2.A report of two families with sarcosinaemia in Hong Kong and revisiting the pathogenetic potential of hypersarcosinaemia.
Shing-Yan LEE ; Kwok-Yin CHAN ; Albert Y W CHAN ; Chi-Kong LAI
Annals of the Academy of Medicine, Singapore 2006;35(8):582-584
INTRODUCTIONSarcosinaemia is a rare metabolic disorder which has not been reported in Asia.
CLINICAL PICTUREThe urine samples of 2 patients were screened as a routine metabolic screening offered for patients with mental retardation in our hospital. We used gas chromatography-mass spectrometry (GC-MS) which is capable of detecting abnormal pattern in amino acids and organic acids. Plasma sarcosine level was further quantified by GC-MS. The same methods were used in the investigations of asymptomatic family members. Urine examination by GC-MS revealed excessive amount of sarcosine in urine (normally undetectable) and their plasma sarcosine levels were raised. The 2 differential diagnoses of presence of sarcosine in urine--glutaric aciduria type II and folate deficiency--were ruled out by the absence of abnormal organic acids in the initial urine screen and by normal serum folate level respectively. Screening of the 2 families identified excessive sarcosine in urine in 2 siblings, one from each family. However, these 2 siblings of indexed patients thus identified have no neurological or developmental problem.
CONCLUSIONOur finding was consistent with the notion that sarcosinaemia is a benign condition picked up coincidentally during screening for mental retardation.
Amino Acid Metabolism, Inborn Errors ; complications ; diagnosis ; Child ; Child, Preschool ; China ; ethnology ; Family Health ; Female ; Gas Chromatography-Mass Spectrometry ; Hong Kong ; Humans ; India ; ethnology ; Intellectual Disability ; complications ; Sarcosine ; blood ; urine ; Sarcosine Dehydrogenase ; deficiency
3.Flexible interwoven termini determine the thermal stability of thermosomes.
Kai ZHANG ; Li WANG ; Yanxin LIU ; Kwok-Yan CHAN ; Xiaoyun PANG ; Klaus SCHULTEN ; Zhiyang DONG ; Fei SUN
Protein & Cell 2013;4(6):432-444
Group II chaperonins, which assemble as double-ring complexes, assist in the refolding of nascent peptides or denatured proteins in an ATP-dependent manner. The molecular mechanism of group II chaperonin assembly and thermal stability is yet to be elucidated. Here, we selected the group II chaperonins (cpn-α and cpn-β), also called thermosomes, from Acidianus tengchongensis and investigated their assembly and thermal stability. We found that the binding of ATP or its analogs contributed to the successful assembly of thermosomes and enhanced their thermal stabilities. Cpn-β is more thermally stable than cpn-α, while the thermal stability of the hetero thermosome cpn-αβ is intermediate. Cryo-electron microscopy reconstructions of cpn-α and cpn-β revealed the interwoven densities of their non-conserved flexible N/C-termini around the equatorial planes. The deletion or swapping of their termini and pH-dependent thermal stability assays revealed the key role of the termini electrostatic interactions in the assembly and thermal stability of the thermosomes.
Acidianus
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metabolism
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Adenosine Triphosphate
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metabolism
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Amino Acid Sequence
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Cryoelectron Microscopy
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Hydrogen-Ion Concentration
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Molecular Sequence Data
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Mutation
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Nucleotides
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metabolism
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Protein Binding
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Protein Folding
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Protein Stability
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Protein Structure, Quaternary
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Sequence Alignment
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Static Electricity
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Temperature
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Thermosomes
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chemistry
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genetics
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metabolism
4.Induced pluripotent stem cells and neurological disease models.
Sa CAI ; Ying-Shing CHAN ; Daisy Kwok-Yan SHUM
Acta Physiologica Sinica 2014;66(1):55-66
The availability of human stem cells heralds a new era for in vitro cell-based modeling of neurodevelopmental and neurodegenerative diseases. Adding to the excitement is the discovery that somatic cells of patients can be reprogrammed to a pluripotent state from which neural lineage cells that carry the disease genotype can be derived. These in vitro cell-based models of neurological diseases hold promise for monitoring of disease initiation and progression, and for testing of new drug treatments on the patient-derived cells. In this review, we focus on the prospective applications of different stem cell types for disease modeling and drug screening. We also highlight how the availability of patient-specific induced pluripotent stem cells (iPS cells) offers a unique opportunity for studying and modeling human neurodevelopmental and neurodegenerative diseases in vitro and for testing small molecules or other potential therapies for these disorders. Finally, the limitations of this technology from the standpoint of reprogramming efficiency and therapeutic safety are discussed.
Drug Evaluation, Preclinical
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Humans
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Induced Pluripotent Stem Cells
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cytology
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pathology
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Models, Neurological
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Nervous System Diseases
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physiopathology
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Neural Stem Cells
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pathology
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Neurodegenerative Diseases
;
physiopathology
5.Development of neural correlates of linear motion in the rat vestibular nucleus.
Chun-Wai MA ; Chun-Hong LAI ; Lei HAN ; Daisy Kwok-Yan SHUM ; Ying-Shing CHAN
Acta Physiologica Sinica 2014;66(1):37-46
The capability of the central vestibular system in utilizing cues arising from the inner ear determines the ability of animals to acquire the sense of head orientations in the three-dimensional space and to shape postural movements. During development, neurons in the vestibular nucleus (VN) show significant changes in their electrophysiological properties. An age-dependent enhancement of membrane excitability is accompanied by a progressive increase in firing rate and discharge regularity. The coding of horizontal and vertical linear motions also exhibits developmental refinement in VN neurons. Further, modification of cell surface receptors, such as glutamate receptors, of developing VN neurons are well-orchestrated in the course of maturation, thereby regulating synaptic efficacy and spatial coding capacity of these neurons in local circuits. Taken together, these characteristic features of VN neurons contribute to developmental establishment of space-centered coordinates within the brain.
Animals
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Ear, Inner
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physiology
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Electrophysiological Phenomena
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Movement
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Neurons
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physiology
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Rats
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Receptors, Cell Surface
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physiology
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Vestibular Nuclei
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physiology
6.Proactive infection control measures to prevent nosocomial transmission of carbapenem-resistant Enterobacteriaceae in a non-endemic area.
Vincent Chi-Chung CHENG ; Jasper Fuk-Woo CHAN ; Sally Cheuk-Ying WONG ; Jonathan Hon-Kwan CHEN ; Josepha Wai-Ming TAI ; Mei-Kum YAN ; Grace See-Wai KWAN ; Herman TSE ; Kelvin Kai-Wang TO ; Pak-Leung HO ; Kwok-Yung YUEN
Chinese Medical Journal 2013;126(23):4504-4509
BACKGROUNDIdentification of hospitalized carbapenem-resistant Enterobacteriaceae (CRE)-positive patient is important in preventing nosocomial transmission. The objective of this study was to illustrate the implementation of proactive infection control measures in preventing nosocomial transmission of CRE in a healthcare region of over 3200 beds in Hong Kong between October 1, 2010 and December 31, 2011.
METHODSThe program included active surveillance culture in patients with history of medical tourism with hospitalization and surgical operation outside Hong Kong within 12 months before admission, and "added test" as an opportunistic CRE screening in all fecal specimens submitted to the laboratory. Outbreak investigation and contact tracing were conducted for CRE-positive patients. Serial quantitative culture was performed on CRE-positive patients and the duration of fecal carriage of CRE was analyzed.
RESULTSDuring the study period, a total of 6533 patients were screened for CRE, of which 76 patients were positive (10 from active surveillance culture, 65 from "added test", and 1 secondary case from contact tracing of 223 patients with no nosocomial outbreak), resulting in an overall rate of CRE fecal carriage of 1.2%. The median time of fecal carriage of CRE was 43 days (range, 13-119 days). Beta-lactam-beta-lactamase-inhibitors, cephalosporins, and fluoroquinolones were associated significantly with high fecal bacterial load when used 90 days before CRE detection, while use of cephalosporins, carbapenems, and fluoroquinolones after CRE detection are significantly associated with longer duration of carriage. The duration of fecal carriage of CRE also correlates significantly with the initial fecal bacterial load (Pearson correlation: 0.53; P = 0.02).
CONCLUSIONProactive infection control measures by enhanced surveillance program identify CRE-positive patients and data obtained are useful for the planning of and resource allocation for CRE control.
Anti-Bacterial Agents ; therapeutic use ; Carbapenems ; therapeutic use ; Cephalosporins ; therapeutic use ; Drug Resistance, Bacterial ; Enterobacteriaceae ; drug effects ; Enterobacteriaceae Infections ; prevention & control ; transmission ; Fluoroquinolones ; therapeutic use ; Humans ; Infection Control ; methods
7.Targeting papain-like protease for broad-spectrum coronavirus inhibition.
Shuofeng YUAN ; Xiaopan GAO ; Kaiming TANG ; Jian-Piao CAI ; Menglong HU ; Peng LUO ; Lei WEN ; Zi-Wei YE ; Cuiting LUO ; Jessica Oi-Ling TSANG ; Chris Chun-Yiu CHAN ; Yaoqiang HUANG ; Jianli CAO ; Ronghui LIANG ; Zhenzhi QIN ; Bo QIN ; Feifei YIN ; Hin CHU ; Dong-Yan JIN ; Ren SUN ; Jasper Fuk-Woo CHAN ; Sheng CUI ; Kwok-Yung YUEN
Protein & Cell 2022;13(12):940-953
The emergence of SARS-CoV-2 variants of concern and repeated outbreaks of coronavirus epidemics in the past two decades emphasize the need for next-generation pan-coronaviral therapeutics. Drugging the multi-functional papain-like protease (PLpro) domain of the viral nsp3 holds promise. However, none of the known coronavirus PLpro inhibitors has been shown to be in vivo active. Herein, we screened a structurally diverse library of 50,080 compounds for potential coronavirus PLpro inhibitors and identified a noncovalent lead inhibitor F0213 that has broad-spectrum anti-coronaviral activity, including against the Sarbecoviruses (SARS-CoV-1 and SARS-CoV-2), Merbecovirus (MERS-CoV), as well as the Alphacoronavirus (hCoV-229E and hCoV-OC43). Importantly, F0213 confers protection in both SARS-CoV-2-infected hamsters and MERS-CoV-infected human DPP4-knockin mice. F0213 possesses a dual therapeutic functionality that suppresses coronavirus replication via blocking viral polyprotein cleavage, as well as promoting antiviral immunity by antagonizing the PLpro deubiquitinase activity. Despite the significant difference of substrate recognition, mode of inhibition studies suggest that F0213 is a competitive inhibitor against SARS2-PLpro via binding with the 157K amino acid residue, whereas an allosteric inhibitor of MERS-PLpro interacting with its 271E position. Our proof-of-concept findings demonstrated that PLpro is a valid target for the development of broad-spectrum anti-coronavirus agents. The orally administered F0213 may serve as a promising lead compound for combating the ongoing COVID-19 pandemic and future coronavirus outbreaks.
Animals
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Coronavirus Papain-Like Proteases/antagonists & inhibitors*
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Cricetinae
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Humans
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Mice
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Pandemics
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SARS-CoV-2/enzymology*
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COVID-19 Drug Treatment