A new case of trisomy 5p

The trisomy 5p (5p13----p ter) was identified by G-banding in a proband girl, whose mother was a balanced translocation carrier 46, XX, t(5;8) (p13;p23). Based on the clinical and cytogenetic findings, previously published and our own, it is possible to define a particular phenotype associated with the dup (5p), including (5p13), or the complete short arm. Patients were of similar phenotype: mental retardation, macrocephaly, hypotonia, mongoloid eye slant, low-set ears, depressed nasal bridge, macroglossia, longer fingers, epicanthus, thick cheeks.     

Trisomy 5p. A case report and review

Trisomy 5p is a clinically discernable syndrome with characteristic clinical features. To date more than 40 patients with trisomy for various regions of short arm of chromosome 5 have been reported. Here we report a case with complete trisomy 5p and present a review of the literature.     

p21-Activated kinase 5: A pleiotropic kinase

The PAKs (p21-activated kinases) are highly conserved serine/threonine protein kinases which comprise six mammalian PAKs. PAK5 (p21-activated kinase 5) is the least understood member of PAKs that regulate many intracellular processes when they are stimulated by activated forms of the small GTPases Cdc42 and Rac. PAK5 takes an important part in multiple signal pathways in mammalian cells and controls a variety of cellular functions including cytoskeleton organization, cell motility and apoptosis. The main goal of this review is to describe the structure, mechanisms underlying its activity regulation, its role in apoptosis and the likely directions of further research.     

Only One 3′-Hydroxyl Group Of ppp 5′A 2′p 5′A 2′p 5′A(2–5A) is Required for Activation of the Mouse 2–5A-Dependent Endonuclease

Abstract

The 3′-hydroxyl groups of each of the adenosines of 2–5A triraer (ppp5′A2′p5′A2′p5′A) were sequentially replaced by hydrogen through a phosphotriester synthetic approach. Biochemical evaluation of these analogs led to the conclusion that only the 3′-hydroxy group of the second adenosine is required for activation of RNase L.     

A Convergent Regiospecific Synthesis of the Lariat-Trinucleotides and A2′p 5′G and A2′p 5′G 3′p 5′C from A O4-2-Nitrophenyl) -Uridine Building Block

Abstract

Total synthesis of title compounds 1_ and 2_ from a common intermediate 7 is reported using the phosphotriester-phosphiteamidite approach. Appropriate NMR evidence has been presented in support of the regiospecific synthesis of target molecules in addition to enzymatic analysis. Present work clearly shows that the NMR evidence is mandatory to establish the isomeric purity of branched RNA molecules; enzymatic or/and electrophoretic analysis alone as tools for confirmation of branched RNA structures can be misleading.     

Partial trisomy-5p

Summary Two sibs with partial trisomy-5p are reported. Their father is the carrier of a balanced translocation 46,XY,t(4q+;5p-). Twelve cases of partial trisomy-5p—including our two patients—have been reported. The most common abnormalities found were mental retardation, short stature, dolichocephaly, prominent nasal bridge, prognathism, seizures, hypotonia, ear abnormalities, increased ulnar loops on the fingertips, and cryptorchidism in affected males.     

Cysteine ubiquitination of PTS1 receptor Pex5p regulates Pex5p recycling

Pex5p is the cytosolic receptor for peroxisome matrix proteins with peroxisome-targeting signal (PTS) type 1 and shuttles between the cytosol and peroxisomes. Here, we show that Pex5p is ubiquitinated at the conserved cysteine(11) in a manner sensitive to dithiothreitol, in a form associated with peroxisomes. Pex5p with a mutation of the cysteine(11) to alanine, termed Pex5p-C11A, abrogates peroxisomal import of PTS1 and PTS2 proteins in wild-type cells. Pex5p-C11A is imported into peroxisomes but not exported, resulting in its accumulation in peroxisomes. These results suggest an essential role of the cysteine residue in the export of Pex5p. Furthermore, domain mapping indicates that N-terminal 158-amino-acid region of Pex5p-C11A, termed 158-CA, is sufficient for such dominant-negative activity by binding to membrane peroxin Pex14p via its two pentapeptide WXXXF/Y motifs. Stable expression of either Pex5p-C11A or 158-CA likewise inhibits the wild-type Pex5p import into peroxisomes, strongly suggesting that Pex5p-C11A exerts the dominant-negative effect at the translocation step via Pex14p. Taken together, these findings show that the cysteine(11) of Pex5p is indispensable for two distinct steps, its import and export. The Pex5p-C11A would be a useful tool for gaining a mechanistic insight into the matrix protein import into peroxisomes.     

A novel role for Cdc5p in DNA replication.

DNA replication initiates from specific chromosomal sites called origins, and in the budding yeast Saccharomyces cerevisiae these sites are occupied by the origin recognition complex (ORC). Dbf4p is proposed to play a role in targeting the G1/S kinase Cdc7p to initiation complexes late in G1. We report that Dbf4p may also recruit Cdc5p to origin complexes. Cdc5p is a member of the Polo family of kinases that is required for the completion of mitosis. Cdc5p and Cdc7p each interact with a distinct domain of Dbf4p. cdc5-1 mutants have a plasmid maintenance defect that can be suppressed by the addition of multiple origins. cdc5-1 orc2-1 double mutants are synthetically lethal. Levels of Cdc5p were found to be cell cycle regulated and peaked in G2/M. These results suggest a role for Cdc5p and possibly Polo-like kinases at origin complexes.     

Characterization of peroxisomal Pex5p from rat liver. Pex5p in the Pex5p-Pex14p membrane complex is a transmembrane protein

Pex5p is the receptor for the vast majority of peroxisomal matrix proteins. Here, we show that about 15% of rat liver Pex5p is found in the peroxisomal fraction representing 0.06% of total peroxisomal protein. This population of Pex5p displays all the characteristics of an intrinsic membrane protein. Protease protection assays indicate that this pool of Pex5p has domains exposed on both sides of the peroxisomal membrane. The strong interaction of Pex5p with the membrane of the organelle is not affected by mild protease treatment of intact organelles, conditions that result in the partial degradation of Pex13p. Cytosolic Pex5p is a monomeric protein. In contrast, virtually all peroxisomal Pex5p was found to be part of a stable 250-kDa protein assembly. This complex was isolated and shown to comprise just two subunits, Pex5p and Pex14p.     

miR-15a-5p和miR-16-5p在骨肉瘤组织中的表达分析

目的:使用microRNAs基因芯片及实时定量PCR法测定骨肉瘤组织中miR-15a-5p和miR-16-5p的相对表达含量,并与瘤旁组织对比,分析骨肉瘤细胞内miR-15a-5p和miR-16-5p的表达变化。方法:选取34例骨肉瘤组织蜡块样本,使用microRNAs基因芯片观察miR-15a-5p和miR-16-5p在骨肉瘤和瘤旁组织内的表达差异;实时定量PCR法测定骨肉瘤组织和瘤旁组织中miR-15a-5p和miR-16-5p的相对表达含量,并将两种结果对比分析。结果:microRNAs基因芯片结果显示,在骨肉瘤组织中,miR-15a-5p在肿瘤中的表达较瘤旁组织低1.79倍,miR-16-5p较瘤旁组织低1.62倍。实时定量PCR实验结果表明,miR-15a-5p和miR-16-5p表达较瘤旁组织降低,差异有统计学意义(P0.05)。经过统计学计算,miR-15a-5p在肿瘤中的表达较瘤旁组织低3.14倍,miR-16-5p较瘤旁组织低5.65倍。结论:在骨肉瘤中,miR-15a-5p和miR-16-5p表达含量降低,提示这两种microRNAs在骨肉瘤中可能做为抑癌因子存在。     

Decolorization of a variety of dyes by Aspergillus flavus A5p1

Bioprocess and Biosystems Engineering - Aspergillus flavus: fungal strain A5p1 is reported here to decolorize a variety of dyes under broad environmental conditions. For the 15 dyes tested, the...     

Yeast Trf5p is a nuclear poly(A) polymerase

Recent analyses have shown that the activity of the yeast nuclear exosome is stimulated by the Trf4p-Air1/2p-Mtr4p polyadenylation (TRAMP) complex. Here, we report that strains lacking the Rrp6p component of the nuclear exosome accumulate polyadenylated forms of many different ribosomal RNA precursors (pre-rRNAs). This polyadenylation is reduced in strains lacking either the poly(A) polymerase Trf4p or its close homologue Trf5p. In contrast, polyadenylation is enhanced by overexpression of Trf5p. Polyadenylation is also markedly increased in strains lacking the RNA helicase Mtr4p, indicating that it is required to couple poly(A) polymerase activity to degradation. Tandem affinity purification-tagged purified Trf5p showed polyadenylation activity in vitro, which was abolished by a double point mutation in the predicted catalytic site. Trf5p co-purified with Mtr4p and Air1p, indicating that it forms a complex, designated TRAMP5, that has functions that partially overlap with the TRAMP complex.     

MicroRNA-425-5p modulates osteoporosis by targeting annexin A2

The disease (COVID-19) novel coronavirus pandemic has so far infected millions resulting in the death of over a million people as of Oct 2020. More than 90% of those infected with COVID-19 show mild or no symptoms but the rest of the infected cases show severe symptoms resulting in significant mortality. Age has emerged as a major factor to predict the severity of the disease and mortality rates are significantly higher in elderly patients. Besides, patients with underlying conditions like Type 2 diabetes, cardiovascular diseases, hypertension, and cancer have an increased risk of severe disease and death due to COVID-19 infection. Obesity has emerged as a novel risk factor for hospitalization and death due to COVID-19. Several independent studies have observed that people with obesity are at a greater risk of severe disease and death due to COVID-19. Here we review the published data related to obesity and overweight to assess the possible risk and outcome in Covid-19 patients based on their body weight. Besides, we explore how the obese host provides a unique microenvironment for disease pathogenesis, resulting in increased severity of the disease and poor outcome.

     

A 24-Residue Peptide (p5), Derived from p35, the Cdk5 Neuronal Activator,Specifically Inhibits Cdk5-p25 Hyperactivity and Tau Hyperphosphorylation

The activity of Cdk5-p35 is tightly regulated in the developing and mature nervous system. Stress-induced cleavage of the activator p35 to p25 and a p10 N-terminal domain induces deregulated Cdk5 hyperactivity and perikaryal aggregations of hyperphosphorylated Tau and neurofilaments, pathogenic hallmarks in neurodegenerative diseases, such as Alzheimer disease and amyotrophic lateral sclerosis, respectively. Previously, we identified a 125-residue truncated fragment of p35 called CIP that effectively and specifically inhibited Cdk5-p25 activity and Tau hyperphosphorylation induced by Aβ peptides in vitro, in HEK293 cells, and in neuronal cells. Although these results offer a possible therapeutic approach to those neurodegenerative diseases assumed to derive from Cdk5-p25 hyperactivity and/or Aβ induced pathology, CIP is too large for successful therapeutic regimens. To identify a smaller, more effective peptide, in this study we prepared a 24-residue peptide, p5, spanning CIP residues Lys²⁴⁵–Ala²⁷⁷. p5 more effectively inhibited Cdk5-p25 activity than did CIP in vitro. In neuron cells, p5 inhibited deregulated Cdk5-p25 activity but had no effect on the activity of endogenous Cdk5-p35 or on any related endogenous cyclin-dependent kinases in HEK293 cells. Specificity of p5 inhibition in cortical neurons may depend on the p10 domain in p35, which is absent in p25. Furthermore, we have demonstrated that p5 reduced Aβ(1–42)-induced Tau hyperphosphorylation and apoptosis in cortical neurons. These results suggest that p5 peptide may be a unique and useful candidate for therapeutic studies of certain neurodegenerative diseases.     

The regulation of cyclin-dependent kinase 5 activity through the metabolism of p35 or p39 Cdk5 activator

Cyclin-dependent kinase 5 (Cdk5) displays kinase activity predominantly in post-mitotic neurons and its physiological roles are unrelated to cell cycle progression. Cdk5 is activated by its binding to a neuron-specific activator, p35 or p39. The protein amount of p35 or p39 is a primary determinant of the Cdk5 activity in neurons, with the amount of p35 or p39 being determined by its synthesis and degradation. The expression of p35 is induced in differentiated neurons and is enhanced by extracellular stimuli such as neurotrophic factors or extracellular matrix molecules, specifically those acting on the ERK/Erg pathway. p35 is a short-lived protein and its degradation determines the life span. Degradation is mediated by the ubiquitin/proteasome system, similar to that for cyclins in proliferating cells. Autophosphorylation of p35 by Cdk5 is a signal for ubiquitination/degradation, and the degradation of p35 is triggered by glutamate treatment in cultured neurons. p35 is cleaved to p25 by calpain at the time of neuronal cell death, and this limited cleavage is suggested to be the cause of neurodegenerative diseases such as Alzheimer's disease. Active Cdk5 changes the cellular localization by cleavage of p35 to p25; p35/Cdk5 is associated with membrane or cytoskeletons, but p25/Cdk5 is a soluble protein. Cleavage also increases the life span of p25 and changes the activity or substrate specificity of Cdk5. p25/Cdk5 shows higher phosphorylating activity to tau than p35/Cdk5 in a phosphorylation site-specific manner. Phosphorylation of p35 suppresses cleavage by calpain. Thus, phosphorylation of p35 modulates its proteolytic pattern, stimulates proteasomal degradation and suppresses calpain cleavage. Phosphorylation is age dependent, as p35 is phosphorylated in foetal brains, but unphosphorylated in adult brains. Therefore, foetal phosphorylated p35 is turned over rapidly, whereas adult unphosphorylated p35 has a long life and is easily cleaved to p25 when calpain is activated. p39 is also a short-lived protein and cleaved to the N-terminal truncation form of p29 by calpain. How the metabolism of p39 is regulated, however, is a future problem to be investigated.     

CDK5 activator p35 downregulates E-cadherin precursor independently of CDK5

Dysfunction of E-cadherins often results in metastasis of cancerous cells. Here we show that p35, a critical regulator of cyclin-dependent kinase 5 (CDK5), specifically depletes the precursor form of E-cadherin, but not the mature form, by using a precursor-specific antibody. Most intriguingly, this downregulation of precursor E-cadherin by p35 is unequivocally independent of CDK5. Moreover, we found that p35 forms complexes with E-cadherin proteins. We also found that p35 co-expression can target E-cadherin to lysosomes and that p35-triggered disappearance of E-cadherin precursor can be blocked specifically by lysosomal protease inhibitors, indicating that p35 induces endocytosis and subsequent degradation of precursor E-cadherin.