78 research outputs found
Π ΠΎΠ»Ρ ΡΠΎΠ²Π΅ΡΡΠ΅Π½ΡΡΠ²ΠΎΠ²Π°Π½ΠΈΡ Π±ΡΡ Π³Π°Π»ΡΠ΅ΡΡΠΊΠΎΠ³ΠΎ ΡΡΠ΅ΡΠ° Π² ΡΠΏΡΠ°Π²Π»Π΅Π½ΠΈΠΈ ΠΏΡΠΎΠΈΠ·Π²ΠΎΠ΄ΡΡΠ²Π΅Π½Π½ΡΠΌΠΈ Π·Π°ΠΏΠ°ΡΠ°ΠΌΠΈ
Π¦Π΅Π»ΡΡ ΠΏΡΠΎΠ²Π΅Π΄Π΅Π½ΠΈΡ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡ ΡΠ²Π»ΡΠ΅ΡΡΡ ΠΎΠ±ΠΎΡΠ½ΠΎΠ²Π°Π½ΠΈΠ΅ Π½Π°ΠΏΡΠ°Π²Π»Π΅Π½ΠΈΠΉ ΠΏΠΎΠ²ΡΡΠ΅Π½ΠΈΡ ΡΡΡΠ΅ΠΊΡΠΈΠ²Π½ΠΎΡΡΠΈ ΠΈΡΠΏΠΎΠ»ΡΠ·ΠΎΠ²Π°Π½ΠΈΡ ΠΌΠ°ΡΠ΅ΡΠΈΠ°Π»ΡΠ½ΡΡ
ΠΏΡΠΎΠΈΠ·Π²ΠΎΠ΄ΡΡΠ²Π΅Π½Π½ΡΡ
Π·Π°ΠΏΠ°ΡΠΎΠ² Π½Π° ΠΏΡΠ΅Π΄ΠΏΡΠΈΡΡΠΈΠΈ Π² ΡΡΠ»ΠΎΠ²ΠΈΡΡ
ΡΡΠ½ΠΎΡΠ½ΠΎΠΉ ΡΠΊΠΎΠ½ΠΎΠΌΠΈΠΊΠΈ
ΠΠΎΠ·ΠΌΠΎΠΆΠ½ΠΎΡΡΡ ΠΏΡΠΎΠ³Π½ΠΎΠ·ΠΈΡΠΎΠ²Π°Π½ΠΈΡ ΠΊΠ»Π΅ΡΠΎΡΠ½ΠΎΠ³ΠΎ ΡΠΈΠΏΠ° ΡΠ²Π΅Π°Π»ΡΠ½ΡΡ ΠΌΠ΅Π»Π°Π½ΠΎΠΌ Π±Π΅Π· ΠΈΡΠΏΠΎΠ»ΡΠ·ΠΎΠ²Π°Π½ΠΈΡ ΠΈΠ½Π²Π°Π·ΠΈΠ²Π½ΡΡ ΠΌΠ΅ΡΠΎΠ΄ΠΎΠ² Π΄ΠΈΠ°Π³Π½ΠΎΡΡΠΈΠΊΠΈ
Π Π΅Π·ΡΠΌΠ΅. Π‘ ΠΏΠΎΠΌΠΎΡΡΡ Π΄ΠΈΡΠΊΡΠΈΠΌΠΈΠ½Π°Π½ΡΠ½ΠΎΠ³ΠΎ Π°Π½Π°Π»ΠΈΠ·Π° ΡΡΡΠ°Π½ΠΎΠ²Π»Π΅Π½Π° Π²ΠΎΠ·ΠΌΠΎΠΆΠ½ΠΎΡΡΡ ΠΎΠΏΡΠ΅Π΄Π΅Π»Π΅Π½ΠΈΡ ΠΊΠ»Π΅ΡΠΎΡΠ½ΠΎΠ³ΠΎ ΡΠΈΠΏΠ° ΠΌΠ΅Π»Π°Π½ΠΎΠΌΡ ΡΠ²Π΅Π°Π»ΡΠ½ΠΎΠ³ΠΎ ΡΡΠ°ΠΊΡΠ° Π² ΠΏΡΠΎΡΠ΅ΡΡΠ΅ ΠΏΡΠΎΠ²Π΅Π΄Π΅Π½ΠΈΡ ΠΊΠΎΠΌΠ±ΠΈΠ½ΠΈΡΠΎΠ²Π°Π½Π½ΠΎΠ³ΠΎ (ΡΠΎΡΠΎΠΊΠΎΠ°Π³ΡΠ»ΡΡΠΈΡ + Π±ΡΠ°Ρ
ΠΈΡΠ΅ΡΠ°ΠΏΠΈΡ) Π»Π΅ΡΠ΅Π½ΠΈΡ. Π Π°Π·ΡΠ°Π±ΠΎΡΠ°Π½Π° Π²ΡΡΠΎΠΊΠΎΠ·Π½Π°ΡΠΈΠΌΠ°Ρ (l = 0,08; Ρ = 0,002) Π΄ΠΈΡΠΊΡΠΈΠΌΠΈΠ½Π°Π½ΡΠ½Π°Ρ ΠΌΠΎΠ΄Π΅Π»Ρ, Π²ΠΊΠ»ΡΡΠ°ΡΡΠ°Ρ ΡΡΠ΄ ΠΊΠ»ΠΈΠ½ΠΈΡΠ΅ΡΠΊΠΈΡ
(ΡΡΠ΅ΠΏΠ΅Π½Ρ ΠΏΠΈΠ³ΠΌΠ΅Π½ΡΠ°ΡΠΈΠΈ, ΠΏΠΎΠ», ΡΠΊΠΎΡΠΎΡΡΡ ΡΠΎΡΡΠ° ΠΌΠ΅Π»Π°Π½ΠΎΠΌΡ) ΠΈ ΠΈΠΌΠΌΡΠ½ΠΎΠ»ΠΎΠ³ΠΈΡΠ΅ΡΠΊΠΈΡ
(ΠΊΠΎΠ»ΠΈΡΠ΅ΡΡΠ²ΠΎ Π’- ΠΈ Π-Π»ΠΈΠΌΡΠΎΡΠΈΡΠΎΠ², ΠΏΡΠΎΡΠ΅Π½Ρ Π’-Ρ
Π΅Π»ΠΏΠ΅ΡΠΎΠ² ΠΈ Π΄Ρ.) ΠΏΠΎΠΊΠ°Π·Π°ΡΠ΅Π»Π΅ΠΉ. ΠΡΠΎΠ±ΠΎΠ΅ ΠΌΠ΅ΡΡΠΎ Π² ΠΌΠΎΠ΄Π΅Π»ΠΈ Π·Π°Π½ΠΈΠΌΠ°ΡΡ ΠΏΡΠΈΠ·Π½Π°ΠΊΠΈ, Π² Π½Π°ΠΈΠ±ΠΎΠ»ΡΡΠ΅ΠΉ ΡΡΠ΅ΠΏΠ΅Π½ΠΈ ΠΎΡΡΠ°ΠΆΠ°ΡΡΠΈΠ΅ Π±ΠΈΠΎΠ»ΠΎΠ³ΠΈΡΠ΅ΡΠΊΠΈΠ΅ ΠΎΡΠΎΠ±Π΅Π½Π½ΠΎΡΡΠΈ ΡΠ²Π΅Π°Π»ΡΠ½ΡΡ
ΠΌΠ΅Π»Π°Π½ΠΎΠΌ ΡΠ°Π·Π»ΠΈΡΠ½ΠΎΠ³ΠΎ ΠΊΠ»Π΅ΡΠΎΡΠ½ΠΎΠ³ΠΎ ΡΠΎΡΡΠ°Π²Π°, Π° ΠΈΠΌΠ΅Π½Π½ΠΎ β ΡΠΊΠΎΡΠΎΡΡΡ ΠΈΠ·ΠΌΠ΅Π½Π΅Π½ΠΈΡ ΡΠ°Π·ΠΌΠ΅ΡΠ° ΠΎΠΏΡΡ
ΠΎΠ»ΠΈ Π² ΠΏΡΠΎΡΠ΅ΡΡΠ΅ Π»Π΅ΡΠ΅Π½ΠΈΡ ΠΈ ΠΈΠ·ΠΌΠ΅Π½Π΅Π½ΠΈΠ΅ ΠΏΠΎΠΊΠ°Π·Π°ΡΠ΅Π»Π΅ΠΉ ΠΊΠ»Π΅ΡΠΎΡΠ½ΠΎΠ³ΠΎ ΠΈΠΌΠΌΡΠ½ΠΈΡΠ΅ΡΠ°.
ΠΠ»ΡΡΠ΅Π²ΡΠ΅ ΡΠ»ΠΎΠ²Π°: ΡΠ²Π΅Π°Π»ΡΠ½Π°Ρ ΠΌΠ΅Π»Π°Π½ΠΎΠΌΠ°, ΠΊΠ»Π΅ΡΠΎΡΠ½ΡΠΉ ΡΠΈΠΏ, ΠΊΠ»ΠΈΠ½ΠΈΠΊΠΎ-ΠΌΠΎΡΡΠΎΠ»ΠΎΠ³ΠΈΡΠ΅ΡΠΊΠΈΠ΅, ΠΈΠΌΠΌΡΠ½ΠΎΠ»ΠΎΠ³ΠΈΡΠ΅ΡΠΊΠΈΠ΅ ΠΏΠΎΠΊΠ°Π·Π°ΡΠ΅Π»ΠΈ, Π΄ΠΈΡΠΊΡΠΈΠΌΠΈΠ½Π°Π½ΡΠ½ΡΠΉ Π°Π½Π°Π»ΠΈΠ·.Summary. Application of the discriminant analysis shows that it is possible to define the cell type of melanoma of uveal tract of the eye in the process of combined (photocoagulation + brachytherapy) treatment. A highly reliable (l= 0,08; Ρ = 0,002) discriminant model was elaborated, involving a number of both clinical (pigmentation level, gender, melanoma growth rate) and immunological (number of T and B lymphocytes, T helper rate, etc.) indicators. In this model, especially important are those traits that most pronouncedly reflect the biological peculiarities of uveal melanomas of various cellular compositions, namely β the pace of tumor size growth in the process of treatment and changes in cell immunity indicators.
Key Words: uveal melanoma, cell type, clinical and morphological, immunological indicators, discriminant analysis
Comparative genomics among cyst nematodes reveals distinct evolutionary histories among effector families and an irregular distribution of effector-associated promoter motifs
JvS, MH and SvdE were supported by a grant from the Applied and Technical Science domain (TTW) of the Netherlands Organization for Scientific Research (NWO) under grant no. 14708. PT received support from the University of St Andrews Bioinformatics Unit (AMD3BIOINF), funded by Wellcome Trust ISSF award 105621/Z/14/Z. MS benefitted from funding by a VENI grant (17282) from the NWO domain Applied and Engineering Sciences.Potato cyst nematodes (PCNs), an umbrella term used for two species, Globodera pallida and G. rostochiensis, belong worldwide to the most harmful pathogens of potato. Pathotype-specific host plant resistances are an essential handle for PCN control. However, the poor delineation of G. pallida pathotypes hampers the efficient use of available host plant resistances. Long-read sequencing technology allowed us to generate a new reference genome of G. pallida population D383 and, as compared to the current reference, the new genome assembly is 42 times less fragmented. For comparison of diversification patterns of six effector families between G. pallida and G. rostochiensis, an additional reference genome was generated for an outgroup, the beet cyst nematode Heterodera schachtii (IRS population). Large evolutionary contrasts in effector family topologies were observed. While VAPs diversified before the split between the three cyst nematode species, the families GLAND5 and GLAND13 only expanded in PCN after their separation from the genus Heterodera. Although DNA motifs in the promoter regions thought to be involved in the orchestration of effector expression ('DOG boxes') were present in all three cyst nematode species, their presence is not a necessity for dorsal gland-produced effectors. Notably, DOG box dosage was only loosely correlated with expression level of individual effector variants. Comparison of the G. pallida genome with those of two other cyst nematodes underlined the fundamental differences in evolutionary history between effector families. Re-sequencing of PCN populations with deviant virulence characteristics will allow for the linking of these characteristics with the composition of the effector repertoire as well as for the mapping of PCN diversification patterns resulting from extreme anthropogenic range expansion.Publisher PDFPeer reviewe
Recommended from our members
Mammalian Circadian Period, But Not Phase and Amplitude, Is Robust Against Redox and Metabolic Perturbations
Circadian rhythms permeate all levels of biology to temporally regulate cell and whole-body physiology, although the cell-autonomous mechanism that confers ~24-h periodicity is incompletely understood. Reports describing circadian oscillations of over-oxidized peroxiredoxin abundance have suggested that redox signaling plays an important role in the timekeeping mechanism. Here, we tested the functional contribution that redox state and primary metabolism make to mammalian cellular timekeeping.
We found a circadian rhythm in flux through primary glucose metabolic pathways, indicating rhythmic NAD(P)H production. Using pharmacological and genetic perturbations, however, we found that timekeeping was insensitive to changes in glycolytic flux, whereas oxidative pentose phosphate pathway (PPP) inhibition and other chronic redox stressors primarily affected circadian gene expression amplitude, not periodicity. Finally, acute changes in redox state decreased PER2 protein stability, phase dependently, to alter the subsequent phase of oscillation.
Circadian rhythms in primary cellular metabolism and redox state have been proposed to play a role in the cellular timekeeping mechanism. We present experimental data testing that hypothesis.
Circadian flux through primary metabolism is cell autonomous, driving rhythmic NAD(P)(+) redox cofactor turnover and maintaining a redox balance that is permissive for circadian gene expression cycles. Redox homeostasis and PPP flux, but not glycolysis, are necessary to maintain clock amplitude, but neither redox nor glucose metabolism determines circadian period. Furthermore, cellular rhythms are sensitive to acute changes in redox balance, at least partly through regulation of PER protein. Redox and metabolic state are, thus, both inputs and outputs, but not state variables, of cellular circadian timekeeping.M.P. was supported by the Dutch Cancer Foundation (KWF, BUIT-2014-6637) and EMBO (ALTF-654-2014). J.S.O. was supported by the Medical Research Council (MC_UP_1201/4) and the Wellcome Trust (093734/Z/10/Z)
Low human dystrophin levels prevent cardiac electrophysiological and structural remodelling in a Duchenne mouse model
Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disorder caused by loss of dystrophin. This lack also affects cardiac structure and function, and cardiovascular complications are a major cause of death in DMD. Newly developed therapies partially restore dystrophin expression. It is unclear whether this will be sufficient to prevent or ameliorate cardiac involvement in DMD. We here establish the cardiac electrophysiological and structural phenotype in young (2-3 months) and aged (6-13 months) dystrophin-deficient mdx mice expressing 100% human dystrophin (hDMD), 0% human dystrophin (hDMDdel52-null) or low levels (similar to 5%) of human dystrophin (hDMDdel52low). Compared to hDMD, young and aged hDMDdel52-null mice displayed conduction slowing and repolarisation abnormalities, while only aged hDMDdel52-null mice displayed increased myocardial fibrosis. Moreover, ventricular cardiomyocytes from young hDMDdel52-null animals displayed decreased sodium current and action potential (AP) upstroke velocity, and prolonged AP duration at 20% and 50% of repolarisation. Hence, cardiac electrical remodelling in hDMDdel52-null mice preceded development of structural alterations. In contrast to hDMDdel52-null, hDMDdel52-low mice showed similar electrophysiological and structural characteristics as hDMD, indicating prevention of the cardiac DMD phenotype by low levels of human dystrophin. Our findings are potentially relevant for the development of therapeutic strategies aimed at restoring dystrophin expression in DMD.Functional Genomics of Muscle, Nerve and Brain Disorder
Natural disease history of mouse models for limb girdle muscular dystrophy types 2D and 2F
Limb-girdle muscular dystrophy types 2D and 2F (LGMD 2D and 2F) are autosomal recessive
disorders caused by mutations in the alpha- and delta sarcoglycan genes, respectively,
leading to severe muscle weakness and degeneration. The cause of the disease has been
well characterized and a number of animal models are available for pre-clinical studies to
test potential therapeutic interventions. To facilitate transition from drug discovery to clinical
trials, standardized procedures and natural disease history data were collected for these
mouse models. Implementing the TREAD-NMD standardized operating procedures, we
here subjected LGMD2D (SGCA-null), LGMD2F (SGCD-null) and wild type (C57BL/6J)
mice to five functional tests from the age of 4 to 32 weeks. To assess whether the functional
test regime interfered with disease pathology, sedentary groups were taken along. Muscle
physiology testing of tibialis anterior muscle was performed at the age of 34 weeks. Muscle
histopathology and gene expression was analysed in skeletal muscles and heart.
Muscle histopathology and gene expression was analysed in skeletal muscles and heart.
Mice successfully accomplished the functional tests, which did not interfere with disease
pathology. Muscle function of SGCA- and SGCD-null mice was impaired and declined over
time. Interestingly, female SGCD-null mice outperformed males in the two and four limb
hanging tests, which proved the most suitable non-invasive tests to assess muscle function.
Muscle physiology testing of tibialis anterior muscle revealed lower specific force and higher
susceptibility to eccentric-induced damage in LGMD mice. Analyzing muscle histopathology
and gene expression, we identified the diaphragm as the most affected muscle in LGMD
strains. Cardiac fibrosis was found in SGCD-null mice, being more severe in males than in
females. Our study offers a comprehensive natural history dataset which will be useful to
design standardized tests and future pre-clinical studies in LGMD2D and 2F miceFunctional Genomics of Muscle, Nerve and Brain Disorder
Comparing Conventional Chemotherapy to Chronomodulated Chemotherapy for Cancer Treatment: Protocol for a Systematic Review
Background: Chronomodulated chemotherapy aims to achieve maximum drug safety and efficacy by adjusting the time of treatment to an optimal biological time as determined by the circadian clock. Although it is a promising alternative to conventional (nonβtime-stipulated) chemotherapy in several instances, the lack of scientific consensus and the increased logistical burden of timed administration limit the use of a chronomodulated administration protocol. Objective: With the goal to increase scientific consensus on this subject, we plan to conduct a systematic review of the current literature to compare the drug safety and efficacy of chronomodulated chemotherapy with those of conventional chemotherapy. Methods: This systematic review will comply with the PRISMA (Preferred Reporting Items for the Systematic Reviews and Meta-Analysis) guidelines. In order to identify relevant studies, we conducted a comprehensive search in PubMed and Embase on May 18, 2020. We included clinical studies that compare either the safety or efficacy of chronomodulated chemotherapy with that of conventional chemotherapy. Potential studies will be reviewed and screened by 2 independent reviewers. Quality assessment will be performed using the National Institutes of Healthβs Study Quality Assessment Tool (Quality Assessment of Controlled Intervention Studies). Disagreements will be resolved by consulting a third independent reviewer. Results: This protocol has received funding, and the search for studies from databases commenced on May 18, 2020. The systematic review is planned to be completed by October 31, 2020. Conclusions: In this systematic review, we will compare drug safety and drug efficacy for cancer patients who were administered either chronomodulated chemotherapy or conventional chemotherapy. Moreover, we will highlight the outcomes and quality of the selected trials for this review
CRYPTOCHROMES confer robustness, not rhythmicity, to circadian timekeeping
Circadian rhythms are a pervasive property of mammalian cells, tissues and behaviour, ensuring physiological adaptation to solar time. Models of cellular timekeeping revolve around transcriptional feedback repression, whereby CLOCK and BMAL1 activate the expression of PERIOD (PER) and CRYPTOCHROME (CRY), which in turn repress CLOCK/BMAL1 activity. CRY proteins are therefore considered essential components of the cellular clock mechanism, supported by behavioural arrhythmicity of CRYβdeficient (CKO) mice under constant conditions. Challenging this interpretation, we find locomotor rhythms in adult CKO mice under specific environmental conditions and circadian rhythms in cellular PER2 levels when CRY is absent. CRYβless oscillations are variable in their expression and have shorter periods than wildβtype controls. Importantly, we find classic circadian hallmarks such as temperature compensation and period determination by CK1Ξ΄/Ξ΅ activity to be maintained. In the absence of CRYβmediated feedback repression and rhythmic Per2 transcription, PER2 protein rhythms are sustained for several cycles, accompanied by circadian variation in protein stability. We suggest that, whereas circadian transcriptional feedback imparts robustness and functionality onto biological clocks, the core timekeeping mechanism is postβtranslational
- β¦