A review of the physicochemical models of the movement of protocells and bacteria was performed. The mechanisms of gliding and movement based on flagella are considered. Based on the models, the ...average speed of movement of protocells and bacteria was calculated. A physicochemical model of bacterial gliding was constructed. The efficiency of the process of converting the energy of ATP into the energy of motion is estimated. A review of models of movement with the help of flagella was performed. A model has been constructed for converting ATP energy into proton and sodium motive forces, which, in turn, are converted into energy of rotor rotation. The problem of the accuracy of operation of nanomachines, on the basis of which the directed movement of bacteria occurs, is discussed. The considered models can be applied to create nanomotors for medical purposes.
Neurodegenerative diseases characterized by aberrant accumulation of undigested cellular components represent unmet medical conditions for which the identification of actionable targets is urgently ...needed. Here we identify a pharmacologically actionable pathway that controls cellular clearance via Akt modulation of transcription factor EB (TFEB), a master regulator of lysosomal pathways. We show that Akt phosphorylates TFEB at Ser467 and represses TFEB nuclear translocation independently of mechanistic target of rapamycin complex 1 (mTORC1), a known TFEB inhibitor. The autophagy enhancer trehalose activates TFEB by diminishing Akt activity. Administration of trehalose to a mouse model of Batten disease, a prototypical neurodegenerative disease presenting with intralysosomal storage, enhances clearance of proteolipid aggregates, reduces neuropathology and prolongs survival of diseased mice. Pharmacological inhibition of Akt promotes cellular clearance in cells from patients with a variety of lysosomal diseases, thus suggesting broad applicability of this approach. These findings open new perspectives for the clinical translation of TFEB-mediated enhancement of cellular clearance in neurodegenerative storage diseases.
Small changes (down to 0.1%) of Ca2+ ion activity in pure solutions of CaCl2, model solutions mimicking blood serum, and blood serum sample are registered by constant potential coulometric ...measurements, using solid contact ion-selective electrodes (ISEs) with poly(vinyl chloride) (PVC) membrane containing ETH 1001 as neutral ionophore. A new measurement protocol is proposed aimed at a significant improvement of the signal-to-noise ratio in the current measurements. A procedure is developed for the PEDOT-PSS deposition on glassy carbon from mixed water-acetonitrile solution. Data are obtained in support of Kragh-Hansen and Vorum’s approach for the quantification of the interaction between Ca2+ ions and bovine serum albumin (BSA).
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•Registration of 0.1% change of Ca2+ concentration in aqueous solutions and in serum.•Linearity of the cumulated charge vs. concentration (not logarithm) of the analyte.•Improved signal-to-noise ratio due to a modified protocol of the measurements.•Galvanostatic deposition of PEDOT-PSS from mixed water-acetonitrile solution.
У статті досліджено перспективи взаємодії Національної поліції України з населенням на засадах партнерства в умовах воєнного стану та проаналізовано нещодавно запровадженні проекти, мета яких є ...ефективне виконання покладених державою завдань, насамперед, пов’язаних з охороною найвищих цінностей держави, до яких відноситься людина, її права і свободи. Наголошується, що запровадження в Україні воєнного стану вимагає не лише вирішення завдань, пов’язаних із запровадженням і здійсненням заходів правового режиму воєнного стану, оскільки у ході відсічі збройної агресії рф проти України органи поліції беруть участь у виконанні завдань територіальної оборони, здійснюють посилене патрулювання, супроводження відповідних вантажів, охорону майна постраждалих осіб, охорону місць руйнувань, доставлення правопорушників, обмеження руху транспорту на небезпечних напрямах, проведення навчань з представниками населення тощо. Висвітлюються основні проблеми, які виникають під час взаємодії органів Національної поліції з населенням на сучасному етапі в умовах правового режиму воєнного стану в Україні, окреслюються шляхи їх вирішення, пропонується розробити нормативно-правовий акт щодо організації взаємодії органів поліції з населенням, в якому слід закріпити мету взаємодії, завдання, дати визначення окремих понять, визначити суб’єктів та керівників органів взаємодії, види та форми взаємодії, особливості взаємного інформування, канали передачі інформації, способи та строки перевірки результативності взаємодії, визначити принципи, а також напрями взаємодії в умовах правового режиму воєнного стану в Україні. Робиться висновок, що під правовим регулюванням взаємодії органів Національної поліції з населенням в умовах правового режиму воєнного стану в Україні слід розуміти систему правових засобів (елементів), сукупність прийомів та способів правового впливу на суспільні відносини, що виникають під час такої взаємодії, за допомогою яких визначається комплекс організаційних та спеціальних заходів, спрямованих на захист від протиправних посягань, а також забезпечення особистої безпеки громадян, протидії правопорушенням.
The rich and immediate perception of a familiar face, including its identity, expression and even intent, is one of the most impressive shared faculties of human and non-human primate brains. Many ...visually responsive neurons in the inferotemporal cortex of macaque monkeys respond selectively to faces, sometimes to only one or a few individuals, while showing little sensitivity to scale and other details of the retinal image. Here we show that face-responsive neurons in the macaque monkey anterior inferotemporal cortex are tuned to a fundamental dimension of face perception. Using a norm-based caricaturization framework previously developed for human psychophysics, we varied the identity information present in photo-realistic human faces, and found that neurons of the anterior inferotemporal cortex were most often tuned around the average, identity-ambiguous face. These observations are consistent with face-selective responses in this area being shaped by a figural comparison, reflecting structural differences between an incoming face and an internal reference or norm. As such, these findings link the tuning of neurons in the inferotemporal cortex to psychological models of face identity perception.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Polyglutamine (polyQ) diseases are caused by expansion of translated CAG repeats in distinct genes leading to altered protein function. In spinocerebellar ataxia type 1 (SCA1), a gain of function of ...polyQ-expanded ataxin-1 (ATXN1) contributes to cerebellar pathology. The extent to which cerebellar toxicity depends on its cognate partner capicua (CIC), versus other interactors, remains unclear. It is also not established whether loss of the ATXN1-CIC complex in the cerebellum contributes to disease pathogenesis. In this study, we exclusively disrupt the ATXN1-CIC interaction in vivo and show that it is at the crux of cerebellar toxicity in SCA1. Importantly, loss of CIC in the cerebellum does not cause ataxia or Purkinje cell degeneration. Expression profiling of these gain- and loss-of-function models, coupled with data from iPSC-derived neurons from SCA1 patients, supports a mechanism in which gain of function of the ATXN1-CIC complex is the major driver of toxicity.
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•Toxicity of polyQ-expanded ATXN1 in the cerebellum requires interaction with CIC•CIC and the ATXN1-CIC complex are dispensable for cerebellar function•Expression profiling reveals gain of function of CIC upon ATXN1 polyQ expansion•Genetic signatures are disrupted in neurons derived from SCA1 patients
Rousseaux, Tschumperlin, Lu, and colleagues show that formation of the ATXN1-CIC complex is critical for polyQ-expanded ATXN1-mediated toxicity. They find that this complex mediates its effects through a gain-of-function mechanism in the cerebellum of SCA1 mice and SCA1 patient-derived neurons.
Splicing regulation is an important step of post-transcriptional gene regulation. It is a highly dynamic process orchestrated by RNA-binding proteins (RBPs). RBP dysfunction and global splicing ...dysregulation have been implicated in many human diseases, but the in vivo functions of most RBPs and the splicing outcome upon their loss remain largely unexplored. Here we report that constitutive deletion of Rbm17, which encodes an RBP with a putative role in splicing, causes early embryonic lethality in mice and that its loss in Purkinje neurons leads to rapid degeneration. Transcriptome profiling of Rbm17-deficient and control neurons and subsequent splicing analyses using CrypSplice, a new computational method that we developed, revealed that more than half of RBM17-dependent splicing changes are cryptic. Importantly, RBM17 represses cryptic splicing of genes that likely contribute to motor coordination and cell survival. This finding prompted us to re-analyze published datasets from a recent report on TDP-43, an RBP implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), as it was demonstrated that TDP-43 represses cryptic exon splicing to promote cell survival. We uncovered a large number of TDP-43-dependent splicing defects that were not previously discovered, revealing that TDP-43 extensively regulates cryptic splicing. Moreover, we found a significant overlap in genes that undergo both RBM17- and TDP-43-dependent cryptic splicing repression, many of which are associated with survival. We propose that repression of cryptic splicing by RBPs is critical for neuronal health and survival. CrypSplice is available at www.liuzlab.org/CrypSplice.
We demonstrate efficient transverse compression of a 12.5 MeV/c muon beam stopped in a helium gas target featuring a vertical density gradient and crossed electric and magnetic fields. The muon stop ...distribution extending vertically over 14 mm was reduced to a 0.25 mm size (rms) within 3.5 μs. The simulation including cross sections for low-energy μ+-He elastic and charge exchange (μ+↔ muonium) collisions describes the measurements well. By combining the transverse compression stage with a previously demonstrated longitudinal compression stage, we can improve the phase space density of a μ+ beam by a factor of 1010 with 10−3 efficiency.
Variants in the leucine-rich repeat kinase 2 (LRRK2) gene are associated with increased risk for familial and sporadic Parkinson's disease (PD). Pathogenic variants in LRRK2, including the common ...variant G2019S, result in increased LRRK2 kinase activity, supporting the therapeutic potential of LRRK2 kinase inhibitors for PD. To better understand the role of LRRK2 in disease and to support the clinical development of LRRK2 inhibitors, quantitative and high-throughput assays to measure LRRK2 levels and activity are needed. We developed and applied such assays to measure the levels of LRRK2 as well as the phosphorylation of LRRK2 itself or one of its substrates, Rab10 (pT73 Rab10). We observed increased LRRK2 activity in various cellular models of disease, including iPSC-derived microglia, as well as in human subjects carrying the disease-linked variant LRRK2 G2019S. Capitalizing on the high-throughput and sensitive nature of these assays, we detected a significant reduction in LRRK2 activity in subjects carrying missense variants in LRRK2 associated with reduced disease risk. Finally, we optimized these assays to enable analysis of LRRK2 activity following inhibition in human peripheral blood mononuclear cells (PBMCs) and whole blood, demonstrating their potential utility as biomarkers to assess changes in LRRK2 expression and activity in the clinic.
Squaraine dyes AM‐1′ and AM‐1 bearing adamantyl termini were synthesized and spectroscopically characterized. AM‐1′ exhibited intense absorption and sharp emission in the far‐red to near‐infrared ...(NIR) spectral region. The degenerate two‐photon absorption (2PA) spectrum of AM‐1′ was obtained over a broad spectral range with a maximum cross section of ca. 360 GM. In aqueous solutions, AM‐1′ displayed a strong tendency for J‐aggregation and the reference AM‐1 exhibited entirely different aggregation behavior. We conclude that both the terminal pendant groups and substituents adjacent to the squaraine core play important roles in determining the aggregation behaviors and optical properties of the resultant squaraine dyes. Further an AM‐1′/β‐cyclodextrin complex dramatically suppressed squaraine π–π stacking and dissociated the J‐aggregate. Fluorescence microscopy imaging of HCT 116 cells incubated with the complex was accomplished, suggesting the potential application of this complex in fluorescence bioimaging.
Squaraine dyes bearing adamantyl terminal groups have been synthesized and spectroscopically characterized. In aqueous solution, AM‐1′ tended to form J‐aggregates. Encapsulating AM‐1′ in β‐cyclodextrin, based on the host–guest interactions, dramatically dissociated the J‐aggregate, restoring fluorescence. Fluorescence microscopy imaging of HCT 116 cells incubated with the complex was accomplished.
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