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Biomedicine & Pharmacotherapy =... Sep 2023The pleckstrin homology [PH] domain is a structural fold found in more than 250 proteins making it the 11th most common domain in the human proteome. 25% of family... (Review)
Review
The pleckstrin homology [PH] domain is a structural fold found in more than 250 proteins making it the 11th most common domain in the human proteome. 25% of family members have more than one PH domain and some PH domains are split by one, or several other, protein domains although still folding to give functioning PH domains. We review mechanisms of PH domain activity, the role PH domain mutation plays in human disease including cancer, hyperproliferation, neurodegeneration, inflammation, and infection, and discuss pharmacotherapeutic approaches to regulate PH domain activity for the treatment of human disease. Almost half PH domain family members bind phosphatidylinositols [PIs] that attach the host protein to cell membranes where they interact with other membrane proteins to give signaling complexes or cytoskeleton scaffold platforms. A PH domain in its native state may fold over other protein domains thereby preventing substrate access to a catalytic site or binding with other proteins. The resulting autoinhibition can be released by PI binding to the PH domain, or by protein phosphorylation thus providing fine tuning of the cellular control of PH domain protein activity. For many years the PH domain was thought to be undruggable until high-resolution structures of human PH domains allowed structure-based design of novel inhibitors that selectively bind the PH domain. Allosteric inhibitors of the Akt1 PH domain have already been tested in cancer patients and for proteus syndrome, with several other PH domain inhibitors in preclinical development for treatment of other human diseases.
Topics: Humans; Pleckstrin Homology Domains; Binding Sites; Blood Proteins; Phosphoproteins; Protein Binding
PubMed: 37399719
DOI: 10.1016/j.biopha.2023.115024 -
Frontiers in Psychiatry 2023The M50 electrophysiological auditory evoked response time can be measured at the superior temporal gyrus with magnetoencephalography (MEG) and its latency is related to...
INTRODUCTION
The M50 electrophysiological auditory evoked response time can be measured at the superior temporal gyrus with magnetoencephalography (MEG) and its latency is related to the conduction velocity of auditory input passing from ear to auditory cortex. In children with autism spectrum disorder (ASD) and certain genetic disorders such as XYY syndrome, the auditory M50 latency has been observed to be elongated (slowed).
METHODS
The goal of this study is to use neuroimaging (diffusion MR and GABA MRS) measures to predict auditory conduction velocity in typically developing (TD) children and children with autism ASD and XYY syndrome.
RESULTS
Non-linear TD support vector regression modeling methods accounted for considerably more M50 latency variance than linear models, likely due to the non-linear dependence on neuroimaging factors such as GABA MRS. While SVR models accounted for ~80% of the M50 latency variance in TD and the genetically homogenous XYY syndrome, a similar approach only accounted for ~20% of the M50 latency variance in ASD, implicating the insufficiency of diffusion MR, GABA MRS, and age factors alone. Biologically based stratification of ASD was performed by assessing the conformance of the ASD population to the TD SVR model and identifying a sub-population of children with unexpectedly long M50 latency.
DISCUSSION
Multimodal integration of neuroimaging data can help build a mechanistic understanding of brain connectivity. The unexplained M50 latency variance in ASD motivates future hypothesis generation and testing of other contributing biological factors.
PubMed: 37252131
DOI: 10.3389/fpsyt.2023.1057221 -
Clinical Medicine (London, England) May 2023
Topics: Humans; Urinary Tract Infections; Anti-Bacterial Agents; Syndrome
PubMed: 37236799
DOI: 10.7861/clinmed.2023-0132 -
Parasitology Research Jul 2023Blastocystis sp. is an enteric protistan parasite that affects individuals worldwide with gastrointestinal symptoms such as abdominal discomfort, diarrhea, and...
Blastocystis sp. is an enteric protistan parasite that affects individuals worldwide with gastrointestinal symptoms such as abdominal discomfort, diarrhea, and flatulence. However, its pathogenicity is controversial due to its presence among asymptomatic individuals. Blastocystis sp. subtype 3 (ST3) is the most prevalent subtype among humans that have been associated with irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis, and colorectal cancer. Axenization of the parasite has been shown to impede its growth thus revealing the importance of accompanying bacteria in ensuring Blastocystis sp. survival. This study aims to identify the influence of accompanying bacteria on the growth of Blastocystis sp. ST3. Blastocystis sp. cultures were treated with Meropenem, Vancomycin, and Amoxicillin-Clavulanic acid (Augmentin). Bacteria-containing supernatant of antibiotic-treated and control cultures were isolated and identified through 16 s rRNA sequencing. Morphological changes of antibiotic-treated Blastocystis sp. ST3 were also observed. The cultures treated with meropenem and augmentin exhibited opposing effects with reduced growth of isolates from symptomatic patients and a significant increase in asymptomatic isolates. Whereas, vancomycin-treated cultures had no difference in the growth of Blastocystis sp. ST3 isolates from symptomatic and asymptomatic patients. Isolates from symptomatic and asymtomatic patients had 6 and 2 distinct bacterial species identified with Proteus mirabilis as the common bacteria among both types of isolates. Morphologically, Blastocystis sp. ST3 cultures exposed to meropenem and augmentin demonstrated an increase in pre-cystic forms. These findings demonstrate the effects of accompanying bacteria on the growth of Blastocystis sp. ST3 that could translate into clinical manifestations observed among Blastocystis sp.-infected patients.
Topics: Humans; Blastocystis; Blastocystis Infections; Vancomycin; Meropenem; Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Feces
PubMed: 37162590
DOI: 10.1007/s00436-023-07842-2 -
Proteus Syndrome: A Rare Disease Of Disproportionate And Asymmetric Overgrowth Of Connective Tissue.Journal of Ayub Medical College,... 2023Proteus syndrome is a rare disease manifested by progressive segmental overgrowth involving the skeletal, Cutaneous, subcutaneous, and nervous systems. We report the...
Proteus syndrome is a rare disease manifested by progressive segmental overgrowth involving the skeletal, Cutaneous, subcutaneous, and nervous systems. We report the case of a 24-year-old female who was born with no obvious abnormality at birth. From the age of 1 year, she developed asymmetric enlargement of her left upper limb and bilateral lower limbs leading to enlargement of the right-hand phalanges with radial deviation, enlargement of the right big toe, lateral deviation of left foot, and discrepancy in the length of lower extremities and kyphoscoliosis. She had become bed-bound for the last few years due to increasing disability. She was diagnosed with Proteus syndrome based on clinical features of progressive course, mosaic distribution, and sporadic occurrence of the lesions.
Topics: Humans; Infant, Newborn; Female; Young Adult; Adult; Proteus Syndrome; Rare Diseases; Hypertrophy; Lower Extremity; Connective Tissue
PubMed: 36849404
DOI: 10.55519/JAMC-01-11210 -
American Journal of Medical Genetics.... May 2023Proteus syndrome is an extremely rare overgrowth condition caused by a somatic variant of the AKT1 gene. It can involve multiple organ systems though rarely is there...
Proteus syndrome is an extremely rare overgrowth condition caused by a somatic variant of the AKT1 gene. It can involve multiple organ systems though rarely is there symptomatic cardiac involvement. Fatty infiltration of the myocardium has been described but has not been reported to cause functional or conduction abnormalities. We present an individual with Proteus syndrome who suffered a sudden cardiac arrest.
Topics: Humans; Adolescent; Proteus Syndrome; Arrhythmias, Cardiac; Tachycardia, Ventricular; Heart Arrest; Death, Sudden, Cardiac
PubMed: 36808868
DOI: 10.1002/ajmg.a.63151 -
Clinical Case Reports Feb 2023Proteus syndrome (PS) is a rare syndrome characterized by asymmetric limb overgrowth, vascular malformation, and hamartomas. In this study we report a case of PS in a...
Proteus syndrome (PS) is a rare syndrome characterized by asymmetric limb overgrowth, vascular malformation, and hamartomas. In this study we report a case of PS in a 13-year-old girl with chief complaint of a new cutaneous lesion that was diagnosed and treated as leishmaniasis.
PubMed: 36789301
DOI: 10.1002/ccr3.6929 -
Anais Brasileiros de Dermatologia 2023
Topics: Humans; Proteus Syndrome; Limb Deformities, Congenital; Fingers; Hypertrophy; Skin Diseases; Vascular Malformations
PubMed: 36754650
DOI: 10.1016/j.abd.2021.11.012