR technique for assessing the seismic vulnerability of the ground and, additionally, the MASW technique for measuring the shear wave velocity of the coastline’s soil. Both of these methodologies are compared and contrasted with one another in this research. The findings indicated that the mean pace of coastline change in Central Bengkulu Regency was 1.5 m/yr, with the maximum velocity recorded at 4.1 m/yr. This high velocity of shoreline change is correlated with the Vs30 value of MASW measurement and Kg of HVSR measurement, where the subsurface soil structure along the coast of Central Bengkulu Regency from Vs30 measurement shows that it is dominated by stiff soil structure that is susceptible to erosion. Outcomes from the study can inform decision-making processes about safeguards and preventative measures to prevent further coastal degradation. HIGHLIGHTS In this paper, we present a framework using application passive and active seismic method with Landsat 8 for knowing the changing of shoreline coastal area in Central Bengkulu Indonesia This study demonstrated that the high velocity of the shifting shoreline is correlated with Vs30 and Kg values The subsurface soil structure is predominantly composed of stiff soil, and the changing shoreline starts at 1.5 mm/yr, which makes the coast of Central Bengkulu vulnerable to erosion GRAPHICAL ABSTRACT

Viral reprogramming of host transcription initiation.

Viruses are master remodelers of the host cell environment in support of infection and virus production. For example, viruses typically regulate cell gene expression through modulating canonical cell promoter activity. Here, we show that Epstein Barr virus (EBV) replication causes 'de novo' transcription initiation at 29674 new transcription start sites throughout the cell genome. De novo transcription initiation is facilitated in part by the unique properties of the viral pre-initiation complex (vPIC) that binds a TATT[T/A]AA, TATA box-like sequence and activates transcription with minimal support by additional transcription factors. Other de novo promoters are driven by the viral transcription factors, Zta and Rta and are influenced by directional proximity to existing canonical cell promoters, a configuration that fosters transcription through existing promoters and transcriptional interference. These studies reveal a new way that viruses interact with the host transcriptome to inhibit host gene expression and they shed light on primal features driving eukaryotic promoter function.

Olenek–Anabar Composite Tectono-Sedimentary Element, northern East Siberia

Abstract The Olenek–Anabar Composite Tectono-Sedimentary Element (OLA CTSE) is located in the northern part of the Siberian Craton. Its structure and depositional history is controlled by two main tectonic events: (i) Mesoproterozoic rifting and (ii) Ediacaran–Cambrian (to Middle Devonian?) post-rift thermal subsidence. The sedimentary succession is mainly represented by Mesoproterozoic–Cambrian strata, including the black shales of the lower–middle Kuonamka Formation. The hydrocarbon potential of the OLA CTSE is defined by the presence of large superficial bitumen fields, anticlinal structures, large reefal build-ups and direct proximity to the potential source rock (Kuonamka Formation). A very scarce grid of seismic profiles and a lack of exploration wells limit the knowledge of the petroleum potential. The lack of seals and broad occurrences of faults, causing significant vertical permeability of sediment cover, and abundant occurrences of mafic and kimberlite magmatism are limiting factors with regard to the petroleum potential. Wells drilled during the Soviet era did not recover any commercial discoveries.

The differential regulation of placenta trophoblast bisphosphoglycerate mutase in fetal growth restriction: preclinical study in mice and observational histological study of human placenta.

Fetal growth restriction (FGR) is a pregnancy complication in which a newborn fails to achieve its growth potential, increasing the risk of perinatal morbidity and mortality. Chronic maternal gestational hypoxia, as well as placental insufficiency are associated with increased FGR incidence; however, the molecular mechanisms underlying FGR remain unknown. Pregnant mice were subjected to acute or chronic hypoxia (12.5% O2) resulting in reduced fetal weight. Placenta oxygen transport was assessed by blood oxygenation level dependent (BOLD) contrast magnetic resonance imaging (MRI). The placentae were analyzed via immunohistochemistry and in situ hybridization. Human placentae were selected from FGR and matched controls and analyzed by immunohistochemistry (IHC). Maternal and cord sera were analyzed by mass spectrometry. We show that murine acute and chronic gestational hypoxia recapitulates FGR phenotype and affects placental structure and morphology. Gestational hypoxia decreased labyrinth area, increased the incidence of red blood cells (RBCs) in the labyrinth while expanding the placental spiral arteries (SpA) diameter. Hypoxic placentae exhibited higher hemoglobin-oxygen affinity compared to the control. Placental abundance of Bisphosphoglycerate mutase (BPGM) was upregulated in the syncytiotrophoblast and spiral artery trophoblast cells (SpA TGCs) in the murine gestational hypoxia groups compared to the control. Hif1α levels were higher in the acute hypoxia group compared to the control. In contrast, human FGR placentae exhibited reduced BPGM levels in the syncytiotrophoblast layer compared to placentae from healthy uncomplicated pregnancies. Levels of 2,3 BPG, the product of BPGM, were lower in cord serum of human FGR placentae compared to control. Polar expression of BPGM was found in both human and mouse placentae syncytiotrophoblast, with higher expression facing the maternal circulation. Moreover, in the murine SpA TGCs expression of BPGM was concentrated exclusively in the apical cell side, in direct proximity to the maternal circulation. This study suggests a possible involvement of placental BPGM in maternal-fetal oxygen transfer, and in the pathophysiology of FGR. This work was supported by the Weizmann Krenter Foundation and the Weizmann - Ichilov (Tel Aviv Sourasky Medical Center) Collaborative Grant in Biomedical Research, by the Minerva Foundation, by the ISF KillCorona grant 3777/19.

Spatial Neurolipidomics at the Single Amyloid-β Plaque Level in Postmortem Human Alzheimer's Disease Brain.

Lipid dysregulations have been critically implicated in Alzheimer's disease (AD) pathology. Chemical analysis of amyloid-β (Aβ) plaque pathology in transgenic AD mouse models has demonstrated alterations in the microenvironment in the direct proximity of Aβ plaque pathology. In mouse studies, differences in lipid patterns linked to structural polymorphism among Aβ pathology, such as diffuse, immature, and mature fibrillary aggregates, have also been reported. To date, no comprehensive analysis of neuronal lipid microenvironment changes in human AD tissue has been performed. Here, for the first time, we leverage matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) through a high-speed and spatial resolution commercial time-of-light instrument, as well as a high-mass-resolution in-house-developed orbitrap system to characterize the lipid microenvironment in postmortem human brain tissue from AD patients carrying Presenilin 1 mutations (PSEN1) that lead to familial forms of AD (fAD). Interrogation of the spatially resolved MSI data on a single Aβ plaque allowed us to verify nearly 40 sphingolipid and phospholipid species from diverse subclasses being enriched and depleted, in relation to the Aβ deposits. This included monosialo-gangliosides (GM), ceramide monohexosides (HexCer), ceramide-1-phosphates (CerP), ceramide phosphoethanolamine conjugates (PE-Cer), sulfatides (ST), as well as phosphatidylinositols (PI), phosphatidylethanolamines (PE), and phosphatidic acid (PA) species (including Lyso-forms). Indeed, many of the sphingolipid species overlap with the species previously seen in transgenic AD mouse models. Interestingly, in comparison to the animal studies, we observed an increased level of localization of PE and PI species containing arachidonic acid (AA). These findings are highly relevant, demonstrating for the first time Aβ plaque pathology-related alteration in the lipid microenvironment in humans. They provide a basis for the development of potential lipid biomarkers for AD characterization and insight into human-specific molecular pathway alterations.

The Counteraction of Corruption in Indonesia Based On the International Agreement (Extradition) Between Indonesia and Singapore

In early 2022, Indonesia signed an extradition agreement with Singapore. This extradition agreement with Singapore is crucial because Singapore has been one of the destinations for Indonesian fugitives, particularly in corruption cases. The territory of Singapore, with its direct proximity to Indonesia and the visa-free arrangement for Indonesian citizens visiting Singapore, creates an environment where criminals can potentially use Singapore as a final destination or transit point for their illegal activities. This analysis examines the counteraction of corruption in Indonesia based on the international agreement (Extradition) between Indonesia and Singapore. The research adopts a normative legal research approach. The extradition agreement between Indonesia and Singapore will facilitate law enforcement authorities in Indonesia in resolving criminal cases where the perpetrators are located in Singapore. This allows law enforcement to take action against the criminals. Extradition also makes potential wrongdoers think twice before attempting to flee to another country, knowing that the destination country has an extradition agreement in place. In the fight against corruption, the Indonesia-Singapore extradition agreement is beneficial in preventing criminals from escaping to other countries, enabling the apprehension of wrongdoers, and facilitating the recovery of assets obtained through corruption.

Prospective Analysis of Radiation-Induced Contrast Enhancement and Health-Related Quality of Life After Proton Therapy for Central Nervous System and Skull Base Tumors

Intracerebral radiation-induced contrast enhancement (RICE) can occur after photon as well as proton beam therapy (PBT). This study evaluated the incidence, characteristics, and risk factors of RICE after PBT delivered to, or in direct proximity to, the brain and its effect on health-related quality of life (HRQoL). Four hundred twenty-one patients treated with pencil beam scanning PBT between 2017 and 2021 were included. Follow-up included clinical evaluation and contrast-enhanced magnetic resonance imaging at 3, 6, and 12 months after treatment completion and annually thereafter. RICE was graded according to Common Terminology Criteria for Adverse Events version 4, and HRQoL parameters were assessed via European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 questionnaires. The median follow-up was 24 months (range, 6-54), and median dose to 1% relative volume of noninvolved central nervous system (D1%CNS) was 54.3 Gy relative biologic effectiveness (RBE; range, 30-76 Gy RBE). The cumulative RICE incidence was 15% (n = 63), of which 10.5% (n = 44) were grade 1, 3.1% (n = 13) were grade 2, and 1.4% (n = 6) were grade 3. No grade 4 or 5 events were observed. Twenty-six of 63 RICE (41.3%) had resolved at the latest follow-up. The median onset after PBT and duration of RICE in patients in whom the lesions resolved were 11.8 and 9.0 months, respectively. On multivariable analysis, D1%CNS > 57.6 Gy RBE, previous in-field radiation, and diabetes mellitus were identified as significant risk factors for RICE development. Previous radiation was the only factor influencing the risk of symptomatic RICE. After PBT, general HRQoL parameters were not compromised. In a matched cohort analysis of 54/50 patients with and without RICE, no differences in global health score or functional and symptom scales were seen. The overall incidence of clinically relevant RICE after PBT is very low and has no significant negative effect on long-term patient QoL.

Carboniferous sills and related metasomatic activity in the area of Asaritsa Peak, West Stara Planina Mountain

Two diorite to monzodiorite sills are recently found among the Silurian sedimentary succession near to Asaritsa peak, West Stara Planina Mountain. Several levels with diagenetic metalliferous nodules occur within shale interval in the sediments. The magmatic rocks are affected by strong propylitic to sericitic alteration (chlorite, sericite, albite and quartz) and only relicts of the rock-forming minerals (feldspar, biotite and clinopyroxene) are observed. The bodies are crosscut by thin quartz veins and disseminated pyrite is observed. The chondrite normalized spidergrams show patterns similar to orogenic rocks, with very high peaks of Th and U and depletion in Sr and Ti. The zircon U-Pb geochronology reveals that the magmatic crystallization is during the Carboniferous period – 326.4±3.2 Ма, with low content of xenocryst most probably from the sedimentary basement. The magmatic activity coincides with the Variscan orogeny formed during the late Paleozoic and most probabaly is related to the evolution of the alkaline Buhovo-Seslavtsi Pluton which is situated just to the south, at a direct proximity. The different composition of the pyrite from the sills and the diagenetic nodules from the sediments is most probably due to their different genesis. While the alterations of the nodules can be attributed to metasomatic processes related to the magmatic activity.

Czy stare i nowe miasto były skazane na konflikt? Głos w dyskusji w świetle nowszych badań

Were the old and new towns doomed to conflict? A voice in the discussion in the light of newer research The article consists of two parts. In the first one I present the causes and forms of conflict between municipalities in one urban centre in medieval Poland. It is a summary of and supplement to the material presented in my book about double and multiple cities in medieval Europe, limited here to Polish lands. In the second part, I engage in a debate with works published since then that question the existence of competition and conflict between municipalities: by Marcin Starzyński in relation to Kazimierz in Cracow and by Piotr Samól in the case of Jungstadt in Gdańsk. Direct proximity determined the intensity of contacts and mutual dependence, which led to tensions, and in some circumstances could lead to acts of violence and material destruction of weaker municipalities. The biggest area of tension was economic rights. Among them, the right to cut cloth, sell beer, rights to markets and fairs played a special role. The main centre usually aimed for a monopoly and sought to encompass the city’s broadly defined environs. However, the essence of the dispute was not the economic or craft activity, but its removal from the control of the old town authorities and the functioning of an independent municipality. The older and usually stronger commune looked down on its neighbour, while the younger one felt humiliated and wronged. In addition, direct proximity often caused military problems: weaker fortifications of the new town or their absence became a cause or pretext for restricting or partially or even completely eliminating construction. Open violence against a neighbouring centre was contrary to the interests of the superior of these municipalities, so it happened rarely, usually during a war in the area. At the same time, tension and rivalry between municipalities did not exclude cooperation in many areas or pragmatic benefits from mutual proximity. It probably constituted a potentially significant factor stimulating the development of such complex urban structures.