gebhart/patrepeval huggingface dataset:
Mapping the Molecular Surface of the Analgesic NaV1.7-Selective Peptide Pn3a Reveals Residues Essential for Membrane and Channel Interactions (2020)

Compelling human genetic studies have identified the voltage-gated sodium channel Na<sub>V</sub>1.7 as a promising therapeutic target for the treatment of pain. The analgesic spider-venom-derived peptide μ-theraphotoxin-Pn3a is an exceptionally potent and selective inhibitor of Na<sub>V</sub>1.7; however, little is known about the structure-activity relationships or channel interactions that define this activity. We rationally designed 17 Pn3a analogues and determined their activity at hNa<sub>V</sub>1.7 using patch-clamp electrophysiology. The positively charged amino acids K22 and K24 were identified as crucial for Pn3a activity, with molecular modeling identifying interactions of these residues with the S3-S4 loop of domain II of hNa<sub>V</sub>1.7. Removal of hydrophobic residues Y4, Y27, and W30 led to a loss of potency (>250-fold), while replacement of negatively charged D1 and D8 residues with a positively charged lysine led to increased potencies (>13-fold), likely through alterations in membrane lipid interactions. Mutating D8 to an asparagine led to the greatest improvement in Pn3a potency at Na<sub>V</sub>1.7 (20-fold), while maintaining >100-fold selectivity over the major off-targets Na<sub>V</sub>1.4, Na<sub>V</sub>1.5, and Na<sub>V</sub>1.6. The Pn3a[D8N] mutant retained analgesic activity <i>in vivo</i>, significantly attenuating mechanical allodynia in a clinically relevant mouse model of postsurgical pain at doses 3-fold lower than those with wild-type Pn3a, without causing motor-adverse effects. Results from this study will facilitate future rational design of potent and selective peptidic Na<sub>V</sub>1.7 inhibitors for the development of more efficacious and safer analgesics as well as to further investigate the involvement of Na<sub>V</sub>1.7 in pain.
Data from Tumor necrosis factor deficiency inhibits mammary tumorigenesis and a tumor necrosis factor neutralizing antibody decreases mammary tumor growth in neu/erbB2 transgenic mice (2023)

&lt;div&gt;Abstract&lt;p&gt;Tumor necrosis factor-α (TNF-α) is a pleiotropic cytokine that is synthesized and secreted by cells of the immune system, as well as by certain epithelia and stroma. Based on our previous studies demonstrating TNF-stimulated proliferation of normal and malignant mammary epithelial cells, we hypothesized that TNF might promote the growth of breast cancer &lt;i&gt;in vivo&lt;/i&gt;. To test this, we generated bigenic mice that overexpressed activated neu/erbB2 in the mammary epithelium and whose TNF status was wild-type, heterozygous, or null. Mammary tumorigenesis was significantly decreased in TNF−/− mice (&lt;i&gt;n&lt;/i&gt; = 30) compared with that in TNF+/+ mice (&lt;i&gt;n&lt;/i&gt; = 27), with a palpable tumor incidence of 10.0% and 44.4%, and palpable tumors/mouse of 0.10 ± 0.06 and 0.67 ± 0.17, respectively. Tumorigenesis in the heterozygous group fell between that in the TNF+/+ and TNF−/− groups, but was not significantly different from either of the homozygous groups. The decreased tumor development in the TNF−/− mice was associated with a decreased proliferative index in the lobular and ductal mammary epithelium. To further investigate the role of TNF in breast cancer, mammary tumor–bearing mice whose tumors overexpressed wild-type neu/erbB2 were treated with a TNF-neutralizing antibody or a control antibody for 4 weeks (&lt;i&gt;n&lt;/i&gt; = 20/group). Mammary tumor growth was significantly inhibited in mice treated with the anti-TNF antibody compared with the control antibody. Together, these data show a stimulatory role for TNF in the growth of breast tumors and suggest that TNF antagonists may be effective in a subset of patients with breast cancer. [Mol Cancer Ther 2009;8(9):2655–63]&lt;/p&gt;&lt;/div&gt;
Subcortical tau‐accumulation predicts neuronal dysfunction in the cortex based on functional connectivity in 4R‐tauopathies (2022)

Abstract Background 4‐repeat (4R) tauopathies are neurodegenerative diseases characterized by cerebral accumulation of 4R tau pathology. The most prominent 4R‐tauopathies are progressive‐supranuclear‐palsy (PSP) and corticobasal‐syndrome (CBS) characterized by tau accumulation in subcortical nuclei as well as cortical neuronal dysfunction, as shown by PET‐assessed hypoperfusion and glucose hypometabolism. Yet, there is a spatial mismatch between subcortical tau deposition patterns and cortical neuronal dysfunction and it is unclear how these two pathological brain changes are interrelated. Here, we hypothesized that subcortical tau pathology induces diaschisis‐like neuronal dysfunction in functionally connected cortical regions. Method We included 47 patients with clinically diagnosed PSP or CBS who underwent structural MRI and 18 F‐PI‐2620 tau‐PET. PI‐2620 PET was recorded using a dynamic one‐shot, two‐stop acquisition protocol, to determine an early 0.5‐2.5min post‐tracer‐injection perfusion window for assessing cortical neuroinjury in 200 cortical ROIs of the Schaefer atlas, as well as a 20‐40min post‐tracer‐injection window to determine 4R‐tau load in 32 subcortical ROIs of the TIAN atlas. We determined tau epicenters as 10% of subcortical ROIs with highest tau‐PET, and assessed the connectivity of tau epicenters to cortical ROIs using an age‐matched 3T resting‐state fMRI template derived from 69 healthy elderly. Using linear regression, we assessed whether i) higher subcortical tau‐PET was associated with overall reduced cortical perfusion and ii) whether cortical hypoperfusion was observed preferentially in regions closely connected to subcortical tau epicenters. Result As hypothesized, higher subcortical tau‐PET was associated with lower cortical perfusion (R=‐0,37, p‐value: &lt;0,011, Fig.1). Using group‐average tau‐PET and perfusion‐PET, we found that the seed‐based connectivity pattern of subcortical tau epicenters predicted cortical perfusion patterns, where cortical regions that were more closely connected to the tau epicenter showed stronger hypoperfusion (R=‐0,16, p‐value: &lt;0,023, Fig.2A). This association was also observed on the subject level, as indicated by overall negative b‐values of the association between tau epicenter connectivity and cortical perfusion (one‐sample t‐test: t‐value: ‐3,45, p‐value: &lt;0,001, Fig.3). Conclusion In 4R‐tauopathies subcortical tau‐accumulation is associated with remote neuronal dysfunction in functionally connected cortical regions. This suggests that subcortical tau pathology may induce diaschisis‐like cortical dysfunction, which may contribute to clinical disease manifestation and clinical heterogeneity.
Clinical Experience With Regenerative Therapy in Heart Failure (2018)

Adoption of regenerative strategies for heart failure is challenged by mixed outcomes in clinical trials. Ongoing development plans strive to improve biotherapeutic potency, optimize delivery, standardize dosing, and target responsive patient populations. The CHART (Congestive Heart Failure Cardiopoietic Regenerative Therapy) program offers advanced experience in clinical development of next-generation regenerative therapies.
2152-PUB: Cardiac Autonomic Dysfunction in Patients with Psoriasis and without Metabolic Syndrome (2020)

Background: Studies have shown a connection between psoriasis (PsO) and metabolic syndrome (MS), diabetes mellitus and cardiovascular disease. In addition, MS is associated with autonomic dysfunction (AD). AD has also been associated with chronic arthritis including psoriatic arthritis, but there is lack of similar evidence in patients with PsO. The aim of this study was to look for an association between PsO and AD, independent of the presence of MS. Methods: Cross-sectional study of subjects with PsO without MS; age, sex and BMI matched healthy controls (HC); and age and sex matched subjects with MS. Subjects underwent skin evaluation by dermatologist, blood work for HbA1c, insulin, glucose, and lipids, sudomotor function testing with SudoscanTM device (Impeto Medical-Paris, France) and cardiac autonomic function testing with ANSAR device (ANX 3.0; ANSAR Group, Inc. Philadelphia). Results: We included 47 subjects (13 PsO, 16 HC and 18 MS). PsO subjects had worse cardiac autonomic function compared to the other groups, although glucose and insulin parameters were similar to the HC group (Table 1). No differences were seen in sudomotor function between the groups. Conclusions: PsO seems to have an association with cardiac autonomic dysfunction, independent of its relationship with insulin resistance and MS. Further studies are needed to clarify the significance of these findings and how they relate to MS and diabetes. Disclosure C.M. Casellini: None. H. Parson: None. M.D. Bailey: None. A. Barney: None. A.S. Van Voorhees: Consultant; Self; Celgene. Other Relationship; Self; AbbVie Inc., Lilly Diabetes. A.I. Vinik: None. E.S. Siraj: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Research Support; Self; Novo Nordisk Inc. Speaker’s Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc.
Design of Anonymous Attribute Authentication Mechanism (2009)

Privacy remains an issue for IT services. Users are concerned that their history of service use may be traceable since each user is assigned a single identifier as a means of authentication.In this paper, we propose a perfectly anonymous attribute authentication scheme that is both unidentifiable and untraceable. Then, we present the evaluation results of a prototype system using a PC and mobile phone with the scheme. The proposed scheme employs a self-blindable certificate that a user can change randomly; thus the certificate is modified for each authentication, and the authentication scheme is unidentifiable and untraceable. Furthermore, our scheme can revoke self-blindable certificates without leaks of confidential private information and check the revocation status without online access.
A harmonic retrieval framework for discontinuous motion estimation (1998)

Motion discontinuities arise when there are occlusions or multiple moving objects in the scene that is imaged. Conventional regularization techniques use smoothness constraints but are not applicable to motion discontinuities. In this paper, we show that discontinuous (or multiple) motion estimation can be viewed as a multicomponent harmonic retrieval problem. From this viewpoint, a number of established techniques for harmonic retrieval ran be applied to solve the challenging problem of discontinuous (or multiple) motion. Compared with existing techniques, the resulting algorithm is not iterative, which not only implies computational efficiency but also obviates concerns regarding convergence or local minima. It also adds flexibility to spatio-temporal techniques which have suffered from lack of explicit modeling of discontinuous motion. Experimental verification of our framework on both synthetic data as well as real image data is provided.
The MITLL NIST LRE 2007 language recognition system (2008)

This paper presents a description of the MIT Lincoln Laboratory language recognition system submitted to the NIST 2007 Language Recognition Evaluation. This system consists of a fusion of four core recognizers, two based on tokenization and two based on spectral similarity. Results for NIST’s 14-language detection task are presented for both the closed-set and open-set tasks and for the 30, 10 and 3 second durations. On the 30 second 14-language closed set detection task, the system achieves a 1% equal error rate.
Mechanistic Studies of Motexafin Gadolinium (Xcytrin®): A Redox Active Agent That Reacts with Electron-Rich Biological Substrates (2005)

Motexafin gadolinium (MGd, Xcytrin®) is a water soluble gadolinium(III) texaphyrin complex that is currently undergoing a Phase III clinical trial as an anticancer agent used in combination with radiation therapy of metastatic non-small cell lung cancer. It is also in clinical trials for use in a number of other oncological applications. Its mechanism of action is thought to rely, at least in part, on its ability to function as a redox cycling agent, capturing electrons from electron-rich endogenous species, so-called reducing metabolites, and transferring them to oxygen to produce various reactive oxygen species that are known to trigger apoptosis. In this chapter, the reaction of MGd and various other congeneric metallotexaphyrin complexes with the prototypical reducing species NADPH, ascorbate, and dithiothreitol, is summarized.
Hide-n-Sense: Privacy-aware secure mHealth sensing (2011)

As healthcare in many countries faces an aging population and rising costs, mobile sensing technologies promise a new opportunity. Using mobile health (mHealth) sensing, which uses medical sensors to collect data about the patients, and mobile phones to act as a gateway between sensors and electronic health record systems, caregivers can continuously monitor the patients and deliver better care. Furthermore, individuals can become better engaged in monitoring and managing their own health. Although some work on mHealth sensing has addressed security, achieving strong privacy for low-power sensors remains a challenge. We make three contributions. First, we propose an mHealth sensing protocol that provides strong security and privacy properties with low energy overhead, suitable for low-power sensors. The protocol uses three novel techniques: adaptive security, to dynamically modify transmission overhead; MAC striping, to make forgery difficult even for small-sized MACs; and an asymmetric resource requirement. Second, we demonstrate a prototype on a Chronos wrist device, and evaluate it experimentally. Third, we provide a security, privacy, and energy analysis of our system. 1
Development of minimally invasive techniques for management of medically-complicated obesity (2014)

The field of bariatric surgery has been rapidly growing and evolving over the past several decades. During the period that obesity has become a worldwide epidemic, new interventions have been developed to combat this complex disorder. The development of new laparoscopic and minimally invasive treatments for medically-complicated obesity has made it essential that gastrointestinal physicians obtain a thorough understanding of past developments and possible future directions in bariatrics. New laparoscopic advancements provide patients and practitioners with a variety of options that have an improved safety profile and better efficacy without open, invasive surgery. The mechanisms of weight loss after bariatric surgery are complex and may in part be related to altered release of regulatory peptide hormones from the gut. Endoscopic techniques designed to mimic the effects of bariatric surgery and endolumenal interventions performed entirely through the gastrointestinal tract offer potential advantages. Several of these new techniques have demonstrated promising, preliminary results. We outline herein historical and current trends in the development of bariatric surgery and its transition to safer and more minimally invasive procedures designed to induce weight loss.
An Explanation for Flow Features of Spike-Type Stall Inception in an Axial Compressor Rotor (2012)

The unsteady behavior and three-dimensional flow structure of spike-type stall inception in an axial compressor rotor were investigated by experimental and numerical analyses. Previous studies revealed that the test compressor falls into a mild stall after emergence of a spike, in which multiple stall cells, each consisting of a tornado-like vortex, are rotating. However, the flow mechanism from the spike onset to the mild stall remains unexplained. The purpose of this study is to describe the flow mechanism of a spike stall inception in a compressor. In order to capture the transient phenomena of spike-type stall inception experimentally, an instantaneous casing pressure field measurement technique was developed, in which 30 pressure transducers measure an instantaneous casing pressure distribution inside the passage for one blade pitch at a rate of 25 samplings per blade passing period. This technique was applied to obtain the unsteady and transient pressure fields on the casing wall during the inception process of the spike stall. In addition, the details of the three-dimensional flow structure at the spike stall inception were analyzed by a numerical approach using the detached-eddy simulation (DES). The instantaneous casing pressure field measurement results at the stall inception show that a low-pressure region starts traveling near the leading edge in the circumferential direction just after the spiky wave was detected in the casing wall pressure trace measured near the rotor leading edge. The DES results reveal the vortical flow structure behind the low-pressure region on the casing wall at the stall inception, showing that the low-pressure region is caused by a tornado-like separation vortex resulting from a leading-edge separation near the rotor tip. A leading-edge separation occurs near the tip at the onset of the spike stall and grows to form the tornado-like vortex connecting the blade suction surface and the casing wall. The casing-side leg of the tornado-like vortex generating the low-pressure region circumferentially moves around the leading-edge line. When the vortex grows large enough to interact with the leading edge of the next blade, the leading-edge separation begins to propagate, and then the compressor falls into a stall with decreasing performance.
Characteristics of top-gate thin-film transistors fabricated on nitrogen-implanted polysilicon films (1995)

The electrical characteristics of top-gate thin-film transistors (TFT's) fabricated on the nitrogen-implanted polysilicon of the doses ranging from 2/spl times/10/sup 12/-2/spl times/10/sup 14/ ions/cm/sup 2/ were investigated in this work. The experimental results showed that nitrogen implanted into polysilicon followed by an 850/spl deg/C 1 h annealing step had some passivation effect and this effect was much enhanced by a following H/sub 2/-plasma treatment. The threshold voltages, subthreshold swings, ON-OFF current ratios, and field effect mobilities of both n-channel and p-channel TFT's were all improved. Moreover, the hot-carrier reliability was also improved. A donor effect of the nitrogen in polysilicon was also found which affected the overall passivation effect on the p-channel TFT's.
Virtual-MIMO feedback and transmission for wireless ad hoc networks (2016)

Ina wireless ad hoc network, single-antenna nodes can cooperate in their transmissions to create a virtual multiple-input multiple-output (MIMO) channel for maximizing the spatial multiplexing gain. However, implementing virtual-MIMO transmission can result in overwhelming overhead, such as channel state information (CSI) feedback and local data exchange, as the number of cooperating nodes increases. To suppress this overhead, we apply the principle of virtual-MIMO transmission to CSI feedback and design a novel framework for supporting parallel feedback streams, called virtual-MIMO feedback. Building on this feedback framework, we optimize virtual-MIMO transmission techniques and quantify their throughput gains in the presence of CSI and local-exchange overhead. To be specific, the outage capacities of these virtual-MIMO techniques are analyzed, and the corresponding bandwidth allocation for local data exchange and long-range transmission is optimized in a way to maximize overall spectral efficiency. Finally, the improvement of spectral efficiency in proposed virtual-MIMO feedback and transmission is demonstrated by the simulation results.
Primary Human Immune Response to Neisseria meningitidis Serogroup C in Interleukin-12--Treated Severe Combined Immunodeficient Mice Engrafted with Human Peripheral Blood Lymphocytes (1997)

Lack of primary immune response in severe combined immunodeficient (SCID) mice engrafted with human peripheral blood lymphocytes (hu-PBL) has limited the applicability of this model. Use of human cytokines, in particular interleukin (IL)-12, was studied in the hu-PBL-SCID model. SCID mice were treated with IL-12 and reconstituted with hu-PBL in T replacement factor. The hu-PBL-SCID mice were immunized with serogroup C meningococcal polysaccharide (MCPS). The MCPS-specific antibody response was determined by ELISA. Thirteen of the 15 immunized, IL-12-treated hu-PBL-SCID mice demonstrated a primary human antibody response to MCPS ranging from 0.25 to 3.3 microg/mL, while no MCPS-specific antibody response was detectable in the 18 controls. Expression of cross-reactive idiotypic markers found on human anti-MCPS antibodies in the immunized hu-PBL-SCID mice was similar to that observed in immunized volunteers.
Abstract 2099: EM-seq enables accurate and precise methylome analysis of challenging DNA samples (2021)

Abstract DNA isolated from blood draws (cell-free DNA (cfDNA)) or from archival material like formalin fixed paraffin embedded (FFPE) tissues have advanced the field of cancer genetics. DNA methylation (5-methylcytosines (5mC) and 5-hydroxymethylcytosines (5hmC)) is a key epigenetic factor that plays an important role in cellular processes and it's misregulation results in diseased states like cancer. Advances in the field of sample preparation from biological matrices and genomics have enabled cancer biomarker identification based on methylation profiling. Bisulfite sequencing has been the gold standard for detection of methylation and is employed for both targeted and whole genome methylation analysis. However, the chemical based bisulfite conversion of cytosines to uracils leads to DNA damage which subsequently translates to shorter DNA insert sizes as well as biases in the data. DNA obtained from cfDNA and FFPE samples is typically of low quality and quantity making DNA methylation profiling using the harsh bisulfite conversion challenging. Robust biomarker detection relies primarily on the ability to profile methylation accurately. To overcome the drawbacks of bisulfite sequencing, we developed an enzyme based methylation detection technology, called NEBNext® Enzymatic Methyl-Seq (EM-Seq™), that minimizes damage to DNA enabling longer insert sizes, lower duplication rates and minimal GC bias resulting in more accurate quantification of methylation in the sample DNA. Using EM-Seq, we profiled cfDNA and lung FFPE DNA. Results for these challenging DNA types showed that the EM-Seq libraries had longer inserts, lower duplication rates, higher percentages of mapped reads and less GC bias compared to WGBS libraries. EM-seq libraries also identified a higher number of CpG's with even coverage facilitating accurate methylation calling. In conclusion, EM-Seq libraries have superior sequencing metrics resulting in robust methylation profiling for these types of challenging DNA samples. Citation Format: V K Chaithanya Ponnaluri, Louise Williams, Matthew A. Campbell, Vaishnavi Panchapakesa, Romualdas Vaisvila, Bradley Langhorst, Eileen Dimalanta, Theodore B. Davis. EM-seq enables accurate and precise methylome analysis of challenging DNA samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2099.