A Survey of Strategies to Modulate the Bone Morphogenetic Protein Signaling Pathway: Current and Future Perspectives.
Créateur:
Brookshire, B, Rosen, V., and Lowery, Jonathan W.
La description:
Bone morphogenetic proteins (BMPs) constitute the largest subdivision of the TGF-? family of ligands and are unequivocally involved in regulating stem cell behavior. Appropriate regulation of canonical BMP signaling is critical for the development and homeostasis of numerous human organ systems, as aberrations in the BMP pathway or its regulation are increasingly associated with diverse human pathologies. In this review, we provide a wide-perspective on strategies that increase or decrease BMP signaling. We briefly outline the current FDA-approved approaches, highlight emerging next-generation technologies, and postulate prospective avenues for future investigation. We also detail how activating other pathways may indirectly modulate BMP signaling, with a particular emphasis on the relationship between the BMP and Activin/TGF-? pathways.
Targeting amyloid precursor protein shuttling and processing - long before amyloid beta formation.
Créateur:
Arbor, Sage
La description:
<strong>Targeting early steps in amyloid-beta production:</strong> Alzheimer's disease (AD) has a long history as the “amyloid deposit” disorder. Many disorders are now known to be caused by protein ?-sheet misfolding and aggregation (<em>e.g</em>., Parkinson's disease: ?-synuclein; Huntington's disease: Huntingtin; spongiform encephalopathy: prion protein) (Rambaran and Serpell, 2008). Commonly, the family of amyloid mental disorders often have multiple aggregating proteins with most having one or two highlighted. For example in AD, amyloid beta (A?) extracellular aggregates in senile plaques (SP) are the most obvious postmortem observation along with intracellular tau tangles. However, AD patients often have accumulation of TDP43 and ?-synuclein (in Lewy bodies) (Josephs <em>et al.</em>, 2014). While reducing A? remains the main AD target, there has been a recent shift from targeting the late forming amyloid plaques, to earlier steps in production of A?. Recent work has suggested that small oligomers of A? could be the neurotoxic compounds with structures on the order of A? octomers forming pores in neuronal membranes causing cell death (Arbor <em>et al.</em>, 2016). Under this paradigm, the larger extracellular amyloid plaques could actually be neuroprotective <em>via</em> a mechanism of sequestering the more deleterious A? monomers. In addition to not being neurotoxic (wrong marker physically) the amyloid plaques present late in disease after neuronal death has occurred (wrong marker temporally). While the field continues to target the already existing A? in AD patients, the effort to target even the production of A? has been reinvigorated. Possible targets include the initial production of amyloid precursor protein (APP), APP insertion in membrane lipid rafts, APP shuttling to early endosome compartments, and processing of APP. The molecular pathways causing this shift away from targeting amyloid plaques as well as therapeutics will be the content of this perspective.
Declaração de direitos:
http://rightsstatements.org/vocab/InC/1.0/
La langue:
English
Identificateur:
10.4103/1673-5374.200800
Type:
Article
Mot-clé:
Alzheimer's disease, amyloid precursor protein, and amyloid beta
Thalattosuchian crocodylomorphs from the Sinemurian (Early Jurassic) of the UK
Créateur:
Young, M., Dufeau, David, Brusatte, S., Bowman, C., Cowgill, T., Schwab, J., Witmer, L., Herrera, Y., Katsamenis, O., Steel, L., and Rigby, M.
Related Url Tesim:
Availabale from the publisher: https://academic.oup.com/zoolinnean/article-abstract/201/3/zlae079/7713265?redirectedFrom=fulltext
La description:
Thalattosuchian crocodylomorphs were a ubiquitous component of shallow marine ecosystems during the Jurassic and Early Cretaceous. Alas, their origins remain a mystery. Here we describe three specimens from the Sinemurian (and possibly Early Pliensbachian) of the UK: a partial cranial rostrum, a series of cervical vertebrae, and two dorsal vertebrae adhered with matrix. These specimens are amongst the oldest known thalattosuchian fossils, with the partial cranial rostrum being the oldest known non-neothalattosuchian thalattosuchian. This partial cranial rostrum has a unique combination of rostral characters never seen before in any crocodylomorph, and helps to elucidate early thalattosuchian internal rostrum evolution, suggesting that the reduction in thalattosuchian paranasal sinuses was not related to either the reorganization of rostral neurovasculature seen in later diverging taxa or the increased cancellous bone microstructure. Based on our CT sample, a shift in cranial bone microstructure occurred in the Eoneustes + Metriorhynchidae subclade, one that coincided with the enlargement of the salt glands and decoupling of the external antorbital fenestra from the paranasal sinuses. Without extensive histological sampling we cannot determine whether the shift to an obligate aquatic lifestyle occurred prior to the evolution of Metriorhynchidae.
Declaração de direitos:
http://rightsstatements.org/vocab/InC/1.0/
La langue:
English
Éditeur:
Oxford University Press and The Linnean Society of London
Identificateur:
https://doi.org/10.1093/zoolinnean/zlae079 and zlae079
Type:
Article
Mot-clé:
Crocodylomorpha, Jurassic, Sinemurian, Systematics, and Thalattosuchia
Article in Press available from Publisher: https://www.clinicalkey.com/service/content/pdf/watermarked/1-s2.0-S0738399121001130.pdf?locale=en_US&searchIndex= and Available via PubMed: https://pubmed.ncbi.nlm.nih.gov/33602574/
La description:
I believe this article emphasizes how emotionally valuable receiving patients' trust is to the practicing physician. It also gives new insight into understanding the emotional loss a physician may experience when leaving private practice, even if they remain active in medicine. Finally, for those entering medicine, it explains the profound personal satisfaction they can experience from long term trusting relationships with patients.
Declaração de direitos:
http://rightsstatements.org/vocab/InC/1.0/
licença:
http://www.europeana.eu/portal/rights/rr-r.html
La langue:
English
Éditeur:
Elsevier
Identificateur:
PMID: 33602574 and DOI: https://doi.org/10.1016/j.pec.2021.02.015
Type:
Article
Mot-clé:
Private practice, Physician patient relationship, Retirement, and Trust
Therapeutic Strategies Targeting Pancreatic Islet β-Cell Proliferation, Regeneration, and Replacement
Créateur:
Goode, Roy A., Hum, Julia M., and Kalwat, M.
Related Url Tesim:
Available from the publisher: https://academic.oup.com/endo/article-abstract/164/1/bqac193/6836713 and Available from the library catalog: https://marianunivindianapolis.on.worldcat.org/oclc/9688508394
La description:
Diabetes results from insufficient insulin production by pancreatic islet β-cells or a loss of β-cells themselves. Restoration of regulated insulin production is a predominant goal of translational diabetes research. Here, we provide a brief overview of recent advances in the fields of β-cell proliferation, regeneration, and replacement. The discovery of therapeutic targets and associated small molecules has been enabled by improved understanding of β-cell development and cell cycle regulation, as well as advanced high-throughput screening methodologies. Important findings in β-cell transdifferentiation, neogenesis, and stem cell differentiation have nucleated multiple promising therapeutic strategies. In particular, clinical trials are underway using in vitro–generated β-like cells from human pluripotent stem cells. Significant challenges remain for each of these strategies, but continued support for efforts in these research areas will be critical for the generation of distinct diabetes therapies.
Declaração de direitos:
http://rightsstatements.org/vocab/InC/1.0/
La langue:
English
Éditeur:
Oxford University Press on behalf of the Endocrine Society
Whole exome sequencing and co-expression analysis identify an SCN1A variant that modifies pathogenicity in a family with genetic epilepsy and febrile seizures plus
Créateur:
Afawi, Z., Goldberg-Stern, H., Helbig, I., Hammer, M., Pendziwiat, M., Cumbay, Medhane, Johnstone, L., Pan, Y., and Cummins, T.
Related Url Tesim:
Available from the library catalog: https://marianunivindianapolis.on.worldcat.org/oclc/9507748739, Available from Pubmed: https://pubmed.ncbi.nlm.nih.gov/35592948/, and Available from the publisher: https://onlinelibrary.wiley.com/doi/10.1111/epi.17296
La description:
Objective: Family members carrying the same SCN1A variant often exhibit differences in the clinical severity of epilepsy. This variable expressivity suggests that other factors aside from the primary sodium channel variant influence the clinical manifestation. However, identifying such factors has proven challenging in humans.
Methods: We perform whole exome sequencing (WES) in a large family in which an SCN1A variant (p.K1372E) is segregating that is associated with a broad spectrum of phenotypes ranging from lack of epilepsy, to febrile seizures and absence seizures, to Dravet syndrome. We assessed the hypothesis that the severity of the SCN1A-related phenotype was affected by alternate alleles at a modifier locus (or loci).
Results: One of our top candidates identified by WES was a second variant in the SCN1A gene (p.L375S) that was shared exclusively by unaffected carriers of the K1372E allele. To test the hypothesized that L375S variant nullifies the loss-of-function effect of K1372E, we transiently expressed Nav1.1 carrying the two variants in HEK293T cells and compared their biophysical properties with the wild-type (WT) variant, and then co-expressed WT with K1372E or L375S with K1372E in equal quantity and tested the functional consequence. The data demonstrated that co-expression of the L375S and K1372E alleles reversed the loss-of-function property brought by the K1372E variant, whereas WT-K1372E co-expression remained partial loss-of-function.
Significance: These results support the hypothesis that L375S counteracts the loss-of-function effect of K1372E such that individuals carrying both alleles in trans do not present epilepsy-related symptoms. We demonstrate that monogenic epilepsies with wide expressivity can be modified by additional variants in the disease gene, providing a novel framework for the gene-phenotype relationship in genetic epilepsies.
Will the Traditional Physical Examination be Another Casualty of Covid 19?
Créateur:
Gelfman, Daniel M.
Related Url Tesim:
Available via the library catalog: https://marianunivindianapolis.on.worldcat.org/oclc/8700309614 and Available online via the publisher: https://www.amjmed.com/article/S0002-9343(20)31022-6/fulltext
Declaração de direitos:
http://rightsstatements.org/vocab/InC/1.0/
La langue:
English
Éditeur:
Alliance for Academic Internal Medicine
Identificateur:
S0002-9343(20)31022-6, https://doi.org/10.1016/j.amjmed.2020.10.026, and AJM 16058
Type:
Article
Mot-clé:
Point of Care Ultrasound, Medical Judgment, Medical Education, and Physical Examination