Miracle-dz/UniFAR-FTUs huggingface dataset:
Microglia heterogeneity in health and disease

Microglia, the resident immune cells of the central nervous system (CNS), have received significant attention due to their critical roles in maintaining brain homeostasis and mediating cerebral immune responses. Understanding the origin of microglia has been a subject of great interest, and emerging evidence suggests that microglia consist of multiple subpopulations with unique molecular and functional characteristics. These subpopulations of microglia may exhibit specialized roles in response to different environmental cues as in disease conditions. The newfound understanding of microglial heterogeneity has significant implications for elucidating their roles in both physiological and pathological conditions. In the context of disease, microglia have been studied rigorously as they play a very important role in neuroinflammation. Dysregulated microglial activation and function contribute to chronic inflammation. Further exploration of microglial heterogeneity and their interactions with other cell types in the CNS will undoubtedly pave the way to novel therapeutic strategies targeting microglia‐mediated pathologies. In this review, we discuss the latest advances in the field of microglia research, focusing specifically on the origin and subpopulations of microglia, the populations of microglia types in the brains of patients with neurodegenerative diseases, and how microglia are regulated in the healthy CNS.
The influence of Acetobacter pomorum bacteria on the developmental progression of Drosophila suzukii via gluconic acid secretion

Insects are rich in various microorganisms, which play diverse roles in affecting host biology. Although most Drosophila species prefer rotten fruits, the agricultural pest Drosophila suzukii attacks ripening fruits before they are harvested. We have reported that the microbiota has positive and negative impacts on the agricultural pest D. suzukii on nutrient‐poor and ‐rich diets, respectively. On nutrient‐poor diets, microbes provide protein to facilitate larval development. But how they impede D. suzukii development on nutrient‐rich diets is unknown. Here we report that Acetobacter pomorum (Apo), a commensal bacterium in many Drosophila species and rotting fruit, has several detrimental effects in D. suzukii. Feeding D. suzukii larvae nutrient‐rich diets containing live Apo significantly delayed larval development and reduced the body weight of emerged adults. Apo induced larval immune responses and downregulated genes of digestion and juvenile hormone metabolism. Knockdown of these genes in germ‐free larvae reproduced Apo‐like weakened phenotypes. Apo was confirmed to secrete substantial amounts of gluconic acid. Adding gluconic acid to the D. suzukii larval diet hindered larval growth and decreased adult body weight. Moreover, the dose of gluconic acid that adversely affected D. suzukii did not negatively affect Drosophila melanogaster, suggesting that D. suzukii is less tolerant to acid than D. melanogaster. Taken together, these findings indicate that D. suzukii is negatively affected by gluconic acid, which may explain why it prefers ripening fruit over Apo‐rich rotting fruit. These results show an insect's tolerance to microbes can influence its ecological niche.
Synergistic coupling between 3D bioprinting and vascularization strategies

Three-dimensional (3D) bioprinting offers promising solutions to the complex challenge of vascularization in biofabrication, thereby enhancing the prospects for clinical translation of engineered tissues and organs. While existing reviews have touched upon 3D bioprinting in vascularized tissue contexts, the current review offers a more holistic perspective, encompassing recent technical advancements and spanning the entire multistage bioprinting process, with a particular emphasis on vascularization. The synergy between 3D bioprinting and vascularization strategies is crucial, as 3D bioprinting can enable the creation of personalized, tissue-specific vascular network while the vascularization enhances tissue viability and function. The review starts by providing a comprehensive overview of the entire bioprinting process, spanning from pre-bioprinting stages to post-printing processing, including perfusion and maturation. Next, recent advancements in vascularization strategies that can be seamlessly integrated with bioprinting are discussed. Further, tissue-specific examples illustrating how these vascularization approaches are customized for diverse anatomical tissues towards enhancing clinical relevance are discussed. Finally, the underexplored intraoperative bioprinting (IOB) was highlighted, which enables the direct reconstruction of tissues within defect sites, stressing on the possible synergy shaped by combining IOB with vascularization strategies for improved regeneration.
Survival After Diagnosis of Esophageal Squamous Cell Carcinoma in Malawi

PURPOSE Esophageal cancer (EC) is the second most common cancer in Malawi, with esophageal squamous cell carcinoma (ESCC) representing >90% of all ECs. Despite significant morbidity and mortality, little is known about disease outcomes. In this study, we assess survival after ESCC diagnosis in Malawi. METHODS We report on ESCC cases enrolled in a case-control study at Kamuzu Central Hospital in Lilongwe from August 2017 to April 2020. Suspected cases completed a questionnaire interview; provided blood, urine, and saliva specimens; and underwent a tumor biopsy for histologic confirmation. Cases were followed up by phone biweekly from enrollment to the study end date (December 31, 2020), date of death, or loss to follow-up. Survival was assessed using Kaplan-Meier analysis with the log-rank test. We also examined associations between treatment and ESCC mortality using Cox regression models. RESULTS There were 300 patients with ESCC enrolled in this study, of whom 290 (97%) had known vital status at the end of follow-up and 10 (3%) were lost to follow-up. Among the 290 patients, 282 (97%) died during follow-up. The median age at enrollment was 55 years (IQR, 48-66), and the median time to death was 106 days (95% CI, 92 to 127). The 1-year, 2-year, and 3-year survival rates were 11% (95% CI, 8 to 15), 3% (95% CI, 1 to 6), and 0.9% (95% CI, 0.8 to 4), respectively. Palliative chemotherapy significantly improved the overall survival of patients with ESCC (Plog-rank = .038) and was significantly associated with reduced mortality (adjusted hazard ratio, 0.71 [95% CI, 0.51 to 0.99]). No significant association was observed between tobacco use, alcohol consumption, or HIV status and mortality. CONCLUSION Survival after diagnosis of ESCC was poor in Malawi. Although palliative chemotherapy was associated with improved survival, prevention and earlier detection remain key priorities to improve ESCC mortality at a population level.
Use of Primary Healthcare Among Chinese Older Adults With Functional Limitations

The aim of this study was to assess the factors associated with primary healthcare (PHC) utilization among older adults with functional limitations, providing insights for improving the effectiveness of PHC for this population. We used the China Health and Retirement Longitudinal Study (CHARLS) dataset, which encompasses 28 provinces in China. Logistic regression was used to analyze the people-related, care context-related, and linkage-related factors associated with PHC utilization. Approximately 55.61% of older adults with functional limitations utilized PHC in the past month, regardless of visit frequency or extent. Participants with lower educational attainment, those reporting more pain, and those living in rural areas had a higher likelihood of PHC utilization. Participants who received inpatient care in the past year had a lower likelihood of PHC utilization. We recommend that policymakers complement existing PHC health programs with increased health and social welfare support for this population.
Diagnostic imaging and the structure-function relationship in glaucoma

This thesis describes a series of investigations into the use of optic nerve head (ONH) imaging in primary open-angle glaucoma (POAG), and its relation to visual function. Accurate diagnosis is a key issue in POAG, particularly the difficult task of separating those with early disease from those healthy individuals who display signs of POAG. The purpose of this work is to improve diagnostic methods in glaucoma through use of ONH imaging and its relationship with visual field (VF) loss. First, the performance of a group of expert clinicians evaluating ONH photographs for glaucomatous damage was investigated. The results showed that even when their assessments are combined discrimination between eyes with and without POAG (based on VF loss) is far from perfect, highlighting the need for improvements in diagnosis. The possibility of combining structural and functional data to aid diagnosis was then considered. This requires VF loss and ONH damage to be strongly topographically related. The strength of this relationship was evaluated in 185 patients with POAG. 10,000 computer-generated maps between the ONH and VF were tested and the topographic relationship measured with each of these was compared to that using a published structure-based map. The weak topographic relationships found suggest that the application of these maps to individual patients is limited with current measures. The next chapter describes how a multispectral imaging (MSI, also called hyperspectral imaging) system was set-up for spatial evaluation of ONH oxygenation using a Beer-Lambert law model. Test-retest repeatability was tested and found to be acceptable for the purposes of the following studies. The MSI system was then used for an investigation of the relationship between ONH oxygenation and VF loss. 33 eyes of 18 patients underwent VF testing, MSI and HRT3 imaging. Superior-inferior asymmetries in VF sensitivity were compared to superior-inferior asymmetries in ONH oxygenation measured by MSI and in neuroretinal rim (NRR) area measured by HRT3. This way we take advantage of the typical progression of POAG and each eye acts as its own reference, negating the effect of a wide normal range and overlap between health and disease. This study found, for the first time, a strong association between ONH oxygenation and VF sensitivity. A re-analysis of the 33 ONH oxygenation maps was then performed to assess oxygenation only in the area of the NRR as defined by the HRT. Superior-inferior asymmetries in NRR oxygenation were then compared to superior-inferior asymmetries in VF loss, and the associations found were similarly strong. This study shows that MSI is capable of detecting areas of NRR deemed healthy tissue by structural imaging techniques, which are in fact poorly oxygenated and associated with VF defects. These findings show that NRR oxygenation measured by MSI is strongly related to VF loss. This important information complements existing technologies and may aid in the future diagnosis and management of patients with POAG.
The recent rapid expansion of multidrug resistant strains of Mycobacterium tuberculosis Ural lineage 4.2 in the Republic of Moldova

The projected trajectory of multidrug resistant tuberculosis (MDR-TB) epidemics depends on the reproductive fitness of circulating strains of MDR M. tuberculosis (Mtb). Previous efforts to characterize the fitness of MDR Mtb have found that Mtb strains of the Beijing sublineage (Lineage 2.2.1) may be more prone to develop resistance and retain fitness in the presence of resistance-conferring mutations than other lineages. Using Mtb genome sequences from all culture-positive cases collected over two years in Moldova, we estimate the fitness of Ural (Lineage 4.2) and Beijing strains, the two lineages in which MDR is concentrated in the country. We estimate that the fitness of MDR Ural strains substantially exceeds that of other susceptible and MDR strains, and we identify several mutations specific to these MDR Ural strains. Our findings suggest that MDR Ural Mtb has been transmitting efficiently in Moldova and poses a substantial risk of spreading further in the region.
Characterization of Per- and Polyfluoroalkyl Substance (PFAS) concentrations in a community-based sample of infants from Samoa

Per- and polyfluoroalkyl substances (PFAS) are persistent contaminants with documented harmful health effects. Despite increasing research, little attention has been given to studying PFAS contamination in low- and middle-income countries, including Samoa, where there is more recent modernization and potential window to examine earlier stages of PFAS exposure and consequences. Using data and biosamples collected through the Foafoaga o le Ola ("Beginning of Life") Study, which recruited a sample of mothers and infants from Samoa, we conducted an exploratory study to describe concentrations of 40 PFAS analytes in infant cord blood collected at birth (n=66) and dried blood spots (DBS) collected at 4 months post-birth (n=50). Of the 40 PFAS analytes tested, 19 were detected in cord blood, with 11 detected in >10% of samples (PFBA, PFPeA, PFHpA, PFOA, PFNA, PFDA, PFUnA, PFTrDA, PFHxS, PFOS, and 9Cl-PF3ONS); 12 analytes were detected in DBS, with 3 detected in >10% of samples (PFBA, PFHxS, and PFOS). PFAS concentrations were generally lower than those reported in existing literature, with the exception of PFHxS, which was detected at higher concentrations. In cord blood, we noted associations between higher PFHxS and male sex, higher PFPeA and residence in Northwest 'Upolu (NWU) compared to the Apia Urban Area (AUA), and lower PFUnA and 9Cl-PF3ONS with greater socioeconomic resources. In DBS, we found associations between higher PFBA and greater socioeconomic resources, and between lower PFBA and PFHxS and residence in NWU versus AUA. However, the latter association did not hold when controlling for socioeconomic resources. Finally, we observed associations between nutrition source at 4 months and DBS PFBA and PFHxS, with formula- or mixed-fed infants having higher concentrations compared to exclusively breastfed infants. This study presents the first evidence of PFAS contamination in Samoa. Additional work in larger samples is needed to identify potentially modifiable determinants of PFAS concentrations, information that is critical for informing environmental and health policy measures.
From initial RNA encoding to the Standard Genetic Code

Multiple prior experiments show that RNA binds chemically varied amino acids within specific oligonucleotide sequences. The smallest, simplest, and therefore most likely primitive RNA binding sites frequently contain conserved triplets corresponding to the Standard Genetic Code (SGC). Here, the implications of such cognate coding triplets are calculated, combining them with an optimized kinetic model for SGC evolution. RNA-amino acid interactions at obseved frequencies choose an SGC-like code, and, using the same mechanism, effectively resist alternative triplet assignments. Resistance to other kinds of coding is evident across varied code initiation scenarios. RNA-mediated assignments at experimental frequencies are sufficient to guide the ‘ribonucleopeotide (RNP) transition’ to a modern RNP code. This can account for extreme selection of the SGC among its astronomical code possibilities; very SGC-like codes are ca. 1/50 to 1/5 of codes within such a population. Nevertheless, full accounting depends on RNA affinities yet unmeasured. Such a code begins as mostly stereochemical, excludes mismatched assignments, and critically relies on properties characteristic of fusible microbes. After its RNP transition in a partially assigned code, evolution accelerates definitively. Other assignment methods (adaptation, co-evolution, revised stereochemistry, LGT) likely complete the modern SGC because stable cellular intermediates with > 1 code exist, allowing compartmental code exchanges. Though initiated using chemical affinities, the 83 order-of-magnitude focus required to find a near-complete SGC among all possible codes was made by sequential evolutionary anthologies, in successive biological settings.
Dissecting the neuronal mechanisms of invariant word recognition

Learning to read places a strong challenge on the visual system. Years of expertise lead to a remarkable capacity to separate highly similar letters and encode their relative positions, thus distinguishing words such as FORM and FROM invariantly over a large range of sizes and absolute positions. How neural circuits achieve invariant word recognition remains unknown. Here we address this issue through computational modeling and brain imaging. We first trained deep neural network models to recognize written words, then analyzed the reading-specialized units that emerged in deep layers. With literacy, units became sensitive to specific letter identities and their distance from the blank space at the left or right of a word, thus acting as “space bigrams” encoding ordinal position using an approximate number code. Using 7T functional MRI and magnetoencephalography in adults, we localized the predicted ordinal code anatomically (visual word form area) and temporally (∼220ms). The proposed neuronal mechanism for invariant word recognition can explain reading errors and makes precise predictions about how position-invariant neural codes arise in brains and artificial systems.
Energy in functional brain states correlates with cognition in adolescent schizophrenia and healthy persons

Adolescent-onset schizophrenia (AOS) is a relatively rare and under-studied form of schizophrenia with more severe cognitive impairments and poorer outcome compared to adult-onset schizophrenia. Several neuroimaging studies have reported alterations in regional activations that account for activity in individual regions (first-order model) and functional connectivity that reveals pairwise co-activations (second-order model) in AOS compared to controls. The pairwise maximum entropy model, also called the Ising model, can integrate both first-order and second-order terms to elucidate a comprehensive picture of neural dynamics and captures both individual and pairwise activity measures into a single quantity known as energy, which is inversely related to the probability of state occurrence. We applied the MEM framework to task functional MRI data collected on 23 AOS individuals in comparison with 53 healthy control subjects while performing the Penn Conditional Exclusion Test (PCET), which measures executive function that has been repeatedly shown to be more impaired in AOS compared to adult-onset schizophrenia. Accuracy of PCET performance was significantly reduced among AOS compared to controls as expected. Average cumulative energy achieved for a participant over the course of the fMRI negatively correlated with task performance, and the association was stronger than any first-order associations. The AOS subjects spent more time in higher energy states that represent lower probability of occurrence and were associated with impaired executive function suggesting that the neural dynamics may be less efficient compared to controls who spent more time in lower energy states occurring with higher probability and hence are more stable and efficient. The energy landscapes in both conditions featured attractors that corresponded to two distinct subnetworks, namely fronto-temporal and parieto-motor. Attractor basins were larger in the controls than in AOS; moreover, fronto-temporal basin size was significantly correlated with cognitive performance in controls but not among the AOS. The single trial trajectories for the AOS group also showed higher variability in concordance with shallow attractor basins among AOS. These findings suggest that the neural dynamics of AOS features more frequent occurrence of less probable states with narrower attractors, which lack the relation to executive function associated with attractors in control subjects suggesting a diminished capacity of AOS to generate task-effective brain states.
The Arabidopsis Information Resource in 2024

Since 1999, The Arabidopsis Information Resource (www.arabidopsis.org) has been curating data about the Arabidopsis thaliana genome. Its primary focus is integrating experimental gene function information from the peer-reviewed literature and codifying it as controlled vocabulary annotations. Our goal is to produce a ‘gold standard’ functional annotation set that reflects the current state of knowledge about the Arabidopsis genome. At the same time, the resource serves as a nexus for community-based collaborations aimed at improving data quality, access and reuse. For the past decade, our work has been made possible by subscriptions from our global user base. This update covers our ongoing biocuration work, some of our modernization efforts that contribute to the first major infrastructure overhaul since 2011, the introduction of JBrowse2, and the resource’s role in community activities such as organizing the structural reannotation of the genome. For gene function assessment, we used Gene Ontology annotations as a metric to evaluate: (1) what is currently known about Arabidopsis gene function, and (2) the set of ‘unknown’ genes. Currently, 74% of the proteome has been annotated to at least one Gene Ontology term. Of those loci, half have experimental support for at least one of the following aspects: molecular function, biological process, or cellular component. Our work sheds light on the genes for which we have not yet identified any published experimental data and have no functional annotation. Drawing attention to these unknown genes highlights knowledge gaps and potential sources of novel discoveries. Article Summary The Arabidopsis Information Resource (TAIR, www.arabidopsis.org) is a comprehensive website about Arabidopsis thaliana, a small plant that’s very easy to grow and analyze in the laboratory and is used to understand how many other plants function. We share our progress in data collection and organization, website and tool improvement, and our involvement in community projects.
CFL1-dependent dynamicity of surface ectoderm filopodia-like protrusions enhances neurulation zippering speed in mice

Progression of caudally-directed embryonic neural tube closure must exceed that of body axis elongation, otherwise closure is incomplete and neural tube defects arise. Genetic deletion and pharmacological antagonism studies establish the critical role of actomyosin regulation in this closure process in mice, but many models of impaired F-actin regulation are limited by early embryonic lethality, which precludes mechanistic insight in vivo. Here, we test the physiological functions of the F-actin severing protein CFL1 by selective deletion in various tissues of mouse embryos undergoing neural tube closure. Loss of CFL1 in the cranial neuroepithelium diminishes selective apical localisation of F-actin and produces dysmorphic, asymmetrical headfolds which fail to meet at the dorsal midline, causing exencephaly, with partial penetrance. During spinal neurulation, neuroepithelial CFL1 is dispensable, but its expression in the surface ectoderm enhances the dynamicity of filopodia-like protrusions involved in the zippering process of midline epithelial fusion. Compared with littermate controls, spinal zippering speed is decreased by 30% in embryos lacking surface ectoderm CFL1 and approximately 30% of embryos develop spina bifida. These findings suggest that molecular-level cytoskeletal regulation by CFL1 sets the cellular-level dynamicity of filopodial extensions which limit tissue-level zippering speed necessary to fully close the neural tube.