Characterization of Mechanosensitive Channels in the Eye

In dieser Arbeit wurde die Expression sieben verschiedener mechano-sensitiver Kanäle (MSKs: PIEZO1, PIEZO2, TRPA1, TRPM3, TRPV4, TRPP2 und TREK1) im Bereich des Ziliarkörpers untersucht. Die Proteine wurden mittels Immunfluoreszenz, Western-Blot und Reverse-Transkriptions-PCR untersucht. MSCs waren sowohl im Ratten-Auge als auch humanen Ziliarkörper-Epithel vorhanden. Die Expression und Lokalisierung der ausgewählten MSKs wurden zudem in einer Zell-Linie des nicht-pigmentierten Ziliarkörperepithels (NPZE) untersucht. Die deutliche Expression mehrerer MSKs könnte auf eine mögliche Rolle bei der Regulierung des Kammerwassers hinweisen. Die Bildung primärer Zilien nach Serumentzug konnte in der Zellkultur der NPZE-Zellen reproduziert und weiter analysiert werden. Entsprechende Befunde konnten in humanen Gewebsproben (Paraffinschnitten) mittels Elektronenmikroskopie und Immunhistologie bestätigt werden. Die Länge der primären Zilien war unabhängig von der Verlängerung des Serumentzugs von 24 auf 48 oder 72 Stunden, mit längerem Nährstoffentzug nahm die Häufigkeit von NPZE-Zellen mit primären Zilien jedoch deutlich zu. Eine doppelte Immunfluoreszenzfärbung zeigte eine Co-lokalisation von TRPP2 mit diesen primären Zilien. In dem Modell der NPZE wurde die Expression der MSKs unter einem erhöhten hydrostatischen Druck untersucht: Es kam zu einer Zunahme der Proteinkonzentration von PIEZO2, TRPP2 und TREK1 mit steigendem Druck. Ebenso veränderte sich der mRNA-Spiegel von PIEZO1, PIEZO2, TRPA1, TRPM3 und TRPP2. Unter der Hemmung von PIEZO2 (siRNA) und hydrostatischem Druck von 60 mmHg für 24 Stunden wurde eine Abnahme aller drei Isoformen von TRPP2-Proteinen gesehen. Die Gabe von TRPP2-siRNA führte andererseits nicht zu einer Veränderung der PIEZO2-Proteinexpression. Die weitere Charakterisierung der MSKs in Augengeweben könnte weitere Einblicke in die potenzielle Funktion okulärer Mechano-Sensoren für die Regulation des Augeninnendrucks liefern und somit Hinweise auf neue molekulare Ziele für die Behandlung des Glaukoms liefern

Nonlinear dynamic behavior analysis of a DC/DC converter with an ultra-high frequency Z-source converter

Z-source converters have been used in new energy sources because of their advantages. These converters have attracted considerable attention under high-frequency conditions given their high power density and high conversion efficiency. However, the stability of a system of ultra-high frequency Z-source converters are likely to be affected because of the inappropriate selection of parameters or the interference of weak signals in the process of the system. These factors will render such converters unable to work properly. The chaotic bifurcation behavior of Z-source converters based on peak current control mode is analyzed in this study. A precise discrete iterative mapping model for such converters is established, and the regional stability of a system is determined based on the characteristic value of changes in the Jacobian matrix. Finally, the bifurcation and chaos phenomena in a high-frequency Z-source converter and the accuracy of the aforementioned analysis are verified via experiments. The conclusion drawn from this study does not only can provide a reference for the stable operation of ultra-high frequency Z-source converters, but also presents a theoretical basis for optimizing system parameters and improving control performance

Auto-tuning MPI Collective Operations on Large-Scale Parallel Systems

MPI libraries are widely used in applications of high performance computing. Yet, effective tuning of MPI colletives on large parallel systems is an outstanding challenge. This process often follows a trial-and-error approach and requires expert insights into the subtle interactions between software and the underlying hardware. This paper presents an empirical approach to choose and switch MPI communication algorithms at runtime to optimize the application performance. We achieve this by first modeling offline, through microbenchmarks, to find how the runtime parameters with different message sizes affect the choice of MPI communication algorithms. We then apply the knowledge to automatically optimize new unseen MPI programs. We evaluate our approach by applying it to NPB and HPCC benchmarks on a 384-node computer cluster of the Tianhe-2 supercomputer. Experimental results show that our approach achieves, on average, 22.7% (up to 40.7%) improvement over the default setting

ConvKyber: Unleashing the Power of AI Accelerators for Faster Kyber with Novel Iteration-based Approaches

The remarkable performance capabilities of AI accelerators offer promising opportunities for accelerating cryptographic algorithms, particularly in the context of lattice-based cryptography. However, current approaches to leveraging AI accelerators often remain at a rudimentary level of implementation, overlooking the intricate internal mechanisms of these devices. Consequently, a significant number of computational resources is underutilized. In this paper, we present a comprehensive exploration of NVIDIA Tensor Cores and introduce a novel framework tailored specifically for Kyber. Firstly, we propose two innovative approaches that efficiently break down Kyber\u27s NTT into iterative matrix multiplications, resulting in approximately a 75% reduction in costs compared to the state-of-the-art scanning-based methods.Secondly, by reversing the internal mechanisms, we precisely manipulate the internal resources of Tensor Cores using assembly-level code instead of inefficient standard interfaces, eliminating memory accesses and redundant function calls. Finally, building upon our highly optimized NTT, we provide a complete implementation for all parameter sets of Kyber. Our implementation surpasses the state-of-the-art Tensor Core based work, achieving remarkable speed-ups of 1.93x, 1.65x, 1.22x and 3.55x for polyvec_ntt, KeyGen, Enc and Dec in Kyber-1024, respectively. Even when considering execution latency, our throughput-oriented full Kyber implementation maintains an acceptable execution latency. For instance, the execution latency ranges from 1.02 to 5.68 milliseconds for Kyber-1024 on R3080 when achieving the peak throughput

ConvKyber: Unleashing the Power of AI Accelerators for Faster Kyber with Novel Iteration-based Approaches

The remarkable performance capabilities of AI accelerators offer promising opportunities for accelerating cryptographic algorithms, particularly in the context of lattice-based cryptography. However, current approaches to leveraging AI accelerators often remain at a rudimentary level of implementation, overlooking the intricate internal mechanisms of these devices. Consequently, a significant number of computational resources is underutilized. In this paper, we present a comprehensive exploration of NVIDIA Tensor Cores and introduce a novel framework tailored specifically for Kyber. Firstly, we propose two innovative approaches that efficiently break down Kyber’s NTT into iterative matrix multiplications, resulting in approximately a 75% reduction in costs compared to the state-of-the-art scanning-based methods. Secondly, by reversing the internal mechanisms, we precisely manipulate the internal resources of Tensor Cores using assembly-level code instead of inefficient standard interfaces, eliminating memory accesses and redundant function calls. Finally, building upon our highly optimized NTT, we provide a complete implementation for all parameter sets of Kyber. Our implementation surpasses the state-of-the-art Tensor Core based work, achieving remarkable speed-ups of 1.93x, 1.65x, 1.22x and 3.55x for polyvec_ntt, KeyGen, Enc and Dec in Kyber-1024, respectively. Even when considering execution latency, our throughput-oriented full Kyber implementation maintains an acceptable execution latency. For instance, the execution latency ranges from 1.02 to 5.68 milliseconds for Kyber-1024 on R3080 when achieving the peak throughput

Intronic enhancers of the human SNCA gene predominantly regulate its expression in brain in vivo.

Evidence from patients with Parkinson's disease (PD) and our previously reported α-synuclein (SNCA) transgenic rat model support the idea that increased SNCA protein is a substantial risk factor of PD pathogenesis. However, little is known about the transcription control of the human SNCA gene in the brain in vivo. Here, we identified that the DYT6 gene product THAP1 (THAP domain-containing apoptosis-associated protein 1) and its interaction partner CTCF (CCCTC-binding factor) act as transcription regulators of SNCA. THAP1 controls SNCA intronic enhancers' activities, while CTCF regulates its enhancer-promoter loop formation. The SNCA intronic enhancers present neurodevelopment-dependent activities and form enhancer clusters similar to "super-enhancers" in the brain, in which the PD-associated single-nucleotide polymorphisms are enriched. Deletion of the SNCA intronic enhancer clusters prevents the release of paused RNA polymerase II from its promoter and subsequently reduces its expression drastically in the brain, which may provide new therapeutic approaches to prevent its accumulation and thus related neurodegenerative diseases defined as synucleinopathies

ZSCAN10 deficiency causes a neurodevelopmental disorder with characteristic oto-facial malformations

Neurodevelopmental disorders are major indications for genetic referral and have been linked to more than 1500 loci including genes encoding transcriptional regulators. The dysfunction of transcription factors often results in characteristic syndromic presentations; however, at least half of these patients lack a genetic diagnosis. The implementation of machine learning approaches has the potential to aid in the identification of new disease genes and delineate associated phenotypes. Next generation sequencing was performed in seven affected individuals with neurodevelopmental delay and dysmorphic features. Clinical characterization included reanalysis of available neuroimaging datasets and 2D portrait image analysis with GestaltMatcher. The functional consequences of ZSCAN10 loss were modelled in mouse embryonic stem cells (mESCs), including a knockout and a representative ZSCAN10 protein truncating variant. These models were characterized by gene expression and western blot analyses, chromatin immunoprecipitation and quantitative PCR (ChIP-qPCR) and immunofluorescence staining. Zscan10 knockout mouse embryos were generated and phenotyped. We prioritized bi-allelic ZSCAN10 loss-of-function variants in seven affected individuals from five unrelated families as the underlying molecular cause. RNA-sequencing analyses in Zscan10−/− mESCs indicated dysregulation of genes related to stem cell pluripotency. In addition, we established in mESCs the loss-of-function mechanism for a representative human ZSCAN10 protein truncating variant by showing alteration of its expression levels and subcellular localization, interfering with its binding to DNA enhancer targets. Deep phenotyping revealed global developmental delay, facial asymmetry and malformations of the outer ear as consistent clinical features. Cerebral MRI showed dysplasia of the semicircular canals as an anatomical correlate of sensorineural hearing loss. Facial asymmetry was confirmed as a clinical feature by GestaltMatcher and was recapitulated in the Zscan10 mouse model along with inner and outer ear malformations. Our findings provide evidence of a novel syndromic neurodevelopmental disorder caused by bi-allelic loss-of-function variants in ZSCAN10

Understanding the highly regioselective cyanothiolation of 1-alkynes catalyzed by palladium phosphine complexes

A computational study with the Becke3LYP DFT functional was carried out on the palladium-catalyzed regioselective cyanothiolation of 1-alkynes with thiocyanates. The full catalytic cycle was computed, starting from the oxidative addition and finishing with the reductive elimination. The two most important issues, namely, the regioselective bond cleavage of thiocyanates and the nature of insertion of 1-alkynes into a Pd-S bond, are discussed. The calculations indicate that the sulfur-cyano (PhS-CN) bond cleavage on Pd(0) is kinetically and thermodynamiclly more favorable than the carbon-sulfur (Ph-SCN) bond cleavage. The kinetic preference of 1,2-insertion over 2,1-insertion in the alkyne insertion step leads to the cyanothiolation products with the SPh group attached to the substituted carbon atom of 1-alkynes