gebhart/patrepeval huggingface dataset:
A novel platform for engineering blood‐brain barrier‐crossing bispecific biologics (2014)

The blood-brain barrier (BBB) prevents the access of therapeutic antibodies to central nervous system (CNS) targets. The engineering of bispecific antibodies in which a therapeutic "arm" is combined with a BBB-transcytosing arm can significantly enhance their brain delivery. The BBB-permeable single-domain antibody FC5 was previously isolated by phenotypic panning of a naive llama single-domain antibody phage display library. In this study, FC5 was engineered as a mono- and bivalent fusion with the human Fc domain to optimize it as a modular brain delivery platform. In vitro studies demonstrated that the bivalent fusion of FC5 with Fc increased the rate of transcytosis (Papp) across brain endothelial monolayer by 25% compared with monovalent fusion. Up to a 30-fold enhanced apparent brain exposure (derived from serum and cerebrospinal fluid pharmacokinetic profiles) of FC5- compared with control domain antibody-Fc fusions after systemic dosing in rats was observed. Systemic pharmacological potency was evaluated in the Hargreaves model of inflammatory pain using the BBB-impermeable neuropeptides dalargin and neuropeptide Y chemically conjugated with FC5-Fc fusion proteins. Improved serum pharmacokinetics of Fc-fused FC5 contributed to a 60-fold increase in pharmacological potency compared with the single-domain version of FC5; bivalent and monovalent FC5 fusions with Fc exhibited similar systemic pharmacological potency. The study demonstrates that modular incorporation of FC5 as the BBB-carrier arm in bispecific antibodies or antibody-drug conjugates offers an avenue to develop pharmacologically active biotherapeutics for CNS indications.
<i>Lcg</i> is a light‐inducible and clock‐controlled gene expressed in the chicken pineal gland (2006)

The circadian clock is an autonomous biological clock that is entrainable to environmental 24-h cycles by receiving time cues such as light. Generally, light given at early and late subjective night, respectively, delays and advances the phase of the circadian oscillator. We previously searched for the chicken pineal genes that are induced by light in a phase-dependent manner. The present study undertook cDNA cloning and characterization of a gene whose expression was remarkably up-regulated by light at late subjective night. The mRNA level of this gene exhibited robust diurnal change in the pineal gland, with a peak in the early (subjective) day under light-dark cycles and constant dark condition, and hence it was designated Lcg (Light-inducible and Clock-controlled Gene). Chicken Lcg encodes a coiled-coil protein composed of 560 amino acid residues. Among chicken tissues, the pineal gland and the retina exhibited relatively high expression levels of LCG. LCG was colocalized with gamma-tubulin, a centrosomal protein, when expressed in COS7 cells, and LCG is the first example of a clock-related molecule being accumulated at the centrosome. Coimmunoprecipitation of LCG with gamma-tubulin in the chicken pineal lysate suggests a link between the circadian oscillator and the centrosomal function.
ChemInform Abstract: Prostaglandin Synthesis. Part 16. The Three‐Component Synthesis of Prostaglandins. (1988)

Abstract A convergent one‐pot construction of the acetylenic prostaglandin (PG) framework (IV) is accomplished by the organocopper‐mediated conjugate addition of the ω side‐chain unit (II) to the protected cyclopentenone (I) followed by trapping of the enolate intermediate by the alkyl iodide (III); transmetalation with use of triphenyltin chloride at the enolate stage serves as key operation for this coupling procedure.
Preclinical Evaluation of IMGC936, a Next-Generation Maytansinoid-based Antibody–drug Conjugate Targeting ADAM9-expressing Tumors (2022)

ADAM metallopeptidase domain 9 (ADAM9) is a member of the ADAM family of multifunctional, multidomain type 1 transmembrane proteins. ADAM9 is overexpressed in many cancers, including non-small cell lung, pancreatic, gastric, breast, ovarian, and colorectal cancer, but exhibits limited expression in normal tissues. A target-unbiased discovery platform based on intact tumor and progenitor cell immunizations, followed by an IHC screen, led to the identification of anti-ADAM9 antibodies with selective tumor-versus-normal tissue binding. Subsequent analysis revealed anti-ADAM9 antibodies were efficiently internalized and processed by tumor cells making ADAM9 an attractive target for antibody-drug conjugate (ADC) development. Here, we describe the preclinical evaluation of IMGC936, a novel ADC targeted against ADAM9. IMGC936 is comprised of a high-affinity humanized antibody site-specifically conjugated to DM21-C, a next-generation linker-payload that combines a maytansinoid microtubule-disrupting payload with a stable tripeptide linker, at a drug antibody ratio of approximately 2.0. In addition, the YTE mutation (M252Y/S254T/T256E) was introduced into the CH2 domain of the antibody Fc to maximize in vivo plasma half-life and exposure. IMGC936 exhibited cytotoxicity toward ADAM9-positive human tumor cell lines, as well as bystander killing, potent antitumor activity in human cell line-derived xenograft and patient-derived xenograft tumor models, and an acceptable safety profile in cynomolgus monkeys with favorable pharmacokinetic properties. Our preclinical data provide a strong scientific rationale for the further development of IMGC936 as a therapeutic candidate for the treatment of ADAM9-positive cancers. A first-in-human study of IMGC936 in patients with advanced solid tumors has been initiated (NCT04622774).
Mode dispersion compensating optical transmission line composed of two-mode optical fibers (2012)

We fabricated mode dispersion compensating optical transmission line composed of two different kinds of two-mode optical fibers with the opposite signs of mode dispersion. Its mode dispersion was successfully controlled within ±700 ps/km at C-band.
Detecting file fragmentation point using sequential hypothesis testing (2008)

File carving is a technique whereby data files are extracted from a digital device without the assistance of file tables or other disk meta-data. One of the primary challenges in file carving can be found in attempting to recover files that are fragmented. In this paper, we show how detecting the point of fragmentation of a file can benefit fragmented file recovery. We then present a sequential hypothesis testing procedure to identify the fragmentation point of a file by sequentially comparing adjacent pairs of blocks from the starting block of a file until the fragmentation point is reached. By utilizing serial analysis we are able to minimize the errors in detecting the fragmentation points. The performance results obtained from the fragmented test-sets of DFRWS 2006 and 2007 show that the method can be effectively used in recovery of fragmented files.
Low distortion embeddings for edit distance (2005)

We show that 0,1d endowed with edit distance embeds into l1 with distortion 2O(√log dlog log d). We further show efficient implementations of the embedding that yield solutions to various computational problems involving edit distance. These include sketching, communication complexity, nearest neighbor search. For all these problems, we improve upon previous bounds.
Access control for SDN controllers (2014)

Based on the OpenFlow model, we propose an access control scheme for SDN controllers. Our scheme accounts for the different network resources, multiple security requirements, conflicts originating from the reconfiguration of network components, and the delegation of access permissions.
Security in an Insecure WLAN Network (2005)

Wireless LANs (WLANs) based on IEEE 802.11 standards are becoming increasingly popular for both business and residential use. However, the very nature of wireless networks exposes the risks and vulnerabilities that a malicious user can exploit and severely compromise the network. In this paper, we provide a design of a secure wireless system (SWS) that can not only detect various attacks and misbehaviors of a 802.11 based wireless networks, but also help recover from them. A prototype implementation is also described.
Polyionic Hydrogels Obtained by Complexation between Xanthan and Chitosan: Their Properties as Supports for Enzyme Immobilization (1994)

A method for the preparation of hydrogels from the complexation of chitosan and xanthan is reported. Stable hydrogels capable of retaining be tween 65 and 95% weight water were prepared. The water retention and prop erties of the hydrogels were studied as a function of the degree of acetylation of chitosan and the ratio chitosan/xanthan used in the preparation of the gel. Spectroscopic FTIR was used to confirm complexation between the amine (chi tosan) and carboxylic (xanthan) groups. Electron micrographs (SEM and TEM) show the formation of a fibrillar structure with characteristic pore sizes be tween 100 and 1000 nm and fibril diameters between 50 and 100 nm. The diffu sion coefficient of 4- O-methyl- d-glucurono-D-xylan Remazol Brilliant Blue R (RBB-xylan) in the complex chitosan-xanthan was 2.02 × 10- 12 m 2 s -1 at 30°C. The chitosan-xanthan complex was used to immobilize two enzymes (endo-1,4- β-xylanase and protease) either as single enzymes or as a binary system. Immo bilization varied between 85 and 98%. The immobilized xylanase activity was significantly greater with respect to the free enzyme while the binary enzyme system promoted protease activity.
Inhibitors of Human Immunodeficiency Virus Type 1 (HIV-1) Attachment. 5. An Evolution from Indole to Azaindoles Leading to the Discovery of 1-(4-Benzoylpiperazin-1-yl)-2-(4,7-dimethoxy-1<i>H</i>-pyrrolo[2,3-<i>c</i>]pyridin-3-yl)ethane-1,2-dione (BMS-488043), a Drug Candidate That Demonstrates Antiviral Activity in HIV-1-Infected Subjects (2009)

Azaindole derivatives derived from the screening lead 1-(4-benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione (1) were prepared and characterized to assess their potential as inhibitors of HIV-1 attachment. Systematic replacement of each of the unfused carbon atoms in the phenyl ring of the indole moiety by a nitrogen atom provided four different azaindole derivatives that displayed a clear SAR for antiviral activity and all of which displayed marked improvements in pharmaceutical properties. Optimization of these azaindole leads resulted in the identification of two compounds that were advanced to clinical studies: (R)-1-(4-benzoyl-2-methylpiperazin-1-yl)-2-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethane-1,2-dione (BMS-377806, 3) and 1-(4-benzoylpiperazin-1-yl)-2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (BMS-488043, 4). In a preliminary clinical study, 4 administered as monotherapy for 8 days, reduced viremia in HIV-1-infected subjects, providing proof of concept for this mechanistic class.
Phase I/II study of the safety, pharmacokinetics, and efficacy of pomalidomide in the treatment of Kaposi sarcoma in individuals with or without HIV. (2013)

TPS10595 Background: Kaposi sarcoma (KS) is a multicentric angioproliferative tumor seen most frequently in people with HIV. It is caused by the gammaherpesvirus Kaposi-sarcoma associated herpesvirus (KSHV, or human herpesvirus 8) and is remarkable for its tendency to progress or regress based on host immune factors. Pomalidomide is an orally available third generation thalidomide derivative with immunomodulatory and antiangiogenic properties that may address unmet clinical needs in KS. Methods: The primary objective is to assess the safety, tolerability and pharmacokinetics of pomalidomide in subjects with KS, whether HIV associated or not, and to explore its antitumor effect at the tolerable dose once determined. This is the first assessment of this agent in patients with HIV and/or KS. Subjects with confirmed KS and no symptomatic pulmonary or visceral KS are eligible. Those with HIV must be compliant with HAART; have achieved an HIV viral load <10,000 copies/mL; and in the phase II portion have KS increasing despite HAART and HIV suppression for ≥2months, or stable despite HAART for ≥3months. In the phase I portion, up to 6 subjects will be treated with pomalidomide 5mg orally daily for 21 days of a 28 day cycle. Subject to evaluation of adverse events and tolerability, this may be deescalated to 3mg orally daily 21 of 28 days in a second cohort of up to 6 subjects. If either dose proves tolerable, the study will proceed to the phase II portion, and enroll up to 15 HIV positive and 10 HIV negative subjects. Antitumor activity will be assessed using modified ACTG KS response criteria in parallel with quality of life assessment. Key correlative studies include evaluation of immune responses including T cell numbers and activation in peripheral blood and tumor tissue and KSHV specific T-cell responses; HIV and KSHV activity and associated cytokines; and the first exploration of effects of pomalidomide pharmacokinetics when administered with common antiretroviral agents. Progress: The study opened to accrual in January 2012. The phase I portion is complete with no DLTs at the dose of 5mg 21 of 28 days. Phase II has accrued 11 subjects (4 HIV negative, 7 HIV positive) at this dose. Clinical trial information: NCT01495598.
Identification of an ADAM17 Cleavage Region in Human CD16 (FcγRIII) and the Engineering of a Non-Cleavable Version of the Receptor in NK Cells (2015)

CD16a and CD16b are IgG Fc receptors expressed by human natural killer (NK) cells and neutrophils, respectively. Both CD16 isoforms undergo a rapid down-regulation in expression by ADAM17-mediated proteolytic cleavage upon cell activation by various stimuli. We examined soluble CD16 released from activated NK cells and neutrophils by mass spectrometric analysis, and identified three separate cleavage sites in close proximity at P1/P1' positions alanine195/valine196, valine196/serine197, and threonine198/isoleucine199, revealing a membrane proximal cleavage region in CD16. Substitution of the serine at position 197 in the middle of the cleavage region for a proline (S197P) effectively blocked CD16a and CD16b cleavage in cell-based assays. We also show that CD16a/S197P was resistant to cleavage when expressed in the human NK cell line NK92 and primary NK cells derived from genetically-engineered human induced pluripotent stem cells. CD16a is a potent activating receptor and despite blocking CD16a shedding, the S197P mutation did not disrupt IgG binding by the receptor or its activation of NK92 cells by antibody-treated tumor cells. Our findings provide further characterization of CD16 cleavage by ADAM17 and they demonstrate that a non-cleavable version of CD16a can be expressed in engineered NK cells.
A human‐specific TNF‐responsive promoter for Goodpasture antigen‐binding protein (2005)

The Goodpasture antigen-binding protein, GPBP, is a serine/threonine kinase whose relative expression increases in autoimmune processes. Tumor necrosis factor (TNF) is a pro-inflammatory cytokine implicated in autoimmune pathogenesis. Here we show that COL4A3BP, the gene encoding GPBP, maps head-to-head with POLK, the gene encoding for DNA polymerase kappa (pol kappa), and shares with it a 140-bp promoter containing a Sp1 site, a TATA-like element, and a nuclear factor kappa B (NFkappaB)-like site. These three elements cooperate in the assembly of a bidirectional transcription complex containing abundant Sp1 and little NFkappaB that is more efficient in the POLK direction. Tumour necrosis factor cell induction is associated with Sp1 release, NFkappaB recruitment and assembly of a complex comparatively more efficient in the COL4A3BP direction. This is accomplished by competitive binding of Sp1 and NFkappaB to a DNA element encompassing a NFkappaB-like site that is pivotal for the 140-bp promoter to function. Consistently, a murine homologous DNA region, which contains the Sp1 site and the TATA-like element but is devoid of the NFkappaB-like site, does not show transcriptional activity in transient gene expression assays. Our findings identify a human-specific TNF-responsive transcriptional unit that locates GPBP in the signalling cascade of TNF and substantiates previous observations, which independently related TNF and GPBP with human autoimmunity.
Cloning of a bovine interferon-alpha gene subfamily and comparisons between genetically engineered and leukocyte bovine interferons. (1985)

Bovine peripheral leukocytes were virally induced for interferon production, and an acid stable, SDS stable, antiviral activity was detected in the preparation. This bovine interferon (BoIFN) was tested for its ability to induce an antiviral state in various mammalian cells and was found to be specific to cells from bovine origin. The BoIFN cross reacts with antibodies against human IFN-alpha but these antibodies do not neutralize the bovine IFN activity. Leukocyte BoIFN exhibits polymorphism upon Affi-Gel Blue chromatography and SDS-PAGE (16k and 24K). The virally induced leukocytes produce a 13S mRNA which upon translation in oocytes yields an active IFN molecule. Bovine genomic library was constructed and screened for BoIFN-alpha sequences, using human IFN-alpha probes. From the clones isolated, five were found to represent distinct genes. Sequence analysis indicate that these genes are closely related (94% homology). One of these genes was expressed in E. coli under the control of trp promoter operator. The physicochemical and biological properties of the bacterial BoIFN-alpha product resemble those of a subpopulation of natural BoIFN.
Identification of a species-specific antigen in Legionella pneumophila by a monoclonal antibody (1984)

A species-specific antigen in Legionella pneumophila was identified by a monoclonal antibody in enzyme-linked immunosorbent and immunofluorescence assays of serogroups 1 through 8. The species-specific antigen was heat stable, and the molecular weight of the major band was 29,000 by immunoblot analysis. In direct immunofluorescence assays, the antigen was cryptic or only partly exposed on the surface of the cells but was effectively exposed by treating the cells with detergent and EDTA. The monoclonal antibody was utilized in direct immunofluorescence assays to specifically identify multiple cultures of L. pneumophila serogroups.
Direct detection of peptides and small proteins in fingermarks and determination of sex by MALDI mass spectrometry profiling (2012)

Matrix Assisted Laser Desorption Ionisation Mass Spectrometry (MALDI MS) can detect and image a variety of endogenous and exogenous compounds from latent fingermarks. This opportunity potentially provides investigators with both an image for suspect identification and chemical information to be used as additional intelligence. The latter becomes particularly important when the fingermark is distorted or smudged or when the suspect is not a previously convicted offender and therefore their fingerprints are not present in the National Fingerprint Database. One of the desirable pieces of intelligence would be the sex of the suspect from the chemical composition of a fingermark. In this study we show that the direct detection of peptides and proteins from fingermarks by MALDI MS Profiling (MALDI MSP), along with the multivariate modeling of the spectra, enables the determination of sex with 85% accuracy. The chemical analysis of the fingermark composition is expected to additionally provide information on traits such as nutritional habits, drug use or hormonal status.
A Combined Decimal and Binary Floating-Point Multiplier (2009)

In this paper, we describe the first hardware design of a combined binary and decimal floating-point multiplier, based on specifications in the IEEE 754-2008 floating-point standard. The multiplier design operates on either (1) 64-bit binary encoded decimal floating-point (DFP) numbers or (2) 64-bit binary floating-point (BFP) numbers. It returns properly rounded results for the rounding modes specified in IEEE 754-2008. The design shares the following hardware resources between the two floating-point datatypes: a 54-bit by 54-bit binary multiplier, portions of the operand encoding/decoding, a 54-bit right shifter, exponent calculation logic, and rounding logic. Our synthesis results show that hardware sharing is feasible and has a reasonable impact on area, latency, and delay. The combined BFP and DFP multiplier occupies only 58% of the total area that would be required by separate BFP and DFP units. Furthermore, the critical path delay of a combined multiplier has a negligible increase over a standalone DFP multiplier, without increasing the number of cycles to perform either BFP or DFP multiplication.
Novel Fibers for Ultra-Short and High-Power Pulses (2007)

Light propagation in higher-order modes of few-mode fibers leads to unique dispersive properties that are challenging or impossible to achieve in conventional fibers. We will describe their application to devices utilising high-peak-power and ultra-short pulses.
Dual-Interface Memory for RF Memory Tag Systems (2012)

In the simplest form the RF memory tag system consists of a stand-alone memory tag with a large non-volatile storage memory (capacity in gigabits), and a reader/writer device. The reader/writer device powers the tag wirelessly during data-transfer. An RF memory tag can be also embedded into an electronic device providing wireless access to storage memory even when the device is without a battery or the battery is empty. This enables totally new applications but set also new requirements for the memory devices. In this paper we analyze the requirements and propose dual-interface memory architecture for the RF memory tag systems.
Determining When Enhanced Pause (Penh) is Sensitive to Changes in Specific Airway Resistance (2011)

Penh is a dimensionless index normally used to evaluate changes in the shape of the airflow pattern entering and leaving a whole-body flow plethysmograph as an animal breathes. The index is sensitive to changes in the distribution of area under the waveform during exhalation and increases in a nonlinear fashion as the normalized area increases near the beginning of the curve. Enhanced pause (Penh) has been used to evaluate changes in pulmonary function and as a method to evaluate airway reactivity. However, the use of Penh to assess pulmonary function has been challenged (Bates et al., 2004; Lundblad et al., 2002; Mitzner et al., 2003; Mitzner & Tankersley, 1998; Petak et al., 2001; Sly et al., 2005). The objective of this study was to show how Penh of the thorax and plethysmograph flow patterns are related. That relationship is used to describe the conditions under which whole-body plethysmograph Penh measurements can be used to detect changes in sRaw.
High temperature method for the conversion of chlorinated organic compounds to methyl chloride for isotopic analysis of chlorine and carbon (1996)

Chlorinated volatile organic compounds (VOCs), including the common solvents TCE, PCE, CCl{sub 4}, CHCl{sub 3}, and TCA, are the most frequently detected groundwater contaminants in the United States. These compounds are EPA priority pollutants that are known or suspected to be carcinogenic or mutagenic in humans. They are readily transported by groundwater. The ability to measure the stable carbon and chlorine isotopes of chlorinated VOCs could be useful in tracing sources of these compounds and their breakdown products in the environment. This paper describes a non-aqueous analytical method by which both carbon dioxide and methyl chloride are produced from the same sample of material for isotope analysis of carbon and chlorine.