gebhart/patrepeval huggingface dataset:
Electrostatic interactions modulate the differential aggregation propensities of IgG1 and IgG4P antibodies and inform charged residue substitutions for improved developability (2019)

Native state aggregation is an important concern in the development of therapeutic antibodies. Enhanced knowledge of mAb native state aggregation mechanisms would permit sequence-based selection and design of therapeutic mAbs with improved developability. We investigated how electrostatic interactions affect the native state aggregation of seven human IgG1 and IgG4P mAb isotype pairs, each pair having identical variable domains that are different for each set of IgG1 and IgG4P constructs. Relative aggregation propensities were determined at pH 7.4, representing physiological conditions, and pH 5.0, representing commonly used storage conditions. Our work indicates that the net charge state of variable domains relative to the net charge state of the constant domains is predominantly responsible for the different native state aggregation behavior of IgG1 and IgG4P mAbs. This observation suggests that the global net charge of a multi domain protein is not a reliable predictor of aggregation propensity. Furthermore, we demonstrate a design strategy in the frameworks of variable domains to reduce the native state aggregation propensity of mAbs identified as being aggregation-prone. Importantly, substitution of specifically identified residues with alternative, human germline residues, to optimize Fv charge, resulted in decreased aggregation potential at pH 5.0 and 7.4, thus increasing developability.
erbB2Overexpression in Uterine Serous Cancer: A Molecular Target for Trastuzumab Therapy (2011)

Endometrial cancer is the most common female genital tract malignancy in the United States. Type I endometrial cancer is usually diagnosed at an early stage, and has a good prognosis. Type II is very aggressive, and is responsible for most uterine cancer relapses and deaths. Uterine serous adenocarcinomas (USC) constitute the majority of Type II variants. They have a higher propensity for lymph node and distant metastases. They are frequently aneuploid and associated with p53 mutations. erbB2 overexpression in USC has been described. The incidence, which is higher in African Americans, ranges from 18-80%. erbB2 overexpression was found to be associated with higher stage, chemoresistance, and worse survival. Trastuzumab a humanized mAb was approved by the FDA for treatment of breast cancers that overexpress erbB2 in combination with standard chemotherapy. Evidence of trastuzumab activity in USC has been reported in vitro, as well as in case reports of advanced and recurrent cases. Promising results were obtained in these heavily pretreated patients either with trastuzumab alone or in combination with chemotherapy. This supports the hypothesis that trastuzumab may very well be an attractive and viable treatment option for advanced stage USC tumors that overexpress the erbB2, and is worthy of further study.
Chondroitin Sulfate Proteoglycans in Spinal Cord Contusion Injury and the Effects of Chondroitinase Treatment (2007)

Chondroitinase treatment of experimental spinal cord injury improves recovery of sensory, motor, and autonomic functions. Chondroitinase catalyzes the cleavage of glycosaminoglycans (GAGs) from the core proteins of chondroitin sulfate proteoglycans (CSPGs). Little is known about changes in production of these proteoglycans in the clinically relevant contusion model of spinal cord injury or if CSPG content is altered by chondroitinase treatment. Female Long-Evans rats were injured with a forceps contusion injury and treated on alternate days with chondroitinase ABCI or control enzyme via an intrathecal catheter. Spinal cords were analyzed at specific times after injury. The cord was divided in 4 mm long segments, one containing the lesion, two rostral and two caudal to the lesion. These segments were assessed for CSPG protein and message content (NG2, neurocan and phosphacan) by Western blotting and real-time PCR. CSPG protein content was increased by one day post injury for all CSPGs investigated, and was increased in all segments examined rostral and caudal to the lesion site. Significant increases in CSPG were observed with peak content detected at 7, 7 and 14 days post injury for NG2, neurocan and phosphacan, respectively. Chondroitinase treatment had little impact upon the CPSG protein content. Changes in message levels of these CSPGs are also reported. This demonstrates that expression patterns of CSPGs in contusion injury are similar to those surrounding surgical hemisection lesions and demonstrates that the sensory and motor function enhancing effects of chondroitinase are likely due to removal of GAG chains rather than reduction in CSPG content.
SMAD1 signaling mediates inhibition of store‐operated Ca 2+ entry on collagen IV expression in glomerular mesangial cells (689.14) (2014)

Objective: The Smad signaling pathway plays a critical role in extracellular matrix protein production in glomeruli in diabetic nephropathy. Store‐operated Ca2+ entry (SOCE) regulates protein synthesis. The aim of the present study was to determine if SOCE in mesangial cells (MCs) suppressed production of collagen type IV (Col IV) by inhibiting Smad1. Methods: Western blot and immunohistochemistry were used to detect target protein expression in cultured MCs and mouse glomeruli, respectively. Systemic administration of nanoparticles containing siRNA against Orai1 was employed to deliver the siRNA to MCs in mice. Results: In cultured human MCs, activation of SOCE by cyclopiazonic acid or thapsigargin (TG) significantly suppressed Ang II‐induced Smad1 phosphorylation. Overexpression of STIM1 dramatically decreased abundance of Smad1 protein. Furthermore, high glucose‐induced Col IV protein expression was significantly inhibited by TG. Inhibition of SOCE by 2‐aminoethoxydiphenyl borate or La3+ increased Col IV expression which was accompanied by an increase in Smad1 protein expression. However, the Col IV response to SOCE inhibition was not observed in MCs with knockdown of Smad1. Moreover, in vivo knockdown of Orai1 in mouse MCs increased expressions of both Smad1 and Col IV in the nanoparticle‐positive glomeruli. Conclusion: SOCE inhibits Col IV expression by inhibiting Smad1 pathway in MCs. Grant Funding Source : NIH/NIDDK
Extracellular vesicle–mediated transfer of constitutively active MyD88L265P engages MyD88wt and activates signaling (2018)

The link between inflammation and cancer is particularly strong in Waldenström macroglobulinemia (WM), a diffuse large B-cell lymphoma wherein the majority of patients harbor a constitutively active mutation in the innate immune-signaling adaptor myeloid differentiation primary response 88 (MyD88). MyD88Leu265Pro (MyD88<sup>L265P</sup>) constitutively triggers the myddosome assembly providing a survival signal for cancer cells. Here, we report detection and a functional role of MyD88 in the extracellular vesicles (EVs) shed from WM cells. MyD88<sup>L265P</sup> was transferred via EVs into the cytoplasm of the recipient mast cells and macrophages, recruiting the endogenous MyD88 that triggered the activation of proinflammatory signaling in the absence of receptor activation. Additionally, internalization of EVs containing MyD88<sup>L265P</sup> was observed in mice with an effect on the bone marrow microenvironment. MyD88-loaded EVs were detected in the bone marrow aspirates of WM patients thus establishing the physiological role of EVs for MyD88<sup>L265P</sup> transmission and shaping of the proinflammatory microenvironment. Results establish the mechanism of transmission of signaling complexes via EVs to propagate inflammation as a new mechanism of intercellular communication.
High-speed magnetically levitated reaction wheels for small satellites (2016)

Mechanical wear and stiction can be eliminated by using magnetic bearings instead of ball bearings in spacecraft reaction wheels. Accordingly, the lifetime of attitude control systems can be increased and a smooth torque can be achieved also at speed zero crossings. Moreover, the microvibration emission of the reaction wheels can be minimized and actively controlled. A further advantage of magnetically levitated reaction wheels is the ability to rotate at speeds higher than the state of the art. High-speed reaction wheels can be made smaller in size; however, they require higher power levels for the same reaction torque. Therefore, this paper analyzes the circulation of energy within different reaction wheels of an attitude control system in order to limit the external power requirement. Moreover, integrated position sensors are used for limiting the axial length of the rotors, thereby further increasing the speed limits that may be resulting from rotor dynamics. A functional demonstrator is built and equipped with two different reaction wheel rotors for initial tests. The electrical machine design and the operation of the magnetically levitated reaction wheel systems are verified experimentally.
Novel Influenza A Viruses Isolated from Canadian Feral Ducks: Including Strains Antigenically Related to Swine Influenza (Hsw1N1) Viruses (1978)

Twelve influenza A viruses, antigenically related to the Ho, H1 and Hsw1 subtypes, were isolated from cloacal samples of feral ducks in Canada. Antigenic comparisons showed that these viruses were most closely related to the recent HSW1N1 isolates from man and pigs, whereas in vivo pathogenicity tests revealed differences between the Hsw1N1 viruses from the ducks and those from humans and pigs. Antigenic characterization of 94 additional influenza A viruses from the ducks showed four haemagglutinin subtypes (Hav1, Hav4, Hav5 and Hav7), an unclassified haemagglutinin, and six neuraminidase subtypes (N1, N2, Neq2, Nav1, Nav2 and Nav5) in various combinations, some of which are novel and have not previously been reported. Three of these duck influenza viruses possessed a haemagglutinin antigenically related to that of classical fowl plaque virus. A much higher percentage of virus isolations were from juvenile ducks (18.5%) than from adults (5%). All of the ducks, from which viruses were isolated, appeared healthy at the time of sampling. Serological studies on a limited number of humans and domestic birds living in close proximity to the Canadian ducks revealed no evidence of interspecies transmission. Our findings suggest that these birds serve as a substantial reservoir of antigenically diverse influenza viruses, including isolates antigenically related to the current human and animal influenza viruses. This reservoir in nature may be perpetuated by a cycle involving annual infection of juvenile birds followed by transmission to the remaining susceptible birds until the next congregation during the breeding season.
Outcome Trends after US Military Concussive Traumatic Brain Injury (2016)

Care for US military personnel with combat-related concussive traumatic brain injury (TBI) has substantially changed in recent years, yet trends in clinical outcomes remain largely unknown. Our prospective longitudinal studies of US military personnel with concussive TBI from 2008-2013 at Landstuhl Regional Medical Center in Germany and twp sites in Afghanistan provided an opportunity to assess for changes in outcomes over time and analyze correlates of overall disability. We enrolled 321 active-duty US military personnel who sustained concussive TBI in theater and 254 military controls. We prospectively assessed clinical outcomes 6-12 months later in 199 with concussive TBI and 148 controls. Global disability, neurobehavioral impairment, depression severity, and post-traumatic stress disorder (PTSD) severity were worse in concussive TBI groups in comparison with controls in all cohorts. Global disability primarily reflected a combination of work-related and nonwork-related disability. There was a modest but statistically significant trend toward less PTSD in later cohorts. Specifically, there was a decrease of 5.9 points of 136 possible on the Clinician Administered PTSD Scale (-4.3%) per year (95% confidence interval, 2.8-9.0 points, p = 0.0037 linear regression, p = 0.03 including covariates in generalized linear model). No other significant trends in outcomes were found. Global disability was more common in those with TBI, those evacuated from theater, and those with more severe depression and PTSD. Disability was not significantly related to neuropsychological performance, age, education, self-reported sleep deprivation, injury mechanism, or date of enrollment. Thus, across multiple cohorts of US military personnel with combat-related concussion, 6-12 month outcomes have improved only modestly and are often poor. Future focus on early depression and PTSD after concussive TBI appears warranted. Adverse outcomes are incompletely explained, however, and additional studies with prospective collection of data on acute injury severity and polytrauma, as well as reduced attrition before follow-up will be required to fully address the root causes of persistent disability after wartime injury.
Starting on the Right Track: Introducing Students to Mechanical Engineering With a Project-Based Machine Design Course (2005)

Over the past four years, we have redesigned Harvard’s introductory mechanical engineering course to introduce the principles, practices, and pleasures of mechanical engineering in an accessible format. The main goals of the course are to provide experience in the design process, demonstrate the connection between engineering science and design early in the curriculum, and build student enthusiasm for engineering, serving to attract and retain students. Unlike most introductory mechanical engineering courses, we cover strength of materials and machine elements, material usually presented much later in the curriculum, in order to provide tools for the students to quantitatively evaluate their designs. By providing just enough of this background knowledge to allow for analysis of designs, we demonstrate the connection between engineering science and design early in curriculum and motivate in-depth coverage of these topics in later courses. The laboratories for the course build enthusiasm for engineering by incorporating exciting design projects and introducing students to some of the most attractive mechanical engineering tools. Students learn 3-D solid modeling with CAD software, create prototypes from CAD models using manual and CNC machining, and reverse engineer common consumer products. Using these tools, students build their own hardware prototypes for both a cantilever beam catapult and a model all-terrain-vehicle. These exercises, carefully chosen to reinforce the strength of materials and machine elements concepts, culminate in design contests that enhance the visibility of engineering within the larger university community and increase student interest in the field.
Improving the effectiveness of vaccination against viral and bacterial pathogens through micronutrient supplementation (2022)

Deficiency of certain micronutrients interferes with the functioning of acquired immunity, which may negatively affect the efficacy and safety of vaccinations. The results of clinical and epidemiological studies have shown that micronutrient supplementation before vaccination increases its efficacy (antibody titers against viral/bacterial pathogens) and safety (prevention of malaise, reduction of disease severity and mortality in case of post-vaccination infection). The aim of the study was to analyze the currently available studies on the relationship between micronutrient status and the results of vaccination against bacteria and viruses. Conclusion . Micronutrient supplementation contributes to the formation of adequate immunity after vaccination and increases the safety of vaccination. Vitamin-mineral complexes represent a cost-effective method to reduce the risks of vaccination in patients with polyhypovitaminosis.
A Blind Validation CFD Challenge Case for 3D Smooth-Body Turbulent Separation (2023)

View Video Presentation: https://doi.org/10.2514/6.2023-3986.vid Virginia Tech, with support from NASA-Langley, has recently acquired high-quality turbulence model validation data for three-dimensional smooth-body flow separation. The geometry, called the BeVERLI Hill (Benchmark Validation Experiments for RANS and LES Investigations), has been studied at subsonic Reynolds numbers of 250k to 650k based on the hill height. Experimental data have been obtained for the hill at zero and 90 degree orientations and includes extensive oil flow visualizations, surface pressures, skin friction via oil film interferometry and laser Doppler velocimetry, and mean and fluctuating velocities using particle image velocimetry, laser Doppler velocimetry, and pitot-static rakes. Extensive boundary conditions and oncoming boundary layer data have also been measured. We propose a blind CFD turbulence modeling challenge case with the BeVERLI Hill oriented at 30 degrees to the oncoming freestream. Two turbulence models are strongly recommended: the standard Spalart-Allmaras model and the Menter k-ω SST model. Additional turbulence model submissions are welcome. While extensive boundary condition information will be made available to participants, the surface pressure, surface skin friction, and velocity data will be withheld until the computations have been submitted, thus making this a blind CFD challenge.
Vorinostat: A Potent Agent to Prevent and Treat Laser-induced Corneal Haze (2012)

Vorinostat is non-cytotoxic and safe for the eye and has potential to prevent laser-induced corneal haze in patients undergoing PRK for high myopia.
Attosecond physics comes of age: from tracing to steering electrons at sub-atomic scales (2007)

Efforts to access ever shorter time scales are motivated by the endeavour to explore the microcosm in ever smaller dimensions. At the turn of the millennium, one and a half decades after the first real-time observation of molecular dynamics with femtosecond laser pulses (1 fs = 10-15 s), we witnessed the emergence of sub-femtosecond (that is: attosecond) pulses (1 as = 10-18 s). They have been produced in the extreme ultraviolet regime by nonlinear frequency conversion of femtosecond laser pulses. A precise control of the hyperfast electric field oscillations of the driving femtosecond pulses not only allowed the controlled generation of single attosecond pulses and their full characterization but also, for the first time, steering and tracing the atomic-scale motion of electrons.
Chemical Factors that Control Lignin Polymerization B (2014)

Lignin is a complex, branched polymer that reinforces plant tissue. Understanding the factors that govern lignin structure is of central importance to the development of technologies for converting lignocellulosic biomass into fuels because lignin imparts resistance to chemical, enzymatic, and mechanical deconstruction. Lignin is formed by enzymatic oxidation of phenolic monomers (monolignols) of three main types, guaiacyl (G), syringyl (S), and p-hydroxyphenyl (H) subunits. It is known that increasing the relative abundance of H subunits results in lower molecular weight lignin polymers and hence more easily deconstructed biomass, but it is not known why. Here, we report an analysis of frontier molecular orbitals in mono-, di-, and trilignols, calculated using density functional theory, which points to a requirement of strong p-electron density on the reacting phenolic oxygen atom of the neutral precursor for enzymatic oxidation to occur. This model is consistent with a proton-coupled electron transfer (PCET) mechanism and for the first time explains why H subunits in certain linkages (β–β or β–5) react poorly and tend to “cap” the polymer. In general, β–5 linkages with either a G or H terminus are predicted to inhibit elongation. More broadly, the model correctly accounts for the reactivity of the phenolic groups in a diverse set of dilignols comprising H and G subunits. Thus, we provide a coherent framework for understanding the propensity toward growth or termination of different terminal subunits in lignin.
Regulatory and effector T cell subsets and dendritic cells in breast cancer (2004)

9697 Background: Successful immune responses against breast cancer may depend on the balance between immune stimulation mediated through dendritic cells (DC) & cytolytic T cells, and immune inhibition mediated in part by CD4+CD25+ regulatory T cells (Treg) and CTLA4 expression on T cells. We hypothesized that low anti-tumor immunity in breast cancer patients might be partially explained by aberrations in the frequencies of these different components of the immune response compared with healthy individuals. Methods: We analyzed whole blood from 26 breast cancer patients (9 stage I, 8 stage II, 3 stage III, 6 stage IV) for Treg, DC subsets, CD8+CD45RA+CCR7- cytolytic effectors, and CTLA4 expressing T cells. Controls were 41 healthy volunteers. Results: Breast cancer patients overall had higher levels of Treg (37+/−14% of CD4+ T cells) than controls (26.3 +/− 9%; p=0.002). Treg were higher in patients with stage II-IV disease, positive lymph nodes, and age < 65. Patients <65 also tended to have higher levels of CTLA4 on both CD4 and CD8+ T cells. Across all patients, there was a high positive correlation (0.82) of CTLA4 expression on Treg and CD8+ T cells, suggesting that the presence of this suppressive molecule may be a more generalized phenomenon in some individuals. The only groups that differed in CD8+CD45RA+CCR7- cytolytic effectors were premenopausal patients who had lower levels than post-menopausal women (37 vs 54%, p=0.04). Across all the patients, there was a modest negative correlation (−0.44) between Treg and CD8+ CD45RA+CCR7- suggesting that Treg may inhibit development of cytotoxic effector T cells. Finally, patients receiving chemotherapy and those with Stage IV disease had lower levels of immunostimulatory CD11c+ DC and higher levels of immunomodulatory CD123+ DC than other patients suggesting a possible negative impact of chemotherapy and advanced disease on stimulatory DC. Conclusions: This data highlights the inhibitory environment of the immune system in breast cancer patients, particularly those with advanced disease and younger age. Modification of this inhibitory environment will be needed to increase the activity of immunotherapy interventions in these patients. No significant financial relationships to disclose.
Cover Feature: Aminotriazole Mn(I) Complexes as Effective Catalysts for Transfer Hydrogenation of Ketones (ChemCatChem 20/2018) (2018)

The Cover Feature shows a Mn (I) complex as excellent catalyst for the transfer hydrogenation of ketones with 2-propanol as hydrogen source. In their Communication, O. Martínez-Ferraté et al. demonstrate that manganese complexes of readily accessible bidentate triazole ligands are effective catalysts for transfer hydrogenation of a broad range of substrates using iso-propanol in presence of various bases including sodium hydroxide. The rapidly expanding structural variety of effective ligand frameworks makes cheap and benign Manganese a very attractive new arrow in the quiver of organometallic chemists. More information can be found in the Communication by O. Martínez-Ferraté et al. on page 4514 in Issue 20, 2018 (DOI: 10.1002/cctc.201800953).