gebhart/patrepeval huggingface dataset:
Probing Structure and Functional Dynamics of (Large) Proteins with Aromatic Rings:  L-GFT-TROSY (4,3)D <u>HC</u>CH NMR Spectroscopy (2005)

NMR assignment of aromatic rings in proteins is a prerequisite for obtaining high-quality solution structures of proteins and for studying the dynamics and folding of their molecular cores. Here we present sensitive PFG-PEP L-GFT-(TROSY) (4,3)D HCCH NMR for identification of aromatic spin systems based on four-dimensional (4D) spectral information which can be rapidly obtained with high digital resolution. The G-matrix Fourier Transform (GFT) experiment relies on newly introduced longitudinal relaxation (L-)optimization for aromatic protons and is optimally suited for both sensitivity and sampling limited data collection, making it particularly attractive for NMR-based structural genomics. Applications are presented for 21 and 13 kDa proteins HR41 and MaR11, targets of the Northeast Structural Genomics Consortium for which data collection is, respectively, sensitivity and sampling limited. Complete assignment of aromatic rings enabled high-quality NMR structure determination, and nearly complete analysis of aromatic proton line widths allowed one to assess the flipping of most rings in HR41. Specifically, the ring of Tyr90 flips very slowly on the seconds time scale, thereby proving the absence of fast larger-amplitude motional modes which could allow the ring to flip. This indicates remarkable rigidity of the substructure in which the ring is embedded. Tyr90 is conserved among ubiquitin-conjugating enzymes E2, to which HR41 belongs, and is located in spatial proximity to the interface between E2 and ubiquitin protein ligase E3. Hence, the conformational rigidity and/or the slow motional mode probed by the ring might be of functional importance.
Cell proliferation as a biomarker for response to immune checkpoint inhibitors in highly inflamed renal cell carcinoma. (2019)

61 Background: Cell proliferation is an important marker of survival in many tumors and we hypothesized that this attribute could be related to response to immune checkpoint inhibitors in RCC. Previously we reported (SITC 2018) moderately proliferative lung cancer has a much higher response rate than either poorly or highly proliferative tumors. Methods: 69 FFPE tumor samples of RCC were evaluated by RNA-seq to measure transcript levels of 394 immune related genes, including 10 related to cell proliferation (BUB1, CCNB2, CDK1, CDKN3, FOXM1, KIAA0101, MAD2L1, MELK, MKI67, TOP2A). Cell proliferation, defined as the mean mRNA expression of these 10 genes was evaluated for association with ORR to ICIs by RECIST v1.1 criteria for both PD-L1 IHC positive and negative cases. Cell proliferation for each case was split into 3 tertiles of poorly ( < 33), moderately (33-66) and highly ( > 66) proliferative compared to a reference population. Poorly and highly proliferative were grouped for comparison to moderately proliferative tumors. Tumors were inflamed or non-inflamed based upon RNA‐seq analysis of CD8 compared to a reference population of more than 500 cases of multiple tumors. Non-inflamed, or immune desert tumors, defined as the lower 25 th percentile of rank for CD8 + T-cells, and greater than 75 th percentile of rank as inflamed. Results: In our cohort of 69 patient the overall ORR was 18.8%. 15.9% of tumors were non-inflamed with an ORR of 9.1%. For 36.2% inflamed tumor the ORR was 32%. For cell proliferation 62.2% were poorly proliferative, 8.7% were highly proliferative, and 29% were moderately. ORR in moderately proliferative tumors was 30% versus 14.2% in poorly/highly proliferative tumors. In inflamed tumors, ORR in moderately proliferative tumors was 37.5% as opposed to 17.6% in poorly/highly proliferative tumors. In 11 non-inflamed tumors, there was only one responder, which was a poorly/highly proliferative tumor. Conclusions: Cell proliferation may play a crucial role in distinguishing RCC patients who may have a clinical benefit to ICI, including the important subgroup of inflamed tumors. Moderately proliferative tumors have a higher ORR than their poorly/highly counterparts.
Ubiquitin chain editing mechanisms on the mammalian proteasome (2013)

The 26S proteasome is now accepted as a versatile and active player for fine‐tuning the substrate degradation cycle rather than a passive degradation machinery as once thought. However, ubiquitin conjugate processing by the mammalian proteasome remains poorly understood, partly due to the lack of specific tools. We recently developed a small‐molecule inhibitor selectively targeting USP14, a major deubiquitinating enzyme on the proteasome. By employing this inhibitor, we revealed that ubiquitin chain processing on the proteasome is surprisingly sophisticated, discriminating very sensitively among substrates on the basis of diverse configurations and architectures of the ubiquitin conjugates. Our data suggest a dynamic engagement of Usp14 in recognizing and processing the chain in the context of proteasome.
Abstract 45: Sortilin Regulates Arterial Calcification in Atherosclerotic Mice and Associates With Cardiovascular Risk in Humans (2016)

Background: Arterial calcification associates with cardiovascular morbidity and mortality. Human genome-wide association studies linked the SORT1 gene encoding sortilin and coronary artery calcification. We previously demonstrated in vitro that calcification requires sortilin phosphorylation by Fam20C. We hypothesized that sortilin mediates arterial calcification in vivo and that serum sortilin levels can predict cardiovascular events. Results: We assessed the effects of genetic deletion of sortilin ( Sort1 ) in LDL receptor-deficient mice ( Ldlr -/- ) consuming a high-fat, high-cholesterol diet. Sort1 -/- Ldlr -/- mice exhibited 80% lower aortic calcification as compared to control Ldlr -/- mice in intact arteries (fluorescence reflectance imaging of a NIRF calcium tracer, p<0.01). Sort1 -/- Ldlr -/- mice showed 88% lower extracted aortic calcium (p<0.05). Histological analysis revealed less tissue non-specific alkaline phosphatase activity and arterial microcalcification. Transfer of Sort1 -deficient bone marrow cells to irradiated atherosclerotic mice does not alter aortic calcification, indicating that immune cell-derived sortilin may not contribute to sortilin-mediated arterial calcification. In contrast to arterial calcium, Sort1 -deficiency did not alter bone mineralization assessed by μCT and histomorphometry. In a community-based cohort of men aged ≥50 (n=830), abdominal aortic calcification (AAC) was assessed by dual energy X-ray absorptiometry using Kauppila score. Serum sortilin levels were measured by ELISA. After adjustment for confounders (including cholesterol concentration), sortilin levels correlated positively with severe AAC. The highest sortilin quartile associated with higher odds of severe AAC even in men without ischemic heart disease (OR=2.0, p<0.05). Among 745 men followed up prospectively for 7.8 years, major adverse cerebrovascular events occurred in 76 men. Elevated serum sortilin associated with higher event risk (adjusted for confounders, HR=2.8, p<0.001) even in men without diabetes (HR=3.5, p<0.001). Conclusions: Sortilin is a novel therapeutic target to modulate the formation of arterial calcification and a biomarker of both aortic calcification and cardiovascular risk.
Creating lactose phosphorylase enzymes by directed evolution of cellobiose phosphorylase (2009)

Disaccharide phosphorylases are interesting enzymes for the production of sugar phosphates from cheap starting materials and for the synthesis of novel glycosides. Cellobiose phosphorylase (CP) from Cellulomonas uda was subjected to directed evolution in order to create enzyme variants with significantly increased lactose phosphorylase (LP) activity, useful for the production of alpha-D-galactose 1-phosphate. In a first round, random mutagenesis was performed on part of the CP gene and the resultant library was selected on minimal lactose medium. One clone containing six amino acid mutations was found with increased LP activity compared with the wild-type CP enzyme. The negative and neutral mutations were eliminated by site-directed mutagenesis and the resultant enzyme variant containing two amino acid substitutions (T508A/N667T) showed more LP activity than the parent mutant. Saturation mutagenesis of the beneficial sites and screening for improved mutants allowed us to identify the T508I/N667A mutant which has 7.5 times higher specific activity on lactose than the wild-type. The kinetic parameters of the mutants were determined and showed that the increased LP activity was caused by a higher k(cat) value. This is the first report of an engineered CP with modified substrate specificity.
Multipoint videoconferencing with scalable video coding (2006)

We describe a system for multipoint videoconferencing that offers extremely low end-to-end delay, low cost and complexity, and high scalability, alongside standard features associated with high-end solutions such as rate matching and personal video layout. The system accommodates heterogeneous receivers and networks based on the Internet Protocol and relies on scalable video coding to provide a coded representation of a source video signal at multiple temporal and spatial resolutions as well as quality levels. These are represented by distinct bitstream components which are created at each end-user encoder. Depending on the specific conferencing environment, some or all of these components are transmitted to a Scalable Video Conferencing Server (SVCS). The SVCS redirects these components to one or more recipients depending on, e.g., the available network conditions and user preferences. The scalable aspect of the video coding technique allows the system to adapt to different network conditions, and also accommodates different end-user requirements (e.g., a user may elect to view another user at a high or low spatial resolution). Performance results concerning flexibility, video quality and delay of the system are presented using the Joint Scalable Video Model (JSVM) of the forthcoming SVC (H.264 Annex G) standard, demonstrating that scalable coding outperforms existing state-of-the-art systems and offers the right platform for building next-generation multipoint videoconferencing systems.
Resistance to bovine respiratory syncytial virus (BRSV) induced in calves by a recombinant bovine herpesvirus-1 expressing the attachment glycoprotein of BRSV. (1998)

The ability of a bovine herpesvirus-1 (BHV-1) recombinant expressing the G protein of bovine respiratory syncytial virus (BRSV) to protect against BRSV infection was examined in calves. A synthetic G gene was inserted behind the gE promoter of BHV-1 to give a gE-negative, BHV-1/G recombinant. Gnotobiotic calves, vaccinated intranasally and intratracheally with BHV-1/G were challenged 6 weeks later with the Snook strain of BRSV. As controls, calves were vaccinated with a gE-negative mutant of BHV-1 which contains a frame-shift (BHV-1/gEfs). Whereas infection with BHV-1/gEfs induced only mild clinical signs, infection with BHV-1/G resulted in more severe clinical disease and higher titres of BHV-1/G were isolated from the lungs when compared with BHV-1/gEfs. Thus, expression of the G protein of BRSV increased the virulence of BHV-1 for calves. Vaccination with BHV-1/G induced BRSV-specific antibody in serum and respiratory secretions. However, only one calf developed low levels of BRSV complement-dependent neutralizing antibody. Although BHV-1/G primed calves for BRSV-specific lymphocyte proliferative responses, there was no evidence for priming of BRSV-specific cytotoxic T cells. After challenge with BRSV, there was a significant reduction in nasopharyngeal excretion of BRSV in BHV-1/G-vaccinated calves compared with controls and BRSV was isolated from the lung of only one of five vaccinated calves compared with all four control animals. In addition, the extent of gross pneumonic lesions 7 days after BRSV challenge was significantly reduced in calves vaccinated with BHV-1/G compared with controls given BHV-1/gEfs.
A New Family of Halogen‐Chelated Hoveyda–Grubbs‐Type Metathesis Catalysts (2012)

Coordination, not insertion: New ruthenium benzylidenes with a chelating halogen atom were easily prepared and showed excellent stability and activity as metathesis catalysts (see figure). Structure-activity studies reveal that strength of the ruthenium-halogen interaction can be tuned across a wide range to set up a family of latent to active catalysts.
Securing the use of sensitive data on remote devices using a hardware-software architecture (2010)

Many corporations, private organizations, and government agencies maintain sensitive data that must be accessed remotely by their employees using portable devices. The organizations have a responsibility to secure the data to ensure that it does not get used inappropriately or get disseminated beyond these trusted users. We have designed a computer architecture for these devices, combining new hardware and software, that allows trust to be placed in the devices even when they are not under the organization's physical control. 
We have designed, implemented, and tested the Authority-mode Secret-Protection Architecture, which places roots of trust in hardware in the processor chip. It provides new hardware mechanisms based on these roots of trust to protect the execution of trusted software and to provide that software with master secrets. The software uses the master secrets to secure the sensitive data and to communicate securely over the network. The user interacts with this software, which enforces security policies while giving access to data. 
The organization designates a central authority that will manage the software on the devices, set security policies, communicate with the devices, and control access to data. Our new hardware mechanisms bind together the device's on-chip roots of trust with the authority's data and trusted software, such that the authority can be assured that the security policies will always be enforced. 
To show how our design can be adapted to other platforms, we provide a modified architecture for embedded devices. We additionally demonstrate how the full architecture can be integrated with trustworthy system software in a mandatory access control system. 
Finally, we have built a testing framework that can help designers validate new security architectures like ours. The framework allows new architectures to be modeled in a virtualization environment, where a separate testing system has complete controllability and observability over hardware and software. It is used to test the effects of various security attacks and to assist in the development of trusted software for the new architecture. We use the framework to test the prototype hardware and software of our architecture.
Photonic crystal fibres for sensor applications (2003)

Photonic crystal fibres (PCF) offer extraordinary control over their waveguiding properties via the geometry of their microstructure. We shall describe the design principles for PCF, their practical fabrication and their potential and actual applications in sensor systems.
Development of a Pulsed Pressure-Based Technique for Cavitation Damage Study (2012)

Cavitation occurs in many fluid systems and can lead to severe material damage. To assist the study of cavitation damage, a novel testing method utilizing pulsed pressure was developed. In this talk, the scientific background and the technical approach of this development are present and preliminary testing results are discussed. It is expected that this technique can be used to evaluate cavitation damage under various testing conditions including harsh environments such as those relevant to geothermal power generation.
Hybrid stretchable circuits on silicone substrate (2014)

When rigid and stretchable components are integrated onto a single elastic carrier substrate, large strain heterogeneities appear in the vicinity of the deformable-non-deformable interfaces. In this paper, we report on a generic approach to manufacture hybrid stretchable circuits where commercial electronic components can be mounted on a stretchable circuit board. Similar to printed circuit board development, the components are electrically bonded on the elastic substrate and interconnected with stretchable electrical traces. The substrate—a silicone matrix carrying concentric rigid disks—ensures both the circuit elasticity and the mechanical integrity of the most fragile materials.
Discovery of (1<i>S</i>,2<i>R</i>,3<i>R</i>)-2,3-Dimethyl-2-phenyl-1-sulfamidocyclopropanecarboxylates: Novel and Highly Selective Aggrecanase Inhibitors (2011)

Aggrecanases, particularly aggrecanase-1 (ADAMTS-4) and aggrecanase-2 (ADAMTS-5), are believed to be key enzymes involved in the articular cartilage breakdown that leads to osteoarthritis. Thus, aggrecanases are considered to be viable drug targets for the treatment of this debilitating disease. A series of (1S,2R,3R)-2,3-dimethyl-2-phenyl-1-sulfamidocyclopropanecarboxylates was discovered to be potent, highly selective, and orally bioavailable aggrecanase inhibitors. These compounds have unique P1' groups comprising novel piperidine- or piperazine-based heterocycles that are connected to a cyclopropane amino acid scaffold via a sulfamido linkage. These P1' groups are quite effective in imparting selectivity over other MMPs, and this selectivity was further increased by incorporation of a methyl substituent in the 2-position of the cyclopropane ring. In contrast to classical hydroxamate-based inhibitors that tend to lack metabolic stability, our aggrecanase inhibitors bear a carboxylate zinc-binding group and have good oral bioavailability. Lead compound 13b, characterized by the novel P1' portion of 1,2,3,4-tetrahydropyrido[3',4':4,5]imidazo[1,2-a]pyridine ring, is a potent and selective aggrecanse inhibitor with excellent pharmacokinetic profiles.
Terahertz Pulse Shaping Using Diffractive Legos (2020)

Recent advances in deep learning have been providing non-intuitive solutions to various inverse problems in optics. At the intersection of machine learning and optics, diffractive networks merge wave-optics with deep learning to design task-specific elements to all-optically perform various tasks such as object classification and machine vision. Here, we present a diffractive network, which is used to shape an arbitrary broadband pulse into a desired optical waveform, forming a compact pulse engineering system. We experimentally demonstrate the synthesis of square pulses with different temporal-widths by manufacturing passive diffractive layers that collectively control both the spectral amplitude and the phase of an input terahertz pulse. Our results constitute the first demonstration of direct pulse shaping in terahertz spectrum, where a complex-valued spectral modulation function directly acts on terahertz frequencies. Furthermore, a Lego-like physical transfer learning approach is presented to illustrate pulse-width tunability by replacing part of an existing network with newly trained diffractive layers, demonstrating its modularity. This learning-based diffractive pulse engineering framework can find broad applications in e.g., communications, ultra-fast imaging and spectroscopy.
Advances in the scintillation performance of LSO:Ce single crystals (2003)

We investigated the scintillation characteristics of 2186 LSO crystals that were cut from over 400 crystal boules. We measured the light output and energy resolution of all crystals and also measured the decay times of a broad sampling of the crystals. We observed a significant reduction in the variation of both light output and decay time in this population of crystals compared to the results previously published in 1998. The reduced variation in scintillation properties may be attributed to better control of the populations of the two Ce scintillation centers in LSO, as well as better control of the effect of quenching centers and the effects of Ce segregation during crystal growth.
PI-Sole: A Low-Cost Solution for Gait Monitoring Using Off-The-Shelf Piezoelectric Sensors and IMU (2019)

In this paper, viability of low-cost off-the-shelf Piezoelectric ceramic disc elements is explored for an insole-based gait monitoring system, `PI-Sole' (Piezo In-Sole). Piezoelectric elements can sense dynamic changes in pressure in a closed-loop environment with good sensitivity and a wide measurement range. In this paper, method to enable these elements to continuously sense plantar pressure while walking is proposed, making them a very cost-efficient alternative to the widely used Force Sensing Resistors (FSR) and pressure plates for monitoring human gait. However, piezoelectric elements show hysteresis in their force response, inducing a drift in calculated pressure which increases with time. A novel and effective method to perform detrending of the signal is also presented utilizing stride contexts from a 6-DoF Inertial Measurement Unit (IMU) and the same is utilized to perform zero-correction in the pressure data. 3-D trajectories of strides are calculated using the IMU, and parameters like stride length, stride height etc. are further derived. In order to test the validity of our proposed methods, important kinetic parameters like Vertical Ground Reaction Force (VGRF) and Center of Pressure (CoP) are calculated using PI-Sole and compared to the ones calculated using FSR's in multiple prior works. Applicability of PI-Sole is demonstrated further by depicting and analysing characteristic differences between a heel-strike toe-off stance type, and a flat-strike stance type, the latter being one of the primary symptoms in many cases of pathological gait, including Parkinsonian gait. Important artefacts from foot's height profile while walking are analysed for both stance types in context of standard gait events. We report a mean error of 2.8cm in stride length calculation, and a mean accuracy of 94.5% in calculating swing/stance duration of gait cycles.
DESIGN AND EVALUATION OF 5′-MODIFIED NUCLEOSIDE ANALOGS AS PRODRUGS FOR AN <i>E. COLI</i> PURINE NUCLEOSIDE PHOSPHORYLASE MUTANT (2005)

Our studies have led to the identification of an E. coli PNP mutant (M64V) that is able to cleave numerous 5'-modified nucleoside analogs with much greater efficiency than the wild-type enzyme. The biological activity of the three best substrates of this mutant (9-[6-deoxy-alpha-L-talofuranosyl]-6-methylpurine (methyl(talo)-MeP-R), 9-[6-deoxy-alpha-L-talofuranosyl]-2-F-adenine, and 9-[alpha-L-lyxofuranosyl]-2-F-adenine) were evaluated so that we can optimally utilize these compounds. Our results indicated that the mechanism of toxicity of methyl(talo)-MeP-R to mice was due to its cleavage to MeP by a bacterial enzyme, and that the toxicity of the two F-Ade analogs was due to their cleavage to F-Ade by mammalian methylthioadenosine phosphorylase.
Design and Synthesis of Tetrahydroisoquinoline Derivatives as Anti-Angiogenesis and Anti-Cancer Agents (2021)

The results indicated that all the compounds showed moderate to high activity for KRas inhibition. The THIQs bearing the chloro group at the 4-position of the phenyl ring (GM-3-18) exhibited significant KRas inhibition against all colon cancer cell lines.
Chemistry of chelocardin II: chemical modifications at C<sub>2″</sub> and C<sub>12a</sub> (1977)

A selective reduction of chelocardin has been developed leading to 12a-deoxychelocardin which retains much of the antibacterial potency of the parent antibiotic, unlike the analogous reduction of tetracycline. Reaction of an N-protected chelocardin with amide acetals leads exclusively to products in which the condensation has occurred at the methyl group of the acyl side chain.