Miracle-dz/UniFAR-FTUs huggingface dataset:
Multi-parametric MRI can detect enhanced myelination in the Gli1-/- mouse brain

Purpose The ability of MRI-based markers to detect myelin in the brain is limited. This study investigated the potential of combining multiple MRI markers, each targeting distinct myelin properties, to improve myelin characterization. Methods We acquired ex vivo multiparametric MRI data at 7 Tesla from control and Gli1−/− mouse brains at postnatal day 10 (P10), which exhibits enhanced myelination in the corpus callosum, followed by myelin basic protein (MBP) stained immunohistochemistry. Results Although most MRI markers included in this study showed significant differences in the corpus callosum between control and Gli1−/−, only fractional anisotropy (FA), mean diffusivity (MD), and T2 had strong correlations with MBP signals. Partial least square regression (PSLR) based on MRI and MBP values from white matter regions suggested that T2 had the highest contributions to myelin estimation. When both white and gray matter regions were included, inhomogeneous MT ratio and FA showed strong contributions. Conclusion This study demonstrates the efficacy of multi-parametric MRI in detecting enhanced myelination in the Gli1-/- mouse brain. T2 and diffusion MRI parameters showed strong correlation with MBP signals in the genu of the corpus callosum at P10. The contribution of individual MRI parameter for detecting myelin can be evaluated using PLSR.
Epigenetic vulnerabilities of leukemia harboring inactivating EZH2 mutations

Epigenetic regulators such as the polycomb repressive complex 2 (PRC2) play a critical role in both normal development and carcinogenesis. Mutations and functional dysregulation of PRC2 complex components such as EZH2 are implicated in various forms of cancer and associated with poor prognosis. This study investigated the epigenetic vulnerabilities of acute myeloid leukemia (AML) and myelodysplastic/myeloproliferative disorders (MDS/MPN) by performing a chemical probe screen in patient cells. Paradoxically, we observed increased sensitivity to EZH2 and EED inhibitors in AML and MDS/MPN patient cells harboring EZH2 mutations. Expression analysis indicated that EZH2 inhibition elicited upregulation of pathways responsible for cell death and growth arrest, specifically in patient cells with mutant EZH2. The identified EZH2 mutations had drastically reduced catalytic activity, resulting in lower cellular H3K27me3 levels and were associated with decreased EZH2 and PRC2 component EED protein levels. Overall, this study provides an important understanding of the role of EZH2 dysregulation in blood cancers and may indicate disease etiology for these poor prognosis AML and MDS/MPN cases.
Chikungunya-virus-specific CD4+ T cells are associated with chronic chikungunya viral arthritic disease in humans

Chikungunya virus (CHIKV) is a mosquito-borne re-emerging viral infection that can cause chronic chikungunya viral arthritic disease (CHIKVD), which is characterized by incapacitating arthralgia and inflammation that can last for months to years following infection. Despite CHIKV outbreaks occurring worldwide and several vaccines currently in development, immune responses to CHIKV in humans remains largely understudied, and targets of T cell response are currently unknown. In this study, we tested peripheral blood mononuclear cells (PBMCs) collected from patients diagnosed with CHIKV infection during the 2014-2015 outbreak in Colombia against pools of overlapping peptides sequentially spanning each CHIKV protein. Using high-resolution flow cytometry, we detected robust CHIKV-specific CD4+, but not CD8+ T cell responses, in these patients. Patients still experiencing disease symptoms six years after infection displayed significantly stronger CHIKV- specific CD4+ T cell responses against nsP1, nsP2 and E2 proteins, compared to patients that resolved the infection. CHIKV-specific CD4+ T cells in symptomatic patients displayed a significantly lower Th1 CD4+ helper T cell responses and were enriched within the Th17 CD4+ helper subset, identifying tumor necrosis factor-alpha (TNFα) as the predominantly produced cytokine. In conclusion, this study comprehensively characterizes the T cell response against CHIKV in humans during the chronic phase and provides insights into the role of T cells and possible treatment of CHIKVD.
Volume Electron Microscopy Reveals Unique Laminar Synaptic Characteristics in the Human Entorhinal Cortex

The entorhinal cortex (EC) plays a pivotal role in memory function and spatial navigation, connecting the hippocampus with the neocortex. The EC integrates a wide range of cortical and subcortical inputs, but its synaptic organization in the human brain is largely unknown. We used volume electron microscopy to perform a 3D analysis of the synapses in all layers of the medial EC (MEC) from the human brain. Using this technology, 12,974 synapses were fully 3D reconstructed at the ultrastructural level. The MEC presented a distinct set of synaptic features, differentiating this region from other human cortical areas. Furthermore, synaptic organization within the MEC was predominantly homogeneous, although layers I and VI exhibited several synaptic characteristics that were distinct from other layers. The present study constitutes an extensive description of the synaptic organization of the neuropil of all layers of the EC, a crucial step to better understand the connectivity of this cortical region, in both health and disease. Significance Statement Analysis of the synaptic characteristics provides crucial data on cortical organization. However, synaptic organization data for the normal human brain is virtually non-existent. The present study analyzes synaptic characteristics of the human entorhinal cortex at the ultrastructural level. This brain region is essential for memory processes and spatial navigation, acting as an interface between sensory areas and the hippocampus. Moreover, the entorhinal cortex is one of the first regions affected by Alzheimer’s disease. The present results provide a large quantitative ultrastructural dataset of synapses in all layers of the entorhinal cortex using 3D electron microscopy. Our findings show remarkable uniformity in the synaptic characteristics. This may seem surprising given the cytoarchitectonic and innervation complexity of the medial entorhinal cortex.
Structure and mechanism of the human CTDNEP1-NEP1R1 membrane protein phosphatase complex necessary to maintain ER membrane morphology

C-terminal Domain Nuclear Envelope Phosphatase 1 (CTDNEP1) is a non-canonical protein serine/threonine phosphatase that regulates ER membrane biogenesis. Inactivating mutations in CTDNEP1 correlate with development of medulloblastoma, an aggressive childhood cancer. The transmembrane protein Nuclear Envelope Phosphatase 1 Regulatory Subunit 1 (NEP1R1) binds CTDNEP1, but the molecular details by which NEP1R1 regulates CTDNEP1 function are unclear. Here, we find that knockdown of CTDNEP1 or NEP1R1 in human cells generate identical phenotypes, establishing CTDNEP1-NEP1R1 as an evolutionarily conserved membrane protein phosphatase complex that restricts ER expansion. Mechanistically, NEP1R1 acts as an activating regulatory subunit that directly binds and increases the phosphatase activity of CTDNEP1. By defining a minimal NEP1R1 domain sufficient to activate CTDNEP1, we determine high resolution crystal structures of the CTDNEP1-NEP1R1 complex bound to a pseudo-substrate. Structurally, NEP1R1 engages CTDNEP1 at a site distant from the active site to stabilize and allosterically activate CTDNEP1. Substrate recognition is facilitated by a conserved Arg residue that binds and orients the substrate peptide in the active site. Together, this reveals mechanisms for how NEP1R1 regulates CTDNEP1 and explains how cancer-associated mutations inactivate CTDNEP1.
Glucose-fed microbiota alters intestinal epithelium and increases susceptibility to bacterial pathogens

Overconsumption of dietary sugar can lead to many negative health effects including the development of Type 2 diabetes, metabolic syndrome, cardiovascular disease, and neurodegenerative disorders. Recently, the human intestinal microbiota strongly associated with our overall health has also been known to be affected by diet. However, mechanistic insight into the importance of the human intestinal microbiota and the effects of chronic sugar ingestion has not been possible largely due to the complexity of the human microbiome which contains hundreds of types of organisms. Here, we use an interspecies C. elegans-E. coli system, where E. coli are subjected to high sugar, then consumed by the bacterivore host C. elegans to become the microbiota. This glucose-fed microbiota results in a significant lifespan reduction accompanied by reduced healthspan including locomotion, stress resistance, and changes in behavior and feeding. Lifespan reduction is also accompanied by two potential major contributors: increased intestinal bacterial density and increased reactive oxygen species. The glucose-fed microbiota accelerated the age-related development of intestinal cell permeability, intestinal distention, and dysregulation of immune effectors. Ultimately, the changes in the intestinal epithelium due to aging with the glucose fed microbiota results in increased susceptibility to multiple bacterial pathogens. Taken together, our data reveal that chronic ingestion of sugar such as a western diet has profound health effects on the host due to changes in the microbiota and may contribute to the current increased incidence of ailments including inflammatory bowel diseases as well as multiple age-related diseases.
Peripheral gating of pain by glial endozepine

We report that diazepam binding inhibitor (DBI) is a glial messenger mediating satellite glia-sensory neuron crosstalk in the dorsal root ganglion (DRG). DBI is highly and specifically expressed in satellite glia cells (SGCs) of mice, rat and human, but not in sensory neurons or other DRG-resident cells. Knockdown of DBI results in a robust mechanical hypersensitivity without significant effects on other sensory modalities. In vivo overexpression of DBI in SGCs reduces sensitivity to mechanical stimulation and alleviates mechanical allodynia in neuropathic and inflammatory pain models. We further show that DBI acts as a partial agonist and positive allosteric modulator at the neuronal GABAA receptors, particularly strongly effecting those with a high-affinity benzodiazepine binding site. Such receptors are selectively expressed by a subpopulation of mechanosensitive DRG neurons and these are also more enwrapped with DBI-expressing glia, as compared to other DRG neurons, suggesting a mechanism for specific effect of DBI on mechanosensation. These findings identified a new, peripheral neuron-glia communication mechanism modulating pain signalling, which can be targeted therapeutically.
FORAGING MECHANISMS IN EXCAVATE FLAGELLATES SHED NEW LIGHT ON THE FUNCTIONAL ECOLOGY OF EARLY EUKARYOTES

The phagotrophic flagellates described as ‘typical excavates’ have been hypothesized to be morphologically similar to the Last Eukaryotic Common Ancestor and understanding the functional ecology of excavates may therefore help shed light on the ecology of these early eukaryotes. Typical excavates are characterized by a posterior flagellum equipped with a vane that beats in a ventral groove. Here, we combined flow visualization and observations of prey capture in representatives of the three clades of excavates with computational fluid dynamic modelling, to understand the functional significance of this cell architecture. We record substantial differences amongst species in the orientation of the vane and the beat plane of the posterior flagellum. Clearance rate magnitudes estimated from flow visualization and modelling are like that of other similarly sized phagotrophic flagellates. The interaction between a vaned flagellum beating in a confinement is modelled to produce a very efficient feeding current at low energy costs, irrespective of the beat plane and vane orientation and of all other morphological variations. Given this predicted uniformity of function, we suggest that the foraging systems of typical excavates studied here may be good proxies to understand those potentially used by our distant ancestors more than 1 billion years ago. Significance Human sperm reminds us of our ancestry: flagellates, unicellular organisms equipped with a flagellum. The last common eukaryotic ancestor (LECA) was a flagellate. Phylogenetic analyses suggest that Excavates, an assemblage of flagellates, are the living organisms most similar to LECA. They have distinct characteristics in common: a ventral groove within which a vaned flagellum is beating. We show how the shared morphology and foraging behavior among 3 excavate clades is fluid dynamically efficient. A similar flagellar arrangement, potentially homologous to that found in the excavates, is found among flagellates from other deep branches of the eukaryotic tree, suggesting that the typical excavate foraging system studied here may have been used by our distant ancestors more than 1 billion years ago.
Two-dose “extended priming” immunization amplifies humoral immune responses by synchronizing vaccine delivery with the germinal center response

“Extended priming” immunization regimens that prolong exposure of the immune system to vaccines during the primary immune response have shown promise in enhancing humoral immune responses to a variety of subunit vaccines in preclinical models. We previously showed that escalating-dosing immunization (EDI), where a vaccine is dosed every other day in an increasing pattern over 2 weeks dramatically amplifies humoral immune responses. But such a dosing regimen is impractical for prophylactic vaccines. We hypothesized that simpler dosing regimens might replicate key elements of the immune response triggered by EDI. Here we explored “reduced ED” immunization regimens, assessing the impact of varying the number of injections, dose levels, and dosing intervals during EDI. Using a stabilized HIV Env trimer as a model antigen combined with a potent saponin adjuvant, we found that a two-shot extended-prime regimen consisting of immunization with 20% of a given vaccine dose followed by a second shot with the remaining 80% of the dose 7 days later resulted in increased total GC B cells, 5-10-fold increased frequencies of antigen-specific GC B cells, and 10-fold increases in serum antibody titers compared to single bolus immunization. Computational modeling of the GC response suggested that this enhanced response is mediated by antigen delivered in the second dose being captured more efficiently as immune complexes in follicles, predictions we verified experimentally. Our computational and experimental results also highlight how properly designed reduced ED protocols enhance activation and antigen loading of dendritic cells and activation of T helper cells to amplify humoral responses. These results suggest that a two-shot priming approach can be used to substantially enhance responses to subunit vaccines.
TPTU: Task Planning and Tool Usage of Large Language Model-based AI Agents

With recent advancements in natural language processing, Large Language Models (LLMs) have emerged as powerful tools for various real-world applications. Despite their prowess, the intrinsic generative abilities of LLMs may prove insufficient for handling complex tasks which necessitate a combination of task planning and the usage of external tools. In this paper, we first propose a structured framework tailored for LLM-based AI Agents and discuss the crucial capabilities necessary for tackling intricate problems. Within this framework, we design two distinct types of agents (i.e., one-step agent and sequential agent) to execute the inference process. Subsequently, we instantiate the framework using various LLMs and evaluate their Task Planning and Tool Usage (TPTU) abilities on typical tasks. By highlighting key findings and challenges, our goal is to provide a helpful resource for researchers and practitioners to leverage the power of LLMs in their AI applications. Our study emphasizes the substantial potential of these models, while also identifying areas that need more investigation and improvement.
19. RARE EARTH ELEMENTS IN NEOGENE SEDIMENTS, SITE 1014, TANNER BASIN, CALIFORNIA BORDERLANDS 1

Neogene sediments recovered over a continuous interval to a depth of 447 meters below seafloor at Site 1014, Tanner Basin, are dominantly calcareous nannofossils and foraminifers and siliciclastic clays. Their rare earth element composition, normalized to North American Shale Composite standard shale, shows a distribution pattern that closely mirrors that of modern seawater. With a distinct negative Ce anomaly and enhanced heavy rare earth elements over light rare earth elements, the field enclosing 48 different analyses (from Hole 1014A) spans a range of 37–109 ppm in total rare earth elements. Weathering and transportation from a terrestrial source contributed little to the rare earth element composition because the latter was mainly acquired during the course of organic matter production and sedimentation. Pore-water reactions and biogenically driven processes subsequently also contributed a diagenetic overprint.
CONSEQUENCES OF INDIVIDUAL DIFFERENCE IN MENTAL IMAGERY ABILITY

Previous work has suggested that individuals differ in mental imagery ability and the way in which they recruit and routinely engage in cognitive tasks that require mental imagery. The present study investigates what the consequences of these individual differences are. Specifically, we examined whether training individuals to engage in visual motion mental imagery may have effects in other cognitive tasks such as the comprehension of linguistic descriptions of motion. To test this, we utilized the motion aftereffect illusion to gain an implicit measure of visual motion imagery ability before and after two different training conditions (imagery training where people either did or did not have to attend to motion-related information). We also measured the motion aftereffect from language following training. To measure language comprehension, participants were given a surprise memory test for the stories that they heard in the linguistic aftereffect task. Participants showed a priming effect from language comprehension rather than an aftereffect. There did not appear to be a relationship between the size of the motion aftereffect from language and language comprehension in this sample. This research helps us to better understand the relationship between mental imagery and language comprehension.
Mobile Assisted Learning: Impact on Students’ Reading Comprehension and Belief

This study made an attempt to examine the effect of teaching students through mobile assisted language learning (MALL) on their reading comprehension performance and belief. In the study, 79 second year English language linear students in Gondar College of Teachers’ Education were taken as participants of the study comprehensively since their size was manageable. Among those, 40 of them were control group and 39 were experimental group. For this effect, the study used quasi-experimental research design. Data were collected via tests (pre and posttests) and questionnaire. The data collected using the pre and posttest were analyzed quantitatively using the independent samples t-test. The questionnaire data were analyzed quantitatively via frequency, percentage, mean and standard deviation. The results of the study divulged that MALL brought difference be-tween the experimental group (EG) and control group (CG). Particularly, with the help of the interventions provided the majority of the EG showed high level of progress in their reading comprehension performance and got affirmative belief towards the use of MALL in reading lessons. However, the CG remained constant. Based on the findings drawn, it was recommended that MALL should be practiced to maximize the students’ reading comprehension performance in EFL reading class-rooms.
A quality-assured dataset of nine radiation components observed at the Shangdianzi regional GAW station in China (2013–2022)

Abstract. The New Baseline Surface Radiation (NBSR) system was established at the Shangdianzi (SDZ) regional Global Atmosphere Watch (GAW) station in 2013 to observe nine broadband radiation components, i.e. the global, direct, diffuse, and upwelling shortwave irradiance (GSWI, DSWI, DifSWI, and UpSWI); the photosynthetically active radiation (PAR); the ultraviolet irradiance (UVAI and UVBI); and the down- and upwelling longwave irradiance (DnLWI and UpLWI). To test the 1 min raw radiometric data, a Hybrid Algorithm for Radiation Data Quality Control (HARDQC) is presented in this study based on well-established methods, together with the solar irradiance dataset and the spectral features of the instrument bands. Subsequently, a NBSR dataset, which consists of radiation data at multiple timescales (i.e. 1 min, hourly, daily, monthly, monthly average hourly, and monthly average daily) over 2013–2022, is established and evaluated. Results show that more than 98.7 % of all radiation components passed the physical possibility test. The percentages of those that passed the extremely rare test are greater than 98.6 % for all radiation components except for the DnLWI (97.1 %). The percentages of those that passed the comparison test are greater than 83.3 % (GSWI), 78.3 % (DSWI), 81.7 % (DifSWI), 93.1 % (UpSWI), 88.9 % (PAR), 95.6 % (UVAI), 96.3 % (UVBI), 99.8 % (DnLWI), and 99.7 % (UpLWI), respectively. Due to data logger faults, removal of the instruments for calibration, and lightning strikes, some apparent data gaps in the upwelling radiation components (January 2015–August 2017) and all radiation components (December 2018; July to September 2021) were detected. Despite the existence of a few imperfections in the NBSR dataset, it is still reliable to apply it in many fields such as the validation of satellite products and numerical models, the investigation of relationships between radiation and atmospheric composition, and the detection of changes in the surface fluxes. The dataset described in this paper is available at https://doi.org/10.1594/PANGAEA.963330 (Quan et al., 2023b).