Sequence Of Events Research Articles

A CLINICAL STUDY TO EVALUATE THE EFFECT OF NAGARADI KWATHA AND CHANDRAPRABHA VATI IN MOOTRASHMARI W.S.R. TO UROLITHIASIS

Ashmari is the formation of stone in Mootravaha srotas, resulting in severe pain as given by the enemy. It is an effect of the complex, physicochemical process that involves a sequence of events in the formation of any urinary stones, including urinary saturation, supersaturation, nucleation and growth of crystals, aggregation and retention of crystals, and finally, stone formation. It affects about 12% of the world's population at some stage in their lifetime in all age groups, sexes, and races but occurs more frequently in men than women aged 20 to 49 years. In India, about 12% of the total population is expected to have urinary stones in their life, out of which 50% may end up with loss of kidney function. Contemporary treatment such as Lithotripsy (ESWL), Percutaneous Nephrolithotomy (PCNL), Retrograde Intra-renal surgery (RIRS), and Laparoscopic Ureter lithotomy adopted in the condition of Urolithiasis is quite costly with high incidence of recurrence. For the present study, Nagaradi Kwatha and Chandraprabha Vati were administered for 14 days. Each patient was observed on the 0-day, 7th, and 15th day of drug intervention with said parameters. The study showed significant clinical improvement in reducing the shoola, mootradosha, Kruchramutrata, and Sarakta mootrata and showed good response in disintegration and the expulsion of Ashmari.

A Comparative Study on Fixed-Order Event Sequence Visualizations: Gantt, Extended Gantt, and Stringline Charts.

We conduct two in-lab experiments (N = 93) to evaluate the effectiveness of Gantt charts, extended Gantt charts, and stringline charts for visualizing fixed-order event sequence data. We first formulate five types of event sequences and define three types of sequence elements: point events, interval events, and the temporal gaps between them. Our two experiments focus on event sequences with a pre-defined, fixed order and measure task error rates and completion time. The first experiment shows single sequences and assesses the three charts' performance in comparing event duration or gap. The second experiment shows multiple sequences and evaluates how well the charts reveal temporal patterns. The results suggest that when visualizing single fixed-order event sequences, 1) Gantt and extended Gantt charts lead to comparable error rates in the duration-comparing task; 2) Gantt charts exhibit either shorter or equal completion time than extended Gantt charts; 3) both Gantt and extended Gantt charts demonstrate shorter completion times than stringline charts; 4) however, stringline charts outperform the other two charts with fewer errors in the comparing task when event type counts are high. Additionally, when visualizing multiple point-based fixed-order event sequences, stringline charts require less time than Gantt charts for people to find temporal patterns. Based on these findings, we discuss design opportunities for visualizing fixed-order event sequences and discuss future avenues for optimizing these charts.

The timing of the Middle Triassic magmatism in the Dolomites area (Southern Alps, Italy): U[sbnd]Pb geochronology of zircon and titanite hosted in plutonic rocks and phonolite dykes

The Middle Triassic magmatic event in the Southern Alps (Italy) is characterised by the emplacement and eruption of multiple magma batches with different geochemical affinities in a short time span. In this work, we present the first geochemical and geochronological data on highly differentiated alkaline dykes (phonolites) exposed in and near the Middle Triassic Predazzo magmatic complex (Southern Alps, Italy) and a first complete geochronological survey of the Predazzo pluton. The phonolites, cutting the Middle Triassic volcanic sequences, are sodalite- and aegirine-bearing and have titanite, apatite and magnetite as accessory phases. Their trace element concentration reflects a geochemical signature similar to the orogenic-like signature typical of the Middle Triassic magmatic rocks of the Predazzo complex. New in situ UPb dating on titanite from the phonolite dykes and UPb dating on zircon separates from all the magmatic units of the Predazzo pluton show that the phonolite dykes were emplaced between 233.8 ± 3.1 Ma and 238.1 ± 4.5 Ma, i.e., overlapping to and postdating the emplacement and crystallisation of plutonic rocks, which yield ages ranging from 237.97 ± 0.15 Ma to 238.31 ± 0.13 Ma. The ages obtained for the diverse suites of the pluton are in good agreement with previous dating and show that silica-saturated to -undersaturated rocks were placed within the same context in a short time span. Thermometry and hygrometry on titanite, clinopyroxene and K-feldspar revealed that phonolites represent volatile- and REE-rich (H2O = 8 ± 0.6 wt%) highly differentiated alkaline melts intruding at relatively low T (752–868 °C), which easily caused the spatially related CuW mineralisation. Comparisons with sub-volcanic rocks exposed in the Central (Edolo) and Western Alps (Finero mafic complex) indicate that the phonolites still preserve the orogenic signature of the Middle Triassic event in the Southalpine, that characterise all magmas emplaced before the opening of the Alpine Tethys in the Late Triassic. These new geochronological constraints on the Predazzo pluton and phonolite dykes enable us to outline the complete sequence of magmatic events associated with the emplacement of the Predazzo volcano-plutonic complex during Mid-Triassic and to speculate about the genesis of CuW mineralisation.

Vulnerability of structures designed with seismic provision due to explosions in mines

The effect of blast-induced ground vibration on structures was examined. The aim was to investigate the extent to which the strength attributed by seismic design can resist the effect of mine blasts, as both earthquakes and blasts generate lateral forces. The study was conducted to see whether and how blasts can be controlled such that seismic design of structures may suffice the purpose of withstanding mine blasts. The responses in the elastic and post-elastic regions were compared for implementation of the concept of performance-based design. The responses of structures were investigated for both single and sequential blasts. The results showed that sequential blast events are more damaging than earthquakes. On the other hand, medium- and long-period structures under a single blast event can withstand blast-induced vibration if designed as per seismic provisions. To safeguard structures under sequential blasts, it is recommended that the number of blast events is controlled. The safety of structures under blast can be determined by knowing the additional strength attributed from the seismic effect. This may help to decide whether separate design provisions for blast-induced ground motion are needed.

Dramatic Enhancement of Macrozoobenthic Species β-Diversity in Response to Artificial Breakwater Construction Along a Tropical Coastline

The beneficial or detrimental effects of human-built marine structures (piers, breakwaters, and seawalls) on macrozoobenthic assemblages and diversities are currently underexplored. The present study investigated the enhancement of β-diversity of oysterbed-associated species on breakwaters constructed along sandy beaches. We compared habitat complexities and species assemblages among artificial breakwater shores (ABS), a natural rocky shore (NS), and an embayment shore (ES). Oysterbed habitat complexity was found to be greatest on the ABS due to the successional colonization of the reef-forming estuarine oyster, Saccostrea echinata, followed by the colonization of boring bivalves and burrowing annelids. High-resolution taxonomic data revealed that the ABS supports the greatest species richness, including 48.1% unique species and 33.3% species shared with the embayment shore. The other shores uniquely or in combination with ABS support up to 11.1% of the total species richness associated with the oysterbeds (n = 81). Taxonomic dominance in terms of species number was Mollusca > Annelida > Arthropoda. This study reveals that ABS enhances β-diversity by ~91% (Jaccard dissimilarity index), which is driven by the sequential cascading events of (1) sheltering of shores, (2) colonization of novel habitat-forming oysters, (3) novel macrozoobenthic species recruitment from adjacent shores and sheltered embayments, including habitat-forming bivalves and annelids, and (4) the recruitment of macrozoobenthic species to boreholes. ABS habitat complexity derives from a spatially distinct, three-tiered ecological engineering system, involving (1) breakwater construction (100 m), (2) reef-forming oysters (10 m), and (3) boring bivalves and burrowing annelids (<10 cm). Irrespective of the purpose of their construction, breakwaters along extended sandy shores can potentially increase the resilience (β-diversity) and regional interconnectivity of hard surface macrozoobenthic species.

Disease Severity Staging System for NOTCH3-Associated Small Vessel Disease, Including CADASIL

Typical cysteine-altering NOTCH3 (NOTCH3cys) variants are highly prevalent (approximately 1 in 300 individuals) and are associated with a broad spectrum of small vessel disease (SVD), ranging from early-onset stroke and dementia (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]) to nonpenetrance. A staging system that captures the full NOTCH3-SVD severity spectrum is needed and currently lacking. To design a simple disease severity staging system that captures the broad clinicoradiological NOTCH3-SVD severity spectrum. A cohort study was performed in which the NOTCH3-SVD severity staging system was developed using a discovery cohort (2019-2020) and validated in independent international CADASIL cohorts (1999-2023) and the UK Biobank. Clinical and imaging data were collected from participants originating from 23 international CADASIL cohorts and from the UK Biobank. Eligibility criteria were presence of a NOTCH3cys variant, availability of brain magnetic resonance imaging, and modified Rankin Scale score. The discovery cohort consisted of 195 NOTCH3cys-positive cases from families with CADASIL; the validation set included 1713 NOTCH3cys-positive cases from 15 countries. The UK Biobank cohort consisted of 101 NOTCH3cys-positive individuals. Data from 2-year (2019-2023) and 18-year (1999-2017) follow-up studies were also analyzed. Data analysis was performed from July 2023 to August 2024. Percentage of cases following the sequence of events of the NOTCH3-SVD stages, and the association between the stages and ischemic stroke, intracerebral hemorrhage, global cognition, processing speed, brain volume, brain microstructural damage, and serum neurofilament light chain (NfL) level. The NOTCH3-SVD staging system encompasses 9 disease stages or substages, ranging from stage 0 (premanifest stage) to stage 4B (end stage). Of all 1908 cases, which included 195 in the discovery cohort (mean [SD] age, 52.4 [12.2] years) and 1713 in the validation cohorts (mean [SD] age, 53.1 [13.0] years), 1789 (94%) followed the sequence of events defined by the NOTCH3-SVD staging system. The NOTCH3-SVD stages were associated with neuroimaging outcomes in the NOTCH3cys-positive cases in the CADASIL cohorts and in the UK Biobank and with cognitive outcomes and serum NfL level in cases from the CADASIL cohorts. The NOTCH3-SVD staging system captured disease progression and was associated with 18-year survival. The NOTCH3-SVD staging system captures the full disease spectrum, from asymptomatic individuals with a NOTCH3cys variant to patients with end-stage disease. The NOTCH3-SVD staging system is a simple but effective tool for uniform disease staging in the clinic and in research.

Construction, Maintenance and Ritual Practices on the Neolithic Rondel at Nowe Objezierze (Northwestern Poland): The chaîne opératoire of Rondel’s Architecture

In the history of the “Danubian Neolithic” society, monumental ceremonial centers appeared around 4800 BCE and lost their importance around 300 years later. Among them, one of the most distinctive forms are rondels. However, it is worth remembering the contemporary Rosheim-type circles and Passy-type tombs. The name “rondels” refers to the currently preserved architectural form, dominated by concentric ditches. The article presents an analysis of the biography of a rondel from Nowe Objezierze (north-western Poland). For this purpose, the chaîne opératoire method was used, which is a very effective tool for reconstructing the full sequence of events including the construction, use and abandonment of the examined monument, in its historical and social context. Thanks to this, it was possible to draw attention to previously little-explored details of planning construction works, the skills of ritual leaders and the seasonal availability of some construction materials. As a consequence, the construction and use of rondels can be presented as a complex ceremonial cycle, stretched over time and interrupted by festivals. When the rondel was ready, the cycle began with renovating the surrounding wall and digging the ditch, most likely reaching its culmination on the day of the winter solstice. The celebrations ended with a ceremony of backfilling of the ditch.

Causal Discovery from Temporal Data: An Overview and New Perspectives

Temporal data, representing chronological observations of complex systems, has always been a typical data structure that can be widely generated by many domains, such as industry, finance, healthcare and climatology. Analyzing the underlying structures, i.e. , the causal relations, could be extremely valuable for various applications. Recently, causal discovery from temporal data has been considered as an interesting yet critical task and attracted much research attention. According to the nature and structure of temporal data, existing causal discovery works can be divided into two highly correlated categories i.e. , multivariate time series causal discovery, and event sequence causal discovery. However, most previous surveys are only focused on the multivariate time series causal discovery but ignore the second category. In this paper, we specify the similarity between the two categories and provide an overview of existing solutions. Furthermore, we provide public datasets, evaluation metrics and new perspectives for temporal data causal discovery.

Seismic radial anisotropy in southeastern Tibetan Plateau and its implications for regional geodynamic evolution

The southeastern Tibetan Plateau exhibits intricate crustal tectonics, encompassing recent seismic megathrust events. Previous research suggested the presence of north-south-oriented channelized viscous flow within the crust. However, recent investigations have unveiled a notable northeast-southwest-oriented geological structure, potentially rigid, intersecting with the presumed crustal channelized flow. Several questions persist regarding the composition of the northeast-southwest-oriented structure, the continuity of crustal channelized flow, and the interplay between them. In this study, dispersion data from a dense seismic array are employed to significantly refine regional crustal models for shear wave velocity and radial anisotropy through ambient noise tomography. The resulting high-resolution model further reveals the style of the crustal deformation and supports the interpretation that the northeast-southwest structure, which shows higher velocity and significant negative radial anisotropy, results from mafic material at the base of crust, obstructing the crustal channelized flow. However, the northeast-southwest structure is not as rigid as the Sichuan Block and exhibits depth-dependent deformation. The interpretation proves useful in further understanding regional earthquake focal mechanisms and strain distribution. Additionally, this research identified a region of generalized negative radial anisotropy in the crust of the western Chuan-Dian fragment, suggesting a reduced horizontal channel crustal flow in this area. Drawing upon various geophysical and geological evidence, we present a geodynamic evolution model, proposing a sequence of events: Permian plume activity resulting in mafic material at the base of the crust near Anninghe-Zemuhe fault, northward advancement of the east Himalayan syntaxis inducing crustal compressional stress field, reduced lower crustal channel flow in the western Chuan-Dian fragment leading to the regional east-west extension, and initiation of the Xianshuihe fault causing shift of strain concentration and depth-dependent deformation near the Anninghe-Zemuhe fault. The geodynamic model provides valuable insights into the regional distribution of crustal strain and the underlying mechanisms of large seismic events.

Pollution Crime Scenario Reconstruction for Effective Environmental Redress

Dealing pollution cases as criminal offences requires proof beyond reasonable doubt for conviction. To meet this highest standard of evidentiary requirement, forensic professionals need to adopt the best tools and methods available to them. “Crime Scene Reconstruction” is a method adopted in traditional crimes to recreate the exact sequence of events leading to the crime from the physical evidences collected at the crime scene. This paper presents the adoption of the method of crime reconstruction to environmental crimes. All stages of traditional crime scene reconstruction, starting from recognition of physical evidence from the scene, its identification and individualization, collection of data, hypothesis formulation, it’s testing and final reconstruction are explained in the context of environmental crimes. An effective method to apply in the reconstruction of an environmental crime scene must rely on several experts of different scientific domains who are united in defining, through the search for evidences, the causal link that connects the “victim”, the “guilt” and the “perpetrator”. Often, the difficulty in such reconstruction is because the perpetrator’s motive is not really connected to environmental aspects, but only the consequential effects are revealed in the environment. However, even if the actions that caused the damage to the environment were not the real motive of the perpetrator, this does not redeem him from the responsibility of associated environmental crimes, but makes the process of reconstructing the crime more complex, especially in the search for the cause-effect relationship. The activity related to the analysis of an environmental crime scene is to be considered a situational awareness activity that aims to evaluate not only a specific action in a scene but the entire dynamics of a complex scenario. Considering the complexities that are characteristic of environmental crimes, we propose one more stage in addition to the general stages of traditional crime reconstruction, that of presenting the reconstructed scenario in a way that is easy for the legal fraternity to comprehend. Finally, the entire procedure of reconstruction is demonstrated using an actual case.

Abstract PR016: Early changes to the colon tumor microenvironment during benign-to- malignant transition

Abstract Colorectal cancer (CRC) is now the first and second leading cause of cancer-related deaths in men and women under 50, respectively, upending prior predictions. While many risk factors have been identified, the etiology of early onset disease is poorly understood, and it is unclear why some benign polyps progress to CRC while most do not. The genetic drivers of colon tumor initiation and progression to malignancy are not sufficient to drive disease on their own, as evidenced by the near ubiquitous presence of oncogenic mutations within morphologically “normal” adult tissues like the colon. This raises several fundamental questions: 1) what are the pioneering molecular and cellular events underlying benign-to-malignant transition following oncogenic mutation? 2) Is this sequence of events predetermined by cancer genetics or are additional (micro)environmental stimuli necessary? 3) How does the benign-to-malignant transition reshape tumor clonal architecture and is this immunogenic? We have begun to address these questions using a combination of rare human colon polyps with evidence of early malignant transition and innovative new mouse models that enable control of stepwise colon cancer progression. These autochthonous models combine in vivo CRISPR-Cas9 and an inducible “split-Cre” system to decouple focal tumor initiation in the distal colon (via Apc knockout) from spatiotemporal control of secondary driver events of malignant progression (e.g., Kras G12D, Trp53 knockout) in rare cells of benign adenomas. We have validated the in vivo functionality of these models, generating early “intramucosal carcinoma” and “adenocarcinoma-in-adenoma”—physiologically relevant and elusive stages of human colon cancer development that have never been reliably captured in model systems to date. Comparing these tumors with spatial transcriptomic data from human specimens, we report distinct transcriptional programs of early progression, a unique stromal reaction associated with early progression, and restructuring of glandular architecture and the stem cell niche in early carcinoma. By delineating the earliest events underlying cancer progression, this work promises to inform new strategies for early detection and prevention. We anticipate that the models will also be particularly valuable in functionally interrogating host and environmental factors that impact risk of early onset cancer. Citation Format: Peter M.K. Westcott, Yihan Qin, Daniel Zhang, Nikita Persaud, Zakeria Aminzada, Nischal Bhandari, Colin McLaughlin, William Rideout III, Santiago Naranjo, Song Han, Rodrigo Romero, Claire Regan, Jonathan Preall, Semir Beyaz, Tyler Jacks, Zhen Zhao, Sepideh Gholami. Early changes to the colon tumor microenvironment during benign-to- malignant transition [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr PR016.

Three-dimensional velocity structure of the MS 6.0 Luxian earthquake source region and adjacent areas based on a dense seismic array

On September 16, 2021, an MS 6.0 earthquake struck Luxian County in the Sichuan basin. To investigate the regional velocity structure and its relationship with seismic activity, we gathered seismic phase data from permanent stations for events occurring between January 2009 and April 2021 as well as data from a dense mobile seismic array that operated from April 2021 to July 2023. Utilizing Double-Difference tomography, we have determined well-constrained earthquake relocations and have derived a detailed 3D velocity structure. Many of the earthquakes exhibit linear clustering patterns, with an average depth of 4.3 km and a NE-SW orientation. Approximately 96 % of the seismic events occurred within a depth range of 0–7 km. The early aftershock sequence of the Luxian event also displayed a linear trend, with a length of 6 km but with an ESE orientation. The mainshock occurred at a depth of 6.2 km, located at the northwestern end of the aftershock sequence. The aftershock sequence along with other linear seismic clusters, predominantly occurred within regions characterized by high seismic velocities and low Poisson's ratios, both within the sedimentary cover above the crystalline basement. The heterogeneity of the velocity structure likely plays a significant role in controlling the occurrence of moderate-to-strong earthquakes in the deeper parts of the study region, which deepens the existing understanding from previous research: pre-existing faults, their scales, and their slip-tendencies under the present-day regional and reservoir-scale stress fields are also controlling factors for induced earthquakes, especially larger ones. We have identified five areas where moderate-to-strong earthquakes are speculated to have a higher likelihood of occurrence. These findings hold considerable importance for local seismic hazard assessments.

Metallaphotocatalytic triple couplings for modular synthesis of elaborate N-trifluoroalkyl anilines

The integration of trifluoromethyl groups and three-dimensional quaternary carbon moieties into organic molecules has emerged as a prominent strategy in medicinal chemistry to augment drug efficacy. Although trifluoromethyl (hetero)aromatic amines and derivatives are prevalent frameworks in pharmaceuticals, the development of trifluoromethyl-embedded, intricately structured alkyl amine scaffolds for medicinal research remains a significant challenge. Herein, we present a metallaphotoredox multicomponent amination strategy employing 3,3,3-trifluoropropene, nitroarenes, tertiary alkylamines, and carboxylic acids. This synthetic pathway offers notable advantages, including the accessibility and cost-effectiveness of starting materials, high levels of chemo- and regioselectivity, and modularity. Furthermore, this approach enables the synthesis of a broad spectrum of aniline compounds featuring both trifluoromethyl group and distal quaternary carbon motifs along the aliphatic chains. The accelerated access to such elaborate N-trifluoroalkyl anilines likely involves three sequential radical-mediated coupling events, providing insightful implications for the retrosynthesis of potential compounds in organic synthesis and drug discovery.

Biomaterial Cues for Regulation of Osteoclast Differentiation and Function in Bone Regeneration

AbstractTissue regeneration involves dynamic dialogue between and among different cells and their surrounding matrices. Bone regeneration is specifically governed by reciprocity between osteoblasts and osteoclasts within the bone microenvironment. Osteoclast‐directed resorption and osteoblast‐directed formation of bone are essential to bone remodeling, and the crosstalk between these cells is vital to curating a sequence of events that culminate in the creation of bone tissue. Among bone biomaterial strategies, many have investigated the use of different material cues to direct the development and activity of osteoblasts. However, less attention has been given to exploring features that similarly target osteoclast formation and activity, with even fewer strategies demonstrating or integrating biomaterial‐directed modulation of osteoblast‐osteoclast coupling. This review aims to describe various biomaterial cues demonstrated to influence osteoclastogenesis and osteoclast function, emphasizing those that enhance a material construct's ability to achieve bone healing and regeneration. Additionally discussed are approaches that influence the communication between osteoclasts and osteoblasts, particularly in a manner that takes advantage of their coupling. Deepening the understanding of how biomaterial cues may dictate osteoclast differentiation, function, and influence on the microenvironment may enable the realization of bone‐replacement interventions with enhanced integrative and regenerative capacities.

NarrativeGenie: Generating Narrative Beats and Dynamic Storytelling with Large Language Models

Interactive narrative in games utilize a combination of dynamic adaptability and predefined story elements to support player agency and enhance player engagement. However, crafting such narratives requires significant manual authoring and coding effort to translate scripts to playable game levels. Advances in pretrained large language models (LLMs) have introduced the opportunity to procedurally generate narratives. This paper presents NarrativeGenie, a framework to generate narrative beats as a cohesive, partially ordered sequence of events that shapes narrative progressions from brief natural language instructions. By leveraging LLMs for reasoning and generation, NarrativeGenie, translates a designer’s story overview into a partially ordered event graph to enable player-driven narrative beat sequencing. Our findings indicate that NarrativeGenie can provide an easy and effective way for designers to generate an interactive game episode with narrative events that align with the intended story arc while at the same time granting players agency in their game experience. We extend our framework to dynamically direct the narrative flow by adapting real-time narrative interactions based on the current game state and player actions. Results demonstrate that NarrativeGenie generates narratives that are coherent and aligned with the designer’s vision.

A new clinical entity bridging the cardiovascular system and the kidney: The Chronic Cardiovascular-Kidney Disorder.

Background The complex relationship between heart and kidney dysfunction has been a subject of medical inquiry since the 19th century. The term "cardio-renal syndrome" (CRS) was introduced in the early 2000s and has since become a focal point of research. CRS is typically categorized into five subtypes based on the sequence of cardiovascular and kidney disease events. Summary The Cardiovascular-Kidney-Metabolic (CKM) syndrome, as defined by the American Heart Association (AHA), describes a set of interrelated metabolic risk factors and their effects on the kidneys and cardiovascular system. This syndrome emphasizes the complexity of managing patients with combined conditions and identifies several knowledge gaps, including disease mechanisms, clinical phenotype variability, and the impact of social determinants of health. The Chronic Cardiovascular-Kidney Disorder (CCKD) framework proposes a shift from the term "syndrome" to "disorder," focusing on concurrent cardiovascular and kidney problems regardless of their sequence. Key messages • The CCKD concept calls for simplification and conceptual clarity, arguing that understanding the bidirectional acceleration of disease progression between heart and kidney dysfunction can lead to more effective treatment strategies. • Both CKM and CCKD share common pathophysiological mechanisms and risk factors, including hypertension, diabetes, obesity, and dyslipidemia. Managing these conditions requires a comprehensive approach that addresses the underlying risk factors and pathophysiological mechanisms. • Future directions include embracing precision medicine, public health strategies, interdisciplinary care models, and ongoing research and innovation. Both frameworks underscore the need for comprehensive, interdisciplinary care models and innovative treatment strategies to address the complex interplay between cardiovascular and kidney diseases.

Open-ended molecular recording of sequential cellular events into DNA.

Genetically encoded DNA recorders noninvasively convert transient biological events into durable mutations in a cell's genome, allowing for the later reconstruction of cellular experiences by DNA sequencing. We present a DNA recorder, peCHYRON, that achieves high-information, durable, and temporally resolved multiplexed recording of multiple cellular signals in mammalian cells. In each step of recording, prime editor, a Cas9-reverse transcriptase fusion protein, inserts a variable triplet DNA sequence alongside a constant propagator sequence that deactivates the previous and activates the next step of insertion. Insertions accumulate sequentially in a unidirectional order, editing can continue indefinitely, and high information is achieved by coexpressing a variety of prime editing guide RNAs (pegRNAs), each harboring unique triplet DNA sequences. We demonstrate that the constitutive expression of pegRNA collections generates insertion patterns for the straightforward reconstruction of cell lineage relationships and that the inducible expression of specific pegRNAs results in the accurate recording of exposures to biological stimuli.

Learned response dynamics reflect stimulus timing and encode temporal expectation violations in superficial layers of mouse V1.

The ability to recognize ordered event sequences is a fundamental component of sensory cognition and underlies the capacity to generate temporally specific expectations of future events based on previous experience. Various lines of evidence suggest that the primary visual cortex participates in some form of predictive processing, but many details remain ambiguous. Here we use two-photon calcium imaging in layer 2/3 of the mouse primary visual cortex (V1) to study changes to neural activity under a multi-day sequence learning paradigm with respect to prediction error responses, stimulus encoding, and time. We find increased neural activity at the time an expected, but omitted, stimulus would have occurred but no significant prediction error responses following an unexpected stimulus substitution. Sequence representations became sparser and less correlated with training, although these changes had no effect on decoding accuracy of stimulus identity or timing. Additionally, we find that experience modifies the temporal structure of stimulus responses to produce a bias towards predictive stimulus-locked activity. Finally, we find significant temporal structure during intersequence rest periods that was largely unchanged by training.

A three-quantile bias correction with spatial transfer for the correction of simulated European river runoff to force ocean models

Abstract. In ocean or Earth system model applications, the riverine freshwater inflow is an important flux affecting salinity and marine stratification in coastal areas. However, in climate change studies, the river runoff based on climate model output often has large biases on local, regional, or even basin-wide scales. If these biases are too large, the ocean model forced by the runoff will drift into a different climate state compared to the observed state, which is particularly relevant for semi-enclosed seas such as the Baltic Sea. To achieve low biases in riverine freshwater inflow in large-scale climate applications, a bias correction is required that can be applied in periods where runoff observations are not available and that allows spatial transferability of its correction factors. In order to meet these requirements, we have developed a three-quantile bias correction that includes different correction factors for low-, medium-, and high-percentile ranges of river runoff over Europe. Here, we present an experimental setup using the Hydrological Discharge (HD) model and its high-resolution (1/12°) grid. First, bias correction factors are derived at the locations of the downstream stations with available daily discharge observations for many European rivers. These factors are then transferred to the respective river mouths and mapped to neighbouring grid boxes belonging to ungauged catchments. The results show that the bias correction generally leads to an improved representation of river runoff. Especially over northern Europe, where many rivers are regulated, the three-quantile bias correction provides an advantage compared to a bias correction that only corrects the mean bias of the river runoff. Evaluating two NEMO (Nucleus for European Modelling of the Ocean) model simulations in the German Bight indicated that the use of the bias-corrected discharges as forcing leads to an improved simulation of sea surface salinity in coastal areas. Although the bias correction is tailored to the high-resolution HD model grid over Europe in the present study, the methodology is suitable for any high-resolution model region with a sufficiently high coverage of river runoff observations. It is also noted that the methodology is applicable to river runoff based on climate hindcasts, as well as on historical climate simulations where the sequence of weather events does not match the actual observed history. Therefore, it may also be applied in climate change simulations.

The phospho-tau cascade, basal forebrain neurodegeneration, and dementia in Alzheimer's disease: Anti-neurodegenerative benefits of acetylcholinesterase inhibitors.

A conundrum in Alzheimer's disease (AD) is why the long-term use of acetylcholinesterase (AChE) inhibitors, intended for treatment of dementia, results in slowing neurodegeneration in the cholinergic basal forebrain, hippocampus, and cortex. The phospho-tau cascade hypothesis presented here attempts to answer that question by unifying three hallmark features of AD into a specific sequence of events. It is proposed that the hyperphosphorylation of tau protein leads to the AD-associated deficit of nerve growth factor (NGF), then to atrophy of the cholinergic basal forebrain and dementia. Because the release of pro-nerve growth factor (pro-NGF) is activity-dependent and is controlled by basal forebrain projections to the hippocampus and cortex, our hypothesis is that AChE inhibitors act by increasing acetylcholine-dependent pro-NGF release and, thus, augmenting the availability of mature NGF and improving basal forebrain survival. If correct, improved central nervous system-selective AChE inhibitor therapy started prophylactically, before AD-associated basal forebrain atrophy and cognitive impairment onset, has the potential to delay not only the onset of dementia but also its rate of advancement. The phospho-tau hypothesis thus suggests that preventing hyperphosphorylation of tau protein, early should be a high priority as a strategy to help reduce dementia and its associated widespread social and economic suffering.