Miracle-dz/UniFAR-FTUs huggingface dataset:
Interactions between systemic diseases and oral microbiota shifts in the aging community: A narrative review

As a gateway to general health and a diverse microbial habitat, the oral cavity is colonized by numerous microorganisms such as bacteria, fungi, viruses, and archaea. Oral microbiota plays an essential role in preserving oral health. Besides, the oral cavity also significantly contributes to systemic health. Physiological aging influences all body systems, including the oral microbial inhabitants. The cited effect can cause diseases by forming dysbiotic communities. Since it has been demonstrated that microbial dysbiosis could disturb the symbiosis state between the host and the resident microorganism, shifting the condition toward a more pathogenic one, this study investigated how the oral microbial shifts in aging could associate with the development or progression of systemic diseases in older adults. The current study focused on the interactions between variations in the oral microbiome and prevalent diseases in older adults, including diabetes mellitus, Sjögren's syndrome, rheumatoid arthritis, pulmonary diseases, cardiovascular diseases, oral candidiasis, Parkinson's disease, Alzheimer's disease, and glaucoma. Underlying diseases can dynamically modify the oral ecology and the composition of its resident oral microbiome. Clinical, experimental, and epidemiological research suggests the associations of systemic disorders with bacteremia and inflammation after oral microbial changes in older adults.
Metformin attenuates white matter injury and cognitive impairment induced by chronic cerebral hypoperfusion

Vascular cognitive impairment and dementia (VCID) is a series of cognitive dysfunction associated with cerebrovascular diseases and currently lacks effective treatments. The white matter, which is essential for neuronal information processing and integration, is nourished by a network of capillaries and is vulnerable to chronic hypoperfusion. Here, we show that metformin, a widely used drug for the treatment of type 2 diabetes, alleviates the white matter damage and improves cognitive impairment in a mouse model of VCID established by bilateral carotid artery stenosis (BCAS)-induced chronic hypoperfusion. Mechanistically, metformin restores the dysfunctions of oligodendrocyte precursor cells (OPCs) under hypoxia. Metformin up-regulates prolyl hydroxylases 2 via activating the AMP-activated protein kinase pathway, leading to hypoxia-inducible factor-1α (HIF-1α) degradation in OPCs. These findings suggest that metformin may have a promising therapeutic role in alleviating cognitive abnormalities by ameliorating white matter damage of VCID.
Do different exosome biogenesis pathways and selective cargo enrichment contribute to exosomal heterogeneity?

Exosomes are emerging intercellular communicators essential for cellular homeostasis during development and differentiation. The dysregulation in exosome‐mediated communication alters cellular networking leads to developmental defects and chronic diseases. Exosomes are heterogeneous in nature depending on differences in size, membrane protein abundance, and differential cargo load. In this review, we have highlighted the latest developments in exosome biogenesis pathways, heterogeneity, and selective enrichment of various exosomal cargoes including proteins, nucleic acids, and mitochondrial DNA. Furthermore, the recent developments in the isolation techniques of exosome subpopulations have also been discussed. The comprehensive knowledge of extracellular vesicle (EV) heterogeneity and selective cargo enrichment during specific pathology may provide a clue for disease severity and early prognosis possibilities. The release of specific exosome subtypes is associated with the progression of specific disease type and hence a probable tool for therapeutics and biomarker development.
Transcription-Driven Translocation of Cohesive and Non-Cohesive Cohesin In Vivo

Abstract Cohesin is a central architectural element of chromosomes that regulates numerous DNA-based events. The complex holds sister chromatids together until anaphase onset and organizes individual chromosomal DNAs into loops and self-associating domains. Purified cohesin diffuses along DNA in an ATP-independent manner but can be propelled by transcribing RNA polymerase. In conjunction with a cofactor, the complex also extrudes DNA loops in an ATP-dependent manner. In this study we examine transcription-driven translocation of cohesin under various conditions in yeast. To this end, obstacles of increasing size were tethered to DNA to act as roadblocks to complexes mobilized by an inducible gene. The obstacles were built from a GFP-lacI core fused to one or more mCherries. A chimera with four mCherries blocked cohesin passage in late G1. During M phase, the threshold barrier depended on the state of cohesion: non-cohesive complexes were also blocked by four mCherries whereas cohesive complexes were blocked by as few as three mCherries. Furthermore cohesive complexes that were stalled at obstacles, in turn, blocked the passage of non-cohesive complexes. That synthetic barriers capture mobilized cohesin demonstrates that transcription-driven complexes translocate processively in vivo. Together, this study reveals unexplored limitations to cohesin movement on chromosomes.
Attitudes, beliefs and social norms regarding infant and young child feeding among Nigerian mothers, fathers and grandmothers across time

Abstract Infant and young child feeding (IYCF) interventions in low‐resource countries mainly target pregnant women and mothers of young children; however, fathers and grandmothers also influence IYCF practices. We conducted focus group discussions with mothers, fathers and grandmothers of young children across three time points in areas where an IYCF social and behaviour change intervention was implemented in Nigeria to explore differences by participant type and shifts over time in attitudes, beliefs and social norms related to breastfeeding and dietary diversity (DD). Overall, across time points, we found more discrepancies in attitudes, beliefs and social norms for early initiation of breastfeeding (EIBF) and exclusive breastfeeding (EBF) among different participant types than for DD. Although most participants agreed EIBF and EBF are good practices, mothers believed this more strongly than fathers and grandmothers; however, at endline, a shift towards acceptance of EIBF and EBF appeared among fathers and grandmothers. Across time points, all participant types acknowledged the nutritional and health benefits of green leafy vegetables and animal‐source foods but described various barriers to feeding them to children. Across time points, all participant types also highlighted the importance of health workers and antenatal visits as important sources of IYCF knowledge and facilitators to following recommended practices. Insights from this study highlight the importance of including key influencers of IYCF practices in qualitative research.
Galois Martingales and the Hyperbolic Subset of the p-adic Mandelbrot Set

in Knoxville and in Berea, Kentucky, he set out for New England to attend Amherst College in Amherst, Massachusetts. During the summers he worked on a research project with professor Jan Pearce of Berea College, initially responding " anything but number theory " when asked what he wanted to work on. After receiving a Bachelor's Degree in Mathematics and French from Amherst in 1998, he headed to Paris, France, to spend a very enjoyable year as a visiting student at the Ecole Normale Superieure in Paris. With his French well-honed, he returned to the U.S. to begin graduate studies in math at Brown University. There, he received his Master's Degree in 2001. By this time his views on number theory had evidently softened, as he embarked on a thesis in that area under the supervision of Joseph Silverman. In the course of his studies at Brown, he has been supported by a University Fellowship, several Teaching Assistantships and Fellowships, and a Dissertation Fellowship. v vi Acknowledgements The completion of this thesis owes much to the many people who have supported and encouraged me during its preparation. First and foremost, I would like to thank my advisor, Joseph Silverman. His wealth of knowledge and keen insight were instrumental both in helping me find a good problem and then solve it. Just as important were his good humor, vast patience, and clear explanations, which never failed to leave me inspired after our weekly meetings. Thanks, Joe, for being so generous with your time, your enthusiasm, and your good humor. I'm also grateful to my readers, Mike Rosen and Jill Pipher. Special thanks goes to Mike Rosen, who had many helpful discussions with me on various aspects of my thesis. Thanks also go to Sinha, all the Mikes, and the many other grad students and postdocs at Brown who've shared their knowledge and many good times. Particular thanks go to Aaron Hoffman, who first tipped me off about the existence of martingales during a post-basketball-game conversation. And hearty thanks too to Natalie Johnson, Doreen Pappas, and Audrey Aguiar, who have bailed me out of all manner of logistical jams over the years. Thank you also to Heinrich Hock and Matthias Vom Hau, my housemates and good friends for the past five years. I will dearly miss living at 440 Wayland Ave. I would be remiss not to mention the two most important mentors …
A Psychometric Evaluation of the Expanded Version of the Inventory of Depression and Anxiety Symptoms (IDAS-II) in Children and Adolescents

The expanded version of the Inventory of Depression and Anxiety Symptoms (IDAS-II) is a self-report measure of 18 empirically derived internalizing symptom dimensions. The measure has shown good psychometric properties in adults but has never been evaluated in children and adolescents. A Swedish version of the IDAS-II was administered to 633 children and adolescents (Mage =16.6 [SD = 2.0]) and 203 adults (Mage = 35.4 [SD = 12.1]). The model/data fit of the 18-factor structure was excellent in both samples and measurement invariance across age groups was supported. All scales showed good to excellent internal consistency and psychometric properties replicated in the younger youth sample (< 16 years). Among youth, good convergent validity was established for all scales and divergent validity for most scales. The IDAS-II was better at identifying youth with current mental health problems than an internationally recommended scale of internalizing symptoms. In conclusion, the IDAS-II shows promise as a measure of internalizing symptoms in youth.
Denosumab Treatment Does Not Halt Progression of Bone Lesions in Multicentric Carpotarsal Osteolysis Syndrome

Here we report the use of denosumab, a monoclonal antibody against receptor activator of nuclear factor κB ligand (RANKL), as monotherapy for multicentric carpotarsal osteolysis syndrome (MCTO) in an 11.5‐year‐old male with a heterozygous missense mutation in MAFB (c.206C>T; p.Ser69Leu). We treated the subject with 0.5 mg/kg denosumab every 60–90 days for 47 months and monitored bone and mineral metabolism, kidney function, joint range of motion (ROM), and bone and joint morphology. Serum markers of bone turnover reduced rapidly, bone density increased, and renal function remained normal. Nevertheless, MCTO‐related osteolysis and joint immobility progressed during denosumab treatment. Symptomatic hypercalcemia and protracted hypercalciuria occurred during weaning and after discontinuation of denosumab and required treatment with zoledronate. When expressed in vitro, the c.206C>T; p.Ser69Leu variant had increased protein stability and produced greater transactivation of a luciferase reporter under the control of the PTH gene promoter than did wild‐type MafB. Based on our experience and that of others, denosumab does not appear to be efficacious for MCTO and carries a high risk of rebound hypercalcemia and/or hypercalciuria after drug discontinuation. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
Prefrontal Manifold Geometry Explains Reaction Time Variability

The stochastic drift-diffusion model proposes that the variability in reaction time is due to randomness during the accumulation of evidence until a decision threshold is reached. However, the neural mechanisms that explain both the randomness and implementation of the decision threshold in the model remain unclear. Here we address these questions using the dynamical systems approach to analyze primate frontal eye field activity and using microstimulation for causal manipulations. We built a mechanistic model in which signals associated with motor plans are bumped out of their attractor state by go-cue signals that emerge ∼60 ms after the go cue. The network then travels through a transition subspace towards a movement-initation subspace that emerges ∼35 ms before movement onset and implements the decision threshold. We postulate that the randomness in evidence accumulation, and hence in reaction times, is explained by the amplification of noise during movement preparation by the geometry of the frontal eye field manifold.
Preference Shifts During Multi-Attribute Value-Based Decisions

When choosing between options with multiple attributes, do we decide by integrating all of the attributes into a unified measure for comparison, or does the comparison occur at the level of each attribute, involving independent competitive processes that can dynamically influence each other? What happens when independent sensory features all carry information about the same decision factor, such as reward value? To investigate these questions, we asked human participants to perform a two-alternative forced choice task in which the reward value of a target was indicated by two independent visual attributes – its brightness (“bottom-up” feature) and its orientation (“top-down” feature). If decisions always occur after integration of both features, there should be no difference in the reaction time (RT) distribution regardless of the attribute combinations that drove the choice. Counter to that prediction, almost two-thirds of the participants exhibited RT differences that depended on the attribute combinations of given targets. The RT was shortest when both attributes were congruent or when the choice was based on the bottom-up feature, and longer when the attributes were in conflict (favoring opposite options), especially when choosing the option favored by the top-down feature. We also observed mid-reach changes-of-mind in a subset of conflict trials, mostly changing from the bottom-up to the top-down-favored target. These data suggest that multi-attribute value-based decisions are better explained by a distributed competition among different features than by a competition based on a single, integrated estimate of choice value. New & Noteworthy This study showed that during value-based decisions, humans do not always take all information about reward value into account to make their choice, but instead can “jump the gun” using partial information. In particular, when different sources of information were in conflict, early decisions were mostly based on fast bottom-up information, and sometimes followed by corrective changes-of-mind based on slower top-down information. Our results suggest that parallel decision processes occur among different information sources, as opposed to between a single integrated “common currency”.
Development and biophysical characterization of a humanized FSH–blocking monoclonal antibody therapeutic formulated at an ultra-high concentration

Highly concentrated antibody formulations are oftentimes required for subcutaneous, self-administered biologics. Here, we report the development of a unique formulation for our first-in-class FSH-blocking humanized antibody, MS-Hu6, which we propose to move to the clinic for osteoporosis, obesity, and Alzheimer’s disease. The studies were carried out using our Good Laboratory Practice (GLP) platform, compliant with the Code of Federal Regulations (Title 21, Part 58). We first used protein thermal shift, size exclusion chromatography, and dynamic light scattering to examine MS-Hu6 concentrations between 1 and 100 mg/mL. We found that thermal, monomeric, and colloidal stability of formulated MS-Hu6 was maintained at a concentration of 100 mg/mL. The addition of the antioxidant L-methionine and chelating agent disodium EDTA improved the formulation’s long-term colloidal and thermal stability. Thermal stability was further confirmed by Nano differential scanning calorimetry (DSC). Physiochemical properties of formulated MS-Hu6, including viscosity, turbidity, and clarity, confirmed with acceptable industry standards. That the structural integrity of MS-Hu6 in formulation was maintained was proven through Circular Dichroism (CD) and Fourier Transform Infrared (FTIR) Spectroscopy. Three rapid freeze–thaw cycles at –80 °C/25 °C or –80 °C/37 °C further revealed excellent thermal and colloidal stability. Furthermore, formulated MS-Hu6, particularly its Fab domain, displayed thermal and monomeric storage stability for more than 90 days at 4°C and 25°C. Finally, the unfolding temperature (Tm) for formulated MS-Hu6 increased by >4.80 °C upon binding to recombinant FSH, indicating highly specific ligand binding. Overall, we document the feasibility of developing a stable, manufacturable and transportable MS-Hu6 formulation at a ultra-high concentration at industry standards. The study should become a resource for developing biologic formulations in academic medical centers.
Generalized Estimating Equations and Gaussian Estimation in Longitudinal Data Analysis

In this dissertation, we first develop a Gaussian estimation procedure for the estimation of regression parameters in correlated (longitudinal) binary response data using working correlation matrix and compare this method with the GEE (generalized estimating equations) method and the weighted GEE method. A Newton-Raphson algorithm is derived for estimating the regression parameters from the Gaussian likelihood estimating equations for known correlation parameters. The correlation parameters of the working correlation matrix are estimated by the method of moments. Consistency properties of the estimators are discussed. A simulation comparison of efficiency of the Gaussian estimates and the GEE estimates of the regression parameters shows that the Gaussian estimates using the unstructured correlation matrix of the responses for a subject are, in general, more efficient than those by the other methods compared. The next best are the Gaussian estimates using the general autocorrelation structure. Two data sets are analyzed and a discussion is given. The main advantage of GEE is its asymptotic unbiased estimation of the marginal regression coefficients even if the correlation structure is misspecified. However, the technique requires that the sample size should be large. In this dissertation, two bias corrected GEE estimators of the regression parameters in longitudinal data are proposed when the sample size is small. Simulations show that the proposed methods do well in reducing bias and have, in general, higher efficiency than the GEE estimates. Two examples are analyzed and a discussion is given. The current GEE method focuses on the modeling of the working correlation matrix assuming a known variance function. However, Wang and Lin (2005) showed that
Copine-6 is a Ca2+ sensor for activity-induced AMPA receptor exocytosis

The recruitment of synaptic AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors underlies the strengthening of neuronal connectivity during learning and memory. This process is triggered by NMDA (N-methyl-D-aspartate) receptor-dependent postsynaptic Ca2+ influx. Synaptotagmin (Syt)-1 and −7 have been proposed as Ca2+-sensors for AMPA receptor exocytosis, but are functionally redundant. Here we identify a cytosolic C2 domain-containing Ca2+-binding protein Copine-6 that forms a complex with AMPA receptors. Loss of Copine-6 expression impairs activity-induced exocytosis of AMPA receptors in primary hippocampal neurons, which is rescued by wild-type Copine-6, but not Ca2+-binding mutants. In contrast, Copine-6 loss-of-function has no effects on steady-state expression or tetrodotoxin-induced synaptic upscaling of surface AMPA receptors. Loss of Syt-1/-7 significantly reduces Copine-6 protein expression. Interestingly, overexpression of wild-type Copine-6, but not the Ca2+-binding mutant, restores activity-dependent exocytosis of AMPA receptors in Syt-1/-7 double-knockdown neurons. We conclude that Copine-6 is a postsynaptic Ca2+-sensor that mediates AMPA receptor exocytosis during synaptic potentiation.
Lipid-anchored Proteasomes Control Membrane Protein Homeostasis

Protein degradation in eukaryotic cells is mainly carried out by the 26S proteasome, a macromolecular complex not only present in the cytosol and nucleus but also associated with various membranes. How proteasomes are anchored to the membrane and the biological meaning thereof have been largely unknown in higher organisms. Here we show that N-myristoylation of the Rpt2 subunit is a general mechanism for proteasome-membrane interaction. Loss of this modification in the Rpt2-G2A mutant cells leads to profound changes in the membrane-associated proteome, perturbs the endomembrane system and undermines critical cellular processes such as cell adhesion, endoplasmic reticulum-associated degradation (ERAD) and membrane protein trafficking. Rpt2G2A/G2A homozygous mutation is embryonic lethal in mice and is sufficient to abolish tumor growth in a nude mice xenograft model. These findings have defined an evolutionarily conserved mechanism for maintaining membrane protein homeostasis and underscored the significance of compartmentalized protein degradation by myristoyl-anchored proteasomes (MAPs) in health and disease.
Transcriptional changes consistent with altered neuronal differentiation, angiogenesis, and tumor plasticity induced in human subpallial telencephalic organoid-glioblastoma chimeras

Glioblastoma multiforme (GBM) is one of the most aggressive and therapy-resistant brain tumors prevalent in both adults and children. Despite extensive research to understand GBM pathology, it remains unclear how neural cells in the human brain interact with GBM cells to support their brain propagation and therapy resistance and whether GBM cells exert any influence on the properties of human neural cells. In this study, we co-culture human stem cell-derived subpallial telencephalic organoids with patient-derived proneural or mesenchymal GBM spheroids to investigate their reciprocal interactions. We show that both proneural and mesenchymal GBM spheroids readily fuse and propagate with human organoids, forming organoid-GBM chimeras, without the need for exogenous growth factors. GBM cells within the chimeras adapt by modulating gene expression profiles consistent with diminished proliferation, heightened hypoxia, increased angiogenesis, and proneural-to-mesenchymal transition in proneural GBM. Both proneural or mesenchymal GBMs also exert an impact on the properties of neural cells in the chimeras, leading to the suppression of neuronal genes and an upregulation expression of genes associated with hypoxia and angiogenesis. Collectively, this study identifies specific genes and molecular pathways that can be altered in GBM and neural cells by reciprocal interactions in a human developing brain-like environment for an increased understanding of GBM pathology and future therapy development.