gebhart/patrepeval huggingface dataset:
Polymer Micropatches as Natural Killer Cell Engagers for Tumor Therapy (2023)

Natural killer (NK) cell therapies have emerged as a potential therapeutic approach to various cancers. Their efficacy, however, is limited by their low persistence and anergy. Current approaches to sustain NK cell persistence <i>in vivo</i> include genetic modification, activation via pretreatment, or coadministration of supporting cytokines or antibodies. Such supporting therapies exhibit limited efficacy <i>in vivo</i>, in part due to the reversal of their effect within the immunosuppressive tumor microenvironment and off-target toxicity. Here, we report a material-based approach to address this challenge. Specifically, we describe the use of polymeric micropatches as a platform for sustained, targeted activation of NK cells, an approach referred to as microparticles as cell engagers (MACE). Poly(lactide-<i>co</i>-glycolic) acid (PLGA) micropatches, 4-8 μm in diameter and surface-modified with NK cell receptor targeting antibodies, exhibited strong adhesion to NK cells and induced their activation without the need of coadministered cytokines. The activation induced by MACE was greater than that induced by nanoparticles, attesting to the crucial role of MACE geometry in the activation of NK cells. MACE-bound NK cells remained viable and exhibited trans-endothelial migration and antitumor activity <i>in vitro</i>. MACE-bound NK cells activated T cells, macrophages, and dendritic cells <i>in vitro</i>. Adoptive transfer of NK-MACE also demonstrated superior antitumor efficacy in a mouse melanoma lung metastasis model compared to unmodified NK cells. Overall, MACE offers a simple, scalable, and effective way of activating NK cells and represents an attractive platform to improve the efficacy of NK cell therapy.
Fluorescent vinblastine probes for live cell imaging (2016)

Herein we describe the synthesis of several fluorescent analogues of the clinically approved microtubule destabilizing agent vinblastine. The evaluated probes are the most potent described and provides the first example of uptake, distribution and live cell imaging using this well known antimitotic agent.
Role of the linker between the zinc binding domain and the polymerization domain of the bacteriophage T7 DNA primase (2006)

T7 DNA primase is composed of a catalytic RNA polymerase domain (RPD) and a zinc binding domain (ZBD) that are connected by an unstructured linker of 16 residues. The two domains are required for initiating the formation of a functional tetraribonucleotide, 5′‐pppACCC‐3′, from ATP and CTP ( de novo synthesis) and for extending 5′‐AC‐3′ diribonucleotides or 5′‐ACC‐3′ triribonucleotides into a functional 5′‐ACCC‐3′ in the presence of CTP (diribonucleotide/triribonucleotide extension) in a template‐directed manner. We have changed the distance between these domains by deleting or adding residues from the linker connecting the two domains. We find that the wild type primase is superior in de novo synthesis compared to primases having longer (21 residues) or shorter (10 residues) linkers. The activity of the altered primases is reduced by 2‐fold and 10‐fold, respectively. Interestingly, the primase with the shorter linker exhibits a 2‐fold enhancement in its ability to extend di‐ and triribonucleotides, whereas the primase with the longer linker extends ribonucleotides 2‐fold less efficiently compared to the wild type primase. The wild type and the altered T7 DNA primases do not extend diribonucleotides by the ZBD of one subunit acting on the RPD of an adjacent subunit ( trans mode), whereas de novo synthesis is feasible in this mode. We propose that the formation of the diribonucleotide and the extension of the dimer or trimer into a functional tetramer is a stepwise process in which distinct interactions of the ZBD are required. This work was supported by United States Public Health Services Grant GM 54397
Structure Formation in an Ionic Liquid Wetting Layer: A Combined STM, IRAS, DFT and MD Study of [C2C1Im][OTf] on Au(111) (2023)

In a solid catalyst with ionic liquid layer (SCILL), ionic liquid (IL) coatings are used to improve the selectivity of noble metal catalysts. To understand the origins of this selectivity control, we performed model studies by surface science methods in ultrahigh vacuum (UHV). We investigated the growth and thermal stability of ultrathin IL films by infrared reflection absorption spectroscopy (IRAS). We combined these experiments with scanning tunneling microscopy (STM) to obtain information on the orientation of the ions, the interactions with the surface, the intermolecular interactions, and the structure formation. Additionally, we performed DFT calculations and molecular dynamics (MD) simulations to interpret the experimental data. We studied the IL 1-ethyl-3-methylimidazolium trifluoromethanesulfonate [C<sub>2</sub> C<sub>1</sub> Im][OTf] on Au(111) surfaces. We observe a weakly bound multilayer of [C<sub>2</sub> C<sub>1</sub> Im][OTf], which is stable up to 390 K, while the monolayer desorbs at ∼450 K. [C<sub>2</sub> C<sub>1</sub> Im][OTf] preferentially adsorbs at the step edges and elbows of the herringbone reconstruction of Au(111). The anion adsorbs via the SO<sub>3</sub> group with the molecular axis perpendicular to the surface. At low coverage, the [C<sub>2</sub> C<sub>1</sub> Im][OTf] crystallizes in a glass-like 2D phase with short-range order. At higher coverage, we observe a phase transition to a 6-membered ring structure with long-range order.
Preparation of a Burkholderia Mallei Vaccine (2001)

Abstract : Since Burkholderia mallie is of significance as an agent of bioterrorism (Category B, Centers for Disease Control, U.S.) and biological warfare, the development of effective vaccines and treatments is of particular concern. Our understanding of the disease caused by this organism is rapidly emerging, and we must move forward with our studies on the pathogenesis of this disease in order to develop new and effective vaccines and/or therapies against this organism. There is considerable dual use potential, since the development of vaccines and treatments can provide important items to assist the World Health Organization, to assist in providing a state of preparedness in case of bioterrorism attacks and to assist signatories of the Biological and Toxin Weapons Convention under Article X of the Convention. The long-term objective of our research is to define at a molecular level the pathogenesis of disease due to Burkholderia ssp. My laboratory is recognized internationally as a world leader in the understanding of the pathogenesis of disease caused by Burkholderia ssp., and considerable advances in understanding of the diseases caused by these organisms have already been made by my laboratory.
QoS analysis of cognitive radios employing HARQ (2017)

Recently, the demand for faster and more reliable data transmission has brought up complex communications systems. As a result, it has become more difficult to carry out closed-form solutions that can provide insight about performance levels. In this paper, different from the existing research, we study a cognitive radio system that employs hybrid-automatic-repeat-request (HARQ) protocols under quality-of-service (QoS) constraints. We assume that the secondary users access the spectrum by utilizing a strategy that is a combination of underlay and interweave access techniques. Considering that the secondary users imperfectly perform channel sensing in order to detect the active primary users and that there is a transmission deadline for each data packet at the secondary transmitter buffer, we formulate the state-transition model of the system. Then, we obtain the state-transition probabilities when HARQ-chase combining is adopted. Subsequently, we provide the packet-loss rate in the channel and achieve the effective capacity. Finally, we substantiate our analytical derivations with numerical results.
Associations of Tissue Tumor Mutational Burden and Mutational Status With Clinical Outcomes With Pembrolizumab Plus Chemotherapy Versus Chemotherapy For Metastatic NSCLC (2022)

These findings support pembrolizumab-combination as first-line treatment in patients with metastatic NSCLC and do not suggest the utility of tTMB, <i>STK11, KEAP1,</i> or <i>KRAS</i> mutation status as a biomarker for this regimen.
Thyroid Hormones Stabilize Acetylcholinesterase mRNA in Neuro-2A Cells That Overexpress the β1 Thyroid Receptor (1995)

We investigated the intracellular events involved in the 3,3',5-triiodo-L-thyronine (T3)-induced accumulation in acetylcholinesterase (AChE) activity in neuroblastoma cells (neuro-2a) that overexpress the human thyroid receptor beta 1 (hTR beta 1). Treatment of these cells with T3 increased AChE activity and its mRNAs after a lag period of 24-48 h, and these levels increased through stabilization of the transcripts by T3. T3 had no effect on the transcriptional rate or processing of AChE transcripts. The protein kinase inhibitor H7 inhibited T3-induced accumulation in AChE activity and its mRNAs, whereas okadaic acid (a potent inhibitor of phosphatases 1 and 2A) potentiated the effect of T3. Okadaic acid and H7 have no effect on the binding of hTR beta 1 to T3 or the transcriptional rate of the AChE gene. Finally, treatment of cells with T3 stimulated cytosolic serine/threonine, but not tyrosine kinase, activities. The time course analysis reveals that the increase in serine/threonine activity precedes the effect of T3 on AChE mRNAs. These results suggest that activation of a serine/threonine protein kinase pathway might be a link between nuclear thyroid hormone receptor activation and stabilization of AChE mRNA.
Agglomeration of Calcium Oxalate Monohydrate in Synthetic Urine (1992)

Summary— The development of agglomerated particles of calcium oxalate monohydrate (COM) on the semi-batch precipitation from a synthetic urine carried out at physiological conditions (37°C, pH = 5.5) was studied by optical and electron scanning microscopy. COM agglomerates develop by primary and secondary agglomeration proceeding simultaneously; the latter mechanism is, however, less important than the former. Citrate ions modify slightly the COM crystal shape and inhibit primary agglomeration. Mucin particles serve as a substrate for preferential formation (nucleation) of new COM crystals. The structure of formed agglomerates closely resembles that of a certain type of COM renal calculi. A combination of primary agglomeration of crystals forming stones and nucleation of new crystals on a mucoprotein layer partially covering their surface constitutes the possible mechanism of such stone development. Experimental data support this mechanism.
Auxora Versus Standard of Care For The Treatment of Severe or Critical COVID-19 Pneumonia: Results From A Randomized Controlled Trial (2020)

Abstract BACKGROUND: Calcium release-activated calcium (CRAC) channel inhibitors stabilize the pulmonary endothelium and block proinflammatory cytokine release, potentially mitigating respiratory complications observed in patients with COVID-19. This study aimed to investigate the safety and efficacy of Auxora, a novel, intravenously administered CRAC channel inhibitor, in adults with severe or critical COVID-19 pneumonia METHODS: A randomized, controlled, open-label study of Auxora was conducted in adults with severe or critical COVID-19 pneumonia. Patients were randomized 2:1 to receive three doses of once-daily Auxora versus standard of care (SOC) alone. The primary objective was to assess safety and tolerability of Auxora. Following FDA guidance, study enrollment was halted early to allow for transition to a randomized, blinded, placebo-controlled study. RESULTS: In total, 17 patients with severe and three with critical COVID-19 pneumonia were randomized to Auxora and nine with severe and one with critical COVID-19 pneumonia to SOC. Similar proportions of patients receiving Auxora and SOC experienced ≥1 adverse event (75% versus 80%, respectively). Fewer patients receiving Auxora experienced serious adverse events versus SOC (30% versus 50%, respectively). Two patients (10%) receiving Auxora and two (20%) receiving SOC died in the 30 days after randomization. Among patients with severe COVID-19 pneumonia, median time to recovery with Auxora was five days versus 12 days with SOC; recovery rate ratio was 1.87 (95%CI, 0.72, 4.89). Invasive mechanical ventilation was needed in 18% of patients with severe COVID-19 pneumonia receiving Auxora versus 50% receiving SOC (absolute risk reduction=32%; 95%CI, -0.07, 0.71). Outcomes measured by an 8-point ordinal scale were significantly improved for patients receiving Auxora, especially for patients with a baseline PaO 2 /FiO 2 =101-200. CONCLUSIONS: Auxora demonstrated a favorable safety profile in patients with severe or critical COVID-19 pneumonia and improved outcomes in patients with severe COVID-19 pneumonia. These results, however, are limited by the open-label study design and small patient population resulting from early cessation of enrollment in response to regulatory guidance. The impact of Auxora on respiratory complications in patients with severe COVID-19 pneumonia will be further assessed in a planned randomized, blinded, placebo-controlled study. Trial registration: ClinicalTrials.gov, NCT04345614. Submitted 7April2020 - https://clinicaltrials.gov/ct2/show/NCT04345614
Facial Misrecognition Systems: Simple Weight Manipulations Force DNNs to Err Only on Specific Persons (2023)

In this paper, we describe how to plant novel types of backdoors in any facial recognition model based on the popular architecture of deep Siamese neural networks. These backdoors force the system to err only on natural images of specific persons who are preselected by the attacker, without controlling their appearance or inserting any triggers. For example, we show how such a backdoored system can classify any two images of a particular person as different people, or any two images of a particular pair of persons as the same person, with almost no effect on the correctness of its decisions for other persons. Surprisingly, we show that both types of backdoors can be implemented by applying linear transformations to the model's last weight matrix, with no additional training or optimization, using only images of the backdoor identities. A unique property of our attack is that multiple backdoors can be independently installed in the same model by multiple attackers, who may not be aware of each other's existence, with almost no interference. We have experimentally verified the attacks on a SOTA facial recognition system. When we tried to individually anonymize ten celebrities, the network failed to recognize two of their images as being the same person in $97.02\%$ to $98.31\%$ of the time. When we tried to confuse between the extremely different-looking Morgan Freeman and Scarlett Johansson, for example, their images were declared to be the same person in $98.47 \%$ of the time. For each type of backdoor, we sequentially installed multiple backdoors with minimal effect on the performance of each other (for example, anonymizing all ten celebrities on the same model reduced the success rate for each celebrity by no more than $1.01\%$). In all of our experiments, the benign accuracy of the network on other persons barely degraded (in most cases, it degraded by less than $0.05\%$).
Particle removal from silicon wafer surface in wet cleaning process (1993)

Particle removal from silicon wafer surfaces was studied using acid and alkaline solutions employed in wet cleaning processes found in semiconductor manufacturing. It was demonstrated that alkaline solutions are superior to acid solutions in terms of particle removal efficiency. The following particle removal mechanism in the alkaline solutions was confirmed: the solutions etch the wafer surfaces to lift off particles, and the particles are then electrically repelled by the wafer surfaces. It was determined experimentally that an etch rate of 0.25 nm/min or more is required to lift off the particles adsorbed on the wafer surfaces. It was also confirmed that when the pH value of NH/sub 4/OH-H/sub 2/O/sub 2/-H/sub 2/O solution becomes higher, polystyrene latex spheres and natural organic particles are oxidized, with their surface turning into a gel and their shape changing. The particle removal efficiency was demonstrated to be degraded by the oxidation of organic particles. The results suggest that the mixing ratio of the NH/sub 4/OH-H/sub 2/O/sub 2/-H/sub 2/O solution should be set at 0.05:1:5.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Conservative streamtube solution of steady-state Euler equations (1984)

This paper presents a new method for solving the steady state Euler equations. The method is similar to streamline curvature methods but has a conserative finite volume formulation which ensures correct shock capturing. Either wall position or wall pressure may be prescribed as boundary conditions, permitting both direct and inverse calculations. In supersonic applications the solution is obtained by space-marching while in subsonic and transonic applications iterative relaxation methods are used. Numerical results are given for: (1) supersonic diffuser with oblique shocks (direct calculation); (2) supersonic jet entering still reservoir (inverse calculation); (3) subsonic bump in a channel with 25 percent blockage (direct and inverse); (4) subsonic high-work turbine cascade (direct); and (5) transonic bump in a channel with 12 percent blockage (direct calculation).
A single mutation in Taiwanese H6N1 influenza hemagglutinin switches binding to human‐type receptors (2017)

In June 2013, the first case of human infection with an avian H6N1 virus was reported in a Taiwanese woman. Although this was a single non-fatal case, the virus continues to circulate in Taiwanese poultry. As with any emerging avian virus that infects humans, there is concern that acquisition of human-type receptor specificity could enable transmission in the human population. Despite mutations in the receptor-binding pocket of the human H6N1 isolate, it has retained avian-type (NeuAcα2-3Gal) receptor specificity. However, we show here that a single nucleotide substitution, resulting in a change from Gly to Asp at position 225 (G225D), completely switches specificity to human-type (NeuAcα2-6Gal) receptors. Significantly, G225D H6 loses binding to chicken trachea epithelium and is now able to bind to human tracheal tissue. Structural analysis reveals that Asp225 directly interacts with the penultimate Gal of the human-type receptor, stabilizing human receptor binding.
A TECHNIQUE FOR MEASURING LOCAL INTERNAL MECHANICAL PROPERTIES OF PERFUSED SOLID ORGANS (2003)

INTRODUCTION Mechanical simulation of soft tissue is increasingly important for the development of new minimally invasive surgical applications. For surgical planning, the prediction of tissue deformation in response to instrument manipulation can improve accuracy of image-guided procedures. For surgical training, simulations permit new surgeons to safely practice a wide variety of procedures. To be effective in these applications, mechanical simulations must be realistic, so that the tissue behaves as in the living organism. This requires accurate in vivo constitutive models for tissues under the large deformations typical of surgical procedures. The complexity of soft tissues makes characterizing their behavior a formidable challenge. Soft tissues exhibit viscoelastic properties, anisotropy, and inhomogeneity [1]. These tissues are drastically altered when no longer perfused, maintained at constant temperature, or bounded by the original surrounding structures as in the commonly tested ex vivo state [1, 2]. To make meaningful measurements requires an experimental environment that is close to the in vivo state and provides force and displacement measurements of the local tissue volume over time. In vivo devices have recently been developed that probe the tissue of interest from its surface and measure the corresponding force response [2-5]. However, these devices typically apply small perturbations to the organ surface and thus only measure superficial regions and do not account for large surgical strains. At present, imaging techniques (e.g. elastography) provide only qualitative or relative material property information for arbitrary organ geometry [6]. We have developed a new technique for probing the local mechanical properties of solid organs such as the liver, kidney, and spleen at arbitrary internal locations while approximating in vivo conditions. A pair of cylindrical bars is carefully inserted into the organ on each side of a local volume causing minimal damage to the volume of interest and allowing for a nearly uniform stress distribution. In the following sections we describe the apparatus and preliminary tests on porcine liver under physiologic conditions. (1) Division of Engineering and Applied Sciences Harvard University Cambridge, MA (2) Division of Health Sciences and Technology Harvard University MIT Cambridge, MA
Cannabinoid CB1 receptor overactivity contributes to the pathogenesis of idiopathic pulmonary fibrosis (2017)

Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease without effective treatment, highlighting the need for identifying new targets and treatment modalities. The pathogenesis of IPF is complex, and engaging multiple targets simultaneously might improve therapeutic efficacy. To assess the role of the endocannabinoid/cannabinoid receptor 1 (endocannabinoid/CB1R) system in IPF and its interaction with inducible nitric oxide synthase (iNOS) as dual therapeutic targets, we analyzed lung fibrosis and the status of the endocannabinoid/CB1R system and iNOS in mice with bleomycin-induced pulmonary fibrosis (PF) and in lung tissue and bronchoalveolar lavage fluid (BALF) from patients with IPF, as well as controls. In addition, we investigated the antifibrotic efficacy in the mouse PF model of an orally bioavailable and peripherally restricted CB1R/iNOS hybrid inhibitor. We report that increased activity of the endocannabinoid/CB1R system parallels disease progression in the lungs of patients with idiopathic PF and in mice with bleomycin-induced PF and is associated with increased tissue levels of interferon regulatory factor-5. Furthermore, we demonstrate that simultaneous engagement of the secondary target iNOS by the hybrid CB1R/iNOS inhibitor has greater antifibrotic efficacy than inhibition of CB1R alone. This hybrid antagonist also arrests the progression of established fibrosis in mice, thus making it a viable candidate for future translational studies in IPF.