Clinical Relevance and Mechanisms of Antagonism Between the BMP and Activin/TGF-β Signaling Pathways.

The transforming growth factor β (TGF-β) superfamily is a large group of signaling molecules that participate in embryogenesis, organogenesis, and tissue homeostasis. These molecules are present in all animal genomes. Dysfunction in the regulation or activity of this superfamily\u27s components underlies numerous human diseases and developmental defects. There are 2 distinct arms downstream of the TGF-β superfamily ligands-the bone morphogenetic protein (BMP) and activin/TGF-β signaling pathways-and these 2 responses can oppose one another\u27s effects, most notably in disease states. However, studies have commonly focused on a single arm of the TGF-β superfamily, and the antagonism between these pathways is unknown in most physiologic and pathologic contexts. In this review, the authors summarize the clinically relevant scenarios in which the BMP and activin/TGF-β pathways reportedly oppose one another and identify several molecular mechanisms proposed to mediate this interaction. Particular attention is paid to experimental findings that may be informative to human pathology to highlight potential therapeutic approaches for future investigation

Elucidating the Antagonistic Relationship Between Bone Morphogenetic Protein and Activin Signaling Pathways in Osteoprogenitor Cells

Osteoporosis is a disease characterized by low bone mineral density due to the rate of bone resorption exceeding that of bone formation. Substantial evidence indicates the Bone Morphogenetic Protein (BMP) pathway promotes bone formation through action of the effectors SMAD1/5/8 while the Activin pathway negatively influences bone mass through action of the effectors SMAD2/3. Recent studies from our lab suggest that BMP and Activin ligands regulate bone mass in a see-saw-like mechanism via competition for a shared pool of receptors, i.e. receptor-level competition. In the present study we seek to test this hypothesis in vitro via signaling responsiveness assays using pathway-specific western blot analyses in the osteogenic cell line W-20-17. We first confirmed that W-20-17 cells respond to exogenous stimulation by BMP2 and Activin-A. Then, we administered recombinant versions of naturally-occurring extracellular ligand traps for BMP2 or Activin ligands (Noggin and Follistatin, respectively) to examine basal antagonism between these pathways. This revealed that, under basal conditions, SMAD1/5/8 activation is repressed by Activin signaling; interestingly, the converse relationship was not observed. To determine the molecular mechanism allowing for this relationship, we treated W-20-17 cells with SB431542, which is an intracellular inhibitor of Activin signaling that functions downstream of receptor engagement, and found no effect on SMAD1/5/8 activation. Collectively, our results suggest Activin-mediated repression of BMP signaling is ligand-dependent but occurs upstream of SMAD2/3 activation. Current studies seek to identify the specific Activin ligand(s) responsible for this effect; gene expression analyses indicates that W-20-17 cells express multiple Activin subunits including Inhβa and Inhβb. Additionally, overpression studies are ongoing to determine if receptor-level competition is involved in mediating these effects. Collectively, our study seeks to elucidate the mechanism(s) that regulate antagonism BMP and Activin signaling pathways to identify novel opportunities for safer and more effective therapies for low bone mass in humans

Determining Factors for Parents to Choose a School: Empirical Analysis of Religious Based Private Schools

This study explores the factors influencing parental decision-making in choosing a school in the context of private, faith-based education. Using a quantitative descriptive and exploratory approach, this research investigates various factors shaping parents' interest in choosing a school. The population examined were parents of students attending private Christian schools, resulting in a purposive sample of 235 respondents. The sampling technique targets parents actively involved in the school community and has varying levels of involvement and perspectives on the school selection process. Data was collected through an online survey conducted between June and September 2023. Next, Confirmatory Factor Analysis (CFA) using SmartPLS was used for data analysis. This study identified eight factors influencing parental decision-making: teacher ability, school location, religious values, school facilities, school image, perceived costs, school environment, and school safety. The implications of these findings highlight the school's strategy to increase its attractiveness, thereby increasing school enrollment rates

Effects of sex chromosome dosage on corpus callosum morphology in supernumerary sex chromosome aneuploidies.

BackgroundSupernumerary sex chromosome aneuploidies (sSCA) are characterized by the presence of one or more additional sex chromosomes in an individual's karyotype; they affect around 1 in 400 individuals. Although there is high variability, each sSCA subtype has a characteristic set of cognitive and physical phenotypes. Here, we investigated the differences in the morphometry of the human corpus callosum (CC) between sex-matched controls 46,XY (N =99), 46,XX (N =93), and six unique sSCA karyotypes: 47,XYY (N =29), 47,XXY (N =58), 48,XXYY (N =20), 47,XXX (N =30), 48,XXXY (N =5), and 49,XXXXY (N =6).MethodsWe investigated CC morphometry using local and global area, local curvature of the CC boundary, and between-landmark distance analysis (BLDA). We hypothesized that CC morphometry would vary differentially along a proposed spectrum of Y:X chromosome ratio with supernumerary Y karyotypes having the largest CC areas and supernumerary X karyotypes having significantly smaller CC areas. To investigate this, we defined an sSCA spectrum based on a descending Y:X karyotype ratio: 47,XYY, 46,XY, 48,XXYY, 47,XXY, 48,XXXY, 49,XXXXY, 46,XX, 47,XXX. We similarly explored the effects of both X and Y chromosome numbers within sex. Results of shape-based metrics were analyzed using permutation tests consisting of 5,000 iterations.ResultsSeveral subregional areas, local curvature, and BLDs differed between groups. Moderate associations were found between area and curvature in relation to the spectrum and X and Y chromosome counts. BLD was strongly associated with X chromosome count in both male and female groups.ConclusionsOur results suggest that X- and Y-linked genes have differential effects on CC morphometry. To our knowledge, this is the first study to compare CC morphometry across these extremely rare groups

Calculating Milnor Numbers and Versal Component Dimensions from P-Resolution Fans

We use Altmann's toric fan description of P-resolutions to formulate a new description of deformation theory invariants for two-dimensional cyclic quotient singularities. In particular, we show how to calculate the dimensions of the (reduced) versal base space components as well as Milnor numbers of smoothings over them.Comment: 8 pages; 2 figures; v2 added section on Milnor numbers, reworked proof of dimension formula, new example, and new titl

Correlations of Online Search Engine Trends with Coronavirus Disease (COVID-19) Incidence: Infodemiology Study

Background: The coronavirus disease (COVID-19) is the latest pandemic of the digital age. With the internet harvesting large amounts of data from the general population in real time, public databases such as Google Trends (GT) and the Baidu Index (BI) can be an expedient tool to assist public health efforts. Objective: The aim of this study is to apply digital epidemiology to the current COVID-19 pandemic to determine the utility of providing adjunctive epidemiologic information on outbreaks of this disease and evaluate this methodology in the case of future pandemics. Methods: An epidemiologic time series analysis of online search trends relating to the COVID-19 pandemic was performed from January 9, 2020, to April 6, 2020. BI was used to obtain online search data for China, while GT was used for worldwide data, the countries of Italy and Spain, and the US states of New York and Washington. These data were compared to real-world confirmed cases and deaths of COVID-19. Chronologic patterns were assessed in relation to disease patterns, significant events, and media reports. Results: Worldwide search terms for shortness of breath, anosmia, dysgeusia and ageusia, headache, chest pain, and sneezing had strong correlations (r>0.60, P<.001) to both new daily confirmed cases and deaths from COVID-19. GT COVID-19 (search term) and GT coronavirus (virus) searches predated real-world confirmed cases by 12 days (r=0.85, SD 0.10 and r=0.76, SD 0.09, respectively, P<.001). Searches for symptoms of diarrhea, fever, shortness of breath, cough, nasal obstruction, and rhinorrhea all had a negative lag greater than 1 week compared to new daily cases, while searches for anosmia and dysgeusia peaked worldwide and in China with positive lags of 5 days and 6 weeks, respectively, corresponding with widespread media coverage of these symptoms in COVID-19. Conclusions: This study demonstrates the utility of digital epidemiology in providing helpful surveillance data of disease outbreaks like COVID-19. Although certain online search trends for this disease were influenced by media coverage, many search terms reflected clinical manifestations of the disease and showed strong correlations with real-world cases and deaths

SARS-CoV-2 Nasopharyngeal Swab Testing—False-Negative Results From a Pervasive Anatomical Misconception

This article is made available for unrestricted research re-use and secondary analysis in any form or be any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.Given our subspecialty focus on nasal anatomy, we have been involved in training personnel at our respective institutions on the proper techniques for NPS collection for SARS-CoV-2 testing, and we have noticed pervasive misperception about the location of the nasopharynx. Although many sites around the world are likely providing proper training, we are concerned that inadequate NPS collection may continue to lead to false-negative results. The rate of false-negative results in reverse transcriptase polymerase chain reaction testing is a great concern because it underestimates the prevalence of SARS-CoV-2 infection, gives a false sense of security to patients and the health care workers caring for them, and limits public health efforts in identifying and tracing the spread of the virus. We hope highlighting that the nasopharynx is back, not up, can help limit false-negative results in testing for SARS-CoV-2 and other respiratory viruses.Dr Higgins reported being a paid research investigator for Optinose and Gossamer and receiving personal fees from Sanofi-Regeneron and Genentech outside the submitted work. Dr Wu reported receiving payment for positions as a speaker for Sanofi-Regeneron and Optinose, a member of a medical advisory board for Optinose and Gossamer, and an investigator for Gossamer outside the submitted work. No other disclosures were reported

Kinetic Characterization of Salmonella FliK-FlhB Interactions Demonstrates Complexity of the Type III Secretion Substrate-Specificity Switch

The bacterial flagellum is a complex macromolecular machine consisting of more than 20000 proteins, most of which must be exported from the cell via a dedicated Type III secretion apparatus. At a defined point in flagellar morphogenesis, hook completion is sensed and the apparatus switches substrate specificity type from rod and hook proteins to filament ones. How the switch works is a subject of intense interest. FIiK and F1hBs play central roles. In the present study, two optical biosensing methods were used to characterize FIiK-F1hB interactions using wild-type and two variant FlhBs from mutants with severe flagellar structural defects. Binding was found to be complex with fast and slow association and dissociation components. Surprisingly, wild-type and variant FlhBs had similar kinetic profiles and apparent affinities, which ranged between I and 10.5 μM, suggesting that the specificity switch is more complex than presently understood. Other binding experiments provided evidence for a conformational change after binding. Liquid chromatography-mass spectrometry (LC-MS) and NMR experiments were performed to identify a cyclic intermediate product whose existence supports the mechanism of autocatalytic cleavage at FlhB residue N269. The present results show that while autocatalytic cleavage is necessary for proper substrate specificity switching, it does not result in an altered interaction with FIiK. strongly suggesting the involvement of other proteins in the mechanism

Development of the corpus callosum and cognition after neonatal encephalopathy

Objective: Neonatal imaging studies report corpus callosum abnormalities after neonatal hypoxic–ischaemic encephalopathy (HIE), but corpus callosum development and relation to cognition in childhood are unknown. Using magnetic resonance imaging (MRI), we examined the relationship between corpus callosum size, microstructure and cognitive and motor outcomes at early school-age children cooled for HIE (cases) without cerebral palsy compared to healthy, matched controls. A secondary aim was to examine the impact of HIE-related neonatal brain injury on corpus callosum size, microstructure and growth. Methods: Participants aged 6–8 years underwent MRI, the Movement Assessment Battery for Children Second Edition and Wechsler Intelligence Scale for Children Fourth Edition. Cross-sectional area, volume, fractional anisotropy and radial diffusivity of the corpus callosum and five subdivisions were measured. Multivariable regression was used to assess associations between total motor score, full-scale IQ (FSIQ) and imaging metrics. Results: Adjusting for age, sex and intracranial volume, cases (N = 40) compared to controls (N = 39) demonstrated reduced whole corpus callosum area (β = −26.9, 95% confidence interval [CI] = −53.17, −0.58), volume (β = −138.5, 95% CI = −267.54, −9.56), fractional anisotropy and increased radial diffusivity (P < 0.05) within segments II–V. In cases, segment V area (β = 0.18, 95% CI = 0.004, 0.35), volume (β = 0.04, 95% CI = 0.001, 0.079), whole corpus callosum fractional anisotropy (β = 13.8 95% CI = 0.6, 27.1) and radial diffusivity (β = −11.3, 95% CI = −22.22, −0.42) were associated with FSIQ. Growth of the corpus callosum was restricted in cases with a FSIQ ≤85, and volume was reduced in cases with mild neonatal multifocal injury compared to white matter injury alone. Interpretation: Following neonatal HIE, morphological and microstructural changes in the corpus callosum are associated with reduced cognitive function at early school age