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Conditions
Published in Sarah Bekaert, Women's Health, 2018
Kidney cyst – a round swelling in the kidney, with a very thin, clear wall, and usually filled with watery fluid. The kidney is composed of blood vessels which carry blood to tiny filters. Each filter is connected to a tube. There are about a million filter-and-tube units in each kidney. A cyst occurs when a single tube expands, often becoming quite large. The exact cause of the swelling of the tube is not known. Some cysts are normal, but there is a possibility that they can interfere with kidney function.
Recording Ion Channels in Cilia Membranes
Published in Jinghua Hu, Yong Yu, Polycystic Kidney Disease, 2019
Leo C.T. Ng, Amitabha Mukhopadhyay, Thuy N. Vien, Paul G. DeCaen
This section is a short primer on ciliopathy diseases. For those interested in a more in-depth review of ciliopathies and their disease mechanisms, we suggest reading reviews by Bisgrove and Yost26 and Oh and Katsanis.27 The importance of the primary cilia in human health is highlighted by more than 35 congenital diseases called “ciliopathies,” which impact the development of organ systems such as the kidney, brain, heart, and eye. While some defects may only affect one single organ, the majority impact multiple organs with a combination of common ciliopathic phenotypes. For example, Joubert syndrome and Joubert-related disorders are caused by variants in the genes encoding for cilia assembly components—such as centrosomal CEP120 and BBS proteins, and the ciliary GTPase ARL13B.28 These syndromic diseases primarily impact the development of the central nervous system but also have comorbidities which affect the renal and visual systems. In addition, dynein complexes are required for the coordinated and rhythmic motion of motile cilia and variants in these components result in impaired or immotile ciliary syndromes. For example, primary ciliary dyskinesis (PCD) is characterized by chronic respiratory tract infections and infertility because the cilia of airway epithelia and the sperm flagellum are immotile.29 Hydrocephalus is a common comorbidity in PCD patients. Here, the beating of motile ependymal cilia is uncoordinated, resulting in an accumulation of cerebrospinal fluid in the ventricles of the brain. Developmental defects are common among individuals with ciliopathies—such as polydactyly (extra digits on hands and toes) and situs inversus or totalis (incorrect positioning of body organs).27 However, the most common comorbidities shared by ciliopathies are polycystic kidney disease (PKD) and other renal defects but the reason for this is not known.30 The most prevalent form of PKD is the autosomal dominant form (ADPKD), a ciliopathy which is caused by gene variants in PKD1 and PKD2—which encode for two cilia-specific proteins polycystin-1 and polycystin-2, respectively.29 ADPKD a common monogenetic disorder (∼1:2000 people) characterized by kidney and liver cysts in adulthood. Embryonic knockout of both alleles of either PKD1 or PKD2 in mice causes renal disease in utero and results in embryonic death.31,32 Homozygous ablation of either gene in mature mice results in progressive kidney cyst formation and recapitulates the ADPKD phenotype found in humans.33,34 Importantly, gene variants which encode for downstream effectors of Ca2+ ciliary signaling are responsible for ciliopathies that share renal comorbidities. Thus, the significance of determining polycystin channel function and the impact of disease-causing variants will likely extend to other renal ciliopathies where localized ciliary Ca2+ dysregulation might be a shared disease-causing mechanism35,36 The ciliary patch clamp configurations discussed in Section 3.3 provides a direct measurement of cilia-localized ion channel biophysics in native and heterologous expression systems.
A patent review of cyclin-dependent kinase 7 (CDK7) inhibitors (2018-2022)
Published in Expert Opinion on Therapeutic Patents, 2023
Markéta Kovalová, Joseph Peter Baraka, Václav Mik, Radek Jorda, Lei Luo, Hao Shao, Vladimír Kryštof
Compound B2 (13) was a potent CDK7 inhibitor scaffold-hopped from YKL-5-124 [22]. The aminopyrazole moiety of YKL-5-124 was retained to maintain the hydrogen bonds with the hinge region and the benzoyl motif as the linker to attach the covalent warhead. A pyridine ring was introduced to form a hydrogen bond with Asn142. Molecular docking suggested that the modification of pyridine at C5 should be tolerated since there was enough space around this region. The iterative optimization of the substituents at the pyridine C5 position and the addition of the Michael acceptor moiety resulted in the most potent compound B2. It inhibited CDK7 with an IC50 value of 4 nM and showed over 100-fold selectivity over the CDKs tested. Compound B2 was further assessed for selectivity using a 51 kinase diversity panel, and nine of them were inhibited by more than 50% at 1 µM, especially GSK3β with 99% inhibition. B2 inhibited GSK3β with an IC50 of 148 nM and was 37-fold selective for CDK7 over GSK3β. Compound B2 had acceptable pharmacokinetic properties with a T1/2 of 3.44 h and good exposure after subcutaneous administration. B2 showed efficacy in an in vitro MDCK cyst model, an ex vivo embryonic kidney cyst model and an ADPKD mouse model with minimal toxicity.
A novel variant affecting the cytoplasmic tail of the FAT1 protocadherin causing coloboma and renal failure: A case report
Published in Ophthalmic Genetics, 2023
Emile R. Vieta-Ferrer, Ehsan Ullah, Delphine Blain, Julie A. Christensen, Carmen C. Brewer, James E. Balow, Aman George, Robert B. Hufnagel, Tiziana Cogliati, Brian P. Brooks
An audiology evaluation revealed a previously undocumented bilateral, asymmetrical, high frequency sensorineural hearing loss (SNHL). Spinal radiographs were normal. A kidney ultrasound found small kidneys (6 cm right, 7 cm left) with a left kidney cyst and a complex cyst or mass in the right kidney.