# University at Buffalo, The State University of New York

• Buffalo, NY, United States
Recent publications
This study explores the impact of antibody surface charge on tissue distribution into various tissues including tumor. Tumor-bearing mice were dosed intravenously with a mixture comprising three antibodies engineered to carry negative charge patches, a balanced charge distribution, or positive patches, respectively (cassette dosing). Tissue levels were analyzed with a specific LC-MS/MS method. In addition, the antibody mix was administered to non-tumor bearing mice. Muscle and skin interstitial fluid were obtained by centrifugation and analyzed by LC-MS/MS. An in vitro endothelium model was explored for its feasibility to mimic the observed distribution differences. A balanced charge distribution was optimal in terms of total tumor exposure, while in other tissues, negatively charged and balanced charged antibodies gave similar results. In contrast, positive charge patches generally resulted in increased serum clearance but markedly enhanced tumor and organ uptake, leading to higher tissue-to-serum ratios. The uptake and availability in the interstitial space were confirmed by specific assessment of antibody levels in the interstitial fluid of the muscle and skin, with similar charge impact as in total tissue. The in vitro model was able to differentiate the transport propensity of this series of antibody variants. In summary, our results show the differential effects of charge patches on an antibody surface on biodistribution and tumor uptake. These insights may help in the design of molecules with biodistribution properties tailored to their purpose, and an optimized safety profile.
Recently, room temperature superconductivity was measured in a carbonaceous sulfur hydride material whose identity remains unknown. Herein, first-principles calculations are performed to provide a chemical basis for structural candidates derived by doping H 3 S with low levels of carbon. Pressure stabilizes unusual bonding configurations about the carbon atoms, which can be six-fold coordinated as CH 6 entities within the cubic H 3 S framework, or four-fold coordinated as methane intercalated into the H-S lattice, with or without an additional hydrogen in the framework. The doping breaks degenerate bands, lowering the density of states at the Fermi level ( N F ), and localizing electrons in C-H bonds. Low levels of CH 4 doping do not increase N F to values as high as those calculated for $$Im\bar{3}m$$ I m 3 ¯ m -H 3 S, but they can yield a larger logarithmic average phonon frequency, and an electron–phonon coupling parameter comparable to that of R 3 m -H 3 S. The implications of carbon doping on the superconducting properties are discussed.
Introduction The minimally invasive step-up approach to pancreatitis improves outcomes. Multidisciplinary working groups may best facilitate this approach. However, support for these working groups requires funding. We hypothesize that patients requiring surgical debridement generate sufficient revenue to sustain these working groups. Furthermore, patients selected for surgical debridement by the working group will have a higher rate of percutaneous and endoscopic intervention in adherence to the step-up approach. Methods We conducted an observational cohort study of all patients with severe acute and/or necrotizing pancreatitis whose care was overseen by our multidisciplinary working group (October 2015 through January 2019). Patient demographics, hospital treatments, and outcomes data were compared between those who underwent surgical debridement and those who did not. Hospital billing data were also collected from those who are undergoing surgical debridement and compared to institutional benchmarks for financial sustainability. Results A total of 108 patients received care overseen by the working group, 10 of which progressed to surgical debridement. The mean contribution margin percentages for each patient in the surgical debridement group were higher than the threshold value for financial sustainability, 39% (60.34% ± 16.66%; P = 0.004). Patients in the surgical debridement group were more likely to undergo intervention by interventional radiologist (odds ratio, 1.58; P = 0.005). The mortality was higher in the nonsurgical debridement group (odds ratio, 15; P = 0.008). Conclusions Our multidisciplinary working group delivered step-up care to patients with pancreatitis. Patients requiring surgical debridement generated a significantly positive contribution margin that could be used to help support the costs associated with providing multidisciplinary care.
The current study analyzed the root causes of 22 helicopter accidents/incidents that took place between 1998 and 2019. Each root cause was coded using three commonly used classification models in aviation HFACS, ATSB, and IATA to identify recurring factors for better targeting of future prevention strategies. The frequency analysis revealed that not following procedure (22 observations), training inadequate or unavailable (17), inadequate regulatory oversight (17), inadequate procedure guidance (16), company management absent or deficient (10) and incorrect manuals/charts/checklists (9) were the most frequent contributing factors. Since none of the existing models could summarize the root causes of 22 occurrences effectively, a scenario-based human-machine-environment-procedure (HMEP) classification scheme was proposed to use organizational influences, people management, technical failure, procedure and document, and environment as the first-layer subcategories. The HMEP scheme was additionally applied to the analysis and coding of 4 helicopter accidents in the USA published by the NTSB. The HMEP scheme revealed that NTSB had identified a significantly greater number of root causes in the manufacturer design, manufacturing & documentation. Overall, HMEP can be used to guide the data collection during accident investigation and subsequently to aggregate aviation accidents to derive recurring factors and compare accident patterns in an efficient manner.
This paper presents a computational design exploration method called GA+TRIZ, which aids designers in defining the design problem clearly, making a parametric model where pertinent variables are included, obtaining a series of suitable solutions, and resolving existing conflicts among design objectives. The goal is to include the designer's qualitative and performance-based quantitative design goals in the design process, while promoting innovative ideas for resolving contradictory design objectives. The method employed is a Genetic Algorithm (GA), earlier implemented in an automated design exploration process called ParaGen, in combination with the Theory of Inventive Problem Solving (TRIZ), a novel methodology to assist architects and structural engineers in the conceptual phase of design. The GA+TRIZ method promotes automated design exploration, investigation of unexpected solutions, and continuous interaction with the computational generating system. Finally, this paper presents two examples that illustrate how the GA+TRIZ method assists designers in problem structuring, design exploration, and decision-making.
This paper presents a comprehensive disassembly sequence planning (DSP) algorithm in the human–robot collaboration (HRC) setting with consideration of several important factors including limited resources and human workers’ safety. The proposed DSP algorithm is capable of planning and distributing disassembly tasks among the human operator, the robot, and HRC, aiming to minimize the total disassembly time without violating resources and safety constraints. Regarding the resource constraints, we consider one human operator and one robot, and a limited quantity of disassembly tools. Regarding the safety constraints, we consider avoiding potential human injuries from to-be-disassembled components and possible collisions between the human operator and the robot due to the short distance between disassembly tasks. In addition, the transitions for tool changing, the moving between disassembly modules, and the precedence constraint of components to be disassembled are also considered and formulated as constraints in the problem formulation. Both numerical and experimental studies on the disassembly of a used hard disk drive (HDD) have been conducted to validate the proposed algorithm.
Cardiac troponin T (encoded by TNNT2 ) is involved in the contraction of cardiomyocytes during beating. The alternative splicing of TNNT2 results in four transcript variants with differential Ca ²⁺ sensitivity. The splicing of TNNT2 involves phosphorylation of the splicing factor SRSF6 by DYRK1A. Altered TNNT2 splicing patterns have been identified in failing human hearts. There is a paucity of studies describing DYRK1A-SRSF6-TNNT2 interplays in human cardiomyocytes. Also, it is not known whether the sensitivity of cardiomyocytes to cardiotoxic anthracyclines is modified in the context of variable DYRK1A-TNNT2 expression. In this study, we investigated the impact of DYRK1A on the endogenous expression of TNNT2 splicing variants in iPSC-derived cardiomyocytes. We also examined whether DYRK1A expression modifies the sensitivity of cardiomyocytes to the cardiotoxic drug daunorubicin (DAU). DYRK1A over-expression increased the abundance of TNNT2 fetal variants by ~ 58% whereas the abundance of the adult cTnT3 variant decreased by ~ 27%. High DYRK1A expression increased the phosphorylation of SRSF6 by ~ 25–65%. DAU cytotoxicity was similar between cardiomyocytes with variable levels of DYRK1A expression. DYRK1A over-expression ameliorated the impact of DAU on beating frequency. This study lays the foundation to further investigate the contribution of variable DYRK1A-TNNT2 expression to Ca ²⁺ handling and beating in human cardiomyocytes.
Numerical models capable of generating robust estimates of isolation‐system and fluid‐structure responses for multidirectional, high‐intensity shaking will be required for analysis, design, and risk assessment of seismically isolated advanced reactors. None of the few studies to date on base‐isolated, fluid‐filled vessels have generated datasets suitable for formal validation of numerical models. Earthquake‐simulator experiments on a fluid‐filled, cylindrical vessel, base isolated using four single concave friction pendulum bearings (SFP isolators) were performed. The dataset was used to validate a numerical model for high intensity, multidirectional seismic inputs. Fluid and isolation‐system responses obtained from analysis of the numerical model were in excellent agreement with experimental results. The numerical models and outcomes from the experiments are broadly applicable to base‐isolated, fluid‐filled vessels, regardless of industry sector.
Superconducting niobium nitride (NbN) continues to be investigated decades on, largely in part to its advantageous superconducting properties and wide use in superconducting electronics. Particularly, NbN-based superconducting nanowire single-photon detectors (SNSPDs) have shown exceptional performance. Recent experimental results have indicated that NbN remains as the material of choice in developing future generation quantum devices. In this perspective, we describe the processing-structure-property relationships governing the superconducting properties of NbN films. We further discuss the complex interplay between the material properties, processing parameters, substrate materials, device architectures, and performance of SNSPDs. We also highlight the latest progress in optimizing SNSPD performance parameters.
Existing ergonomic risk assessment tools require monitoring of multiple risk factors. To eliminate the direct observation, we investigated the effectiveness of an end-to-end framework that works with the data from a single wearable sensor. The framework is used to identify the performed task as the major contextual risk factor, and then estimate the task duration and number of repetitions as two main indicators of task intensity. For evaluation of the framework, we recruited 37 participants to complete 10 simulated work tasks in a laboratory setting. In testing, we achieved an average accuracy of 92% for task identification, 7.3% error in estimation of task duration, and 7.1% error for counting the number of task repetitions. Moreover, we showed the utility of the framework outputs in two ergonomic tools to estimate the risk of injury. Overall, we indicated the feasibility of using data from wearable sensors to automate the ergonomic risk assessment in workplaces.
Chronic social isolation stress during adolescence induces susceptibility for neuropsychiatric disorders. Here we show that 5-week post-weaning isolation stress induces sex-specific behavioral abnormalities and neuronal activity changes in the prefrontal cortex (PFC), basal lateral amygdala (BLA), and ventral tegmental area (VTA). Chemogenetic manipulation, optogenetic recording, and in vivo calcium imaging identify that the PFC to BLA pathway is causally linked to heightened aggression in stressed males, and the PFC to VTA pathway is causally linked to social withdrawal in stressed females. Isolation stress induces genome-wide transcriptional alterations in a region-specific manner. Particularly, the upregulated genes in BLA of stressed males are under the control of activated transcription factor CREB, and CREB inhibition in BLA normalizes gene expression and reverses aggressive behaviors. On the other hand, neuropeptide Hcrt (Hypocretin/Orexin) is among the top-ranking downregulated genes in VTA of stressed females, and Orexin-A treatment rescues social withdrawal. These results have revealed molecular mechanisms and potential therapeutic targets for stress-related mental illness.
To power microelectronics for the internet-of-things applications, high-performance miniature batteries, called microbatteries, are critically important. Given their limited size, the three-dimensional design of microbatteries is key to maximizing their performance. Therefore, a computational strategy to identify the target battery architecture has major implications for performance improvement. In this paper, we propose a data-driven 3D battery optimization system at the full cell level that combines an automatic geometry generator based on Monte Carlo Tree Search and highly accurate machine-learning-based performance simulators. The performance of the proposed method is demonstrated by designing high-performance 3D batteries with more than 5.5 times efficiency compared with the approach based on a randomized algorithm. One of the designed geometries displayed greater power and energy densities due to more than 10% reduced internal resistance than the reported state-of-the-art geometry at the current density of higher than 15.8 mA/cm2. The results demonstrate the effectiveness of the method.
In many cases, understanding species’ responses to climate change requires understanding variation among individuals in response to such change. For species with strong symbiotic relationships, such as many coral reef species, genetic variation in symbiont responses to temperature may affect the response to increased ocean temperatures. To assess variation among symbiont genotypes, we examined the population dynamics and physiological responses of genotypes of Breviolum antillogorgium in response to increased temperature. We found broad temperature tolerance across genotypes, with all genotypes showing positive growth at 26, 30, and 32°C. Genotypes differed in the magnitude of the response of growth rate and carrying capacity to increasing temperature, suggesting that natural selection could favor different genotypes at different temperatures. However, the historical temperature at which genotypes were reared (26 or 30°C) was not a good predictor of contemporary temperature response. We found increased photosynthetic rates and decreased respiration rates with increasing contemporary temperature, and differences in physiology among genotypes, but found no significant differences in the response of these traits to temperature among genotypes. In species with such broad thermal tolerance, selection experiments on symbionts outside of the host may not yield results sufficient for evolutionary rescue from climate change. Our work presents the results of an experiment that examines individual variation in symbionts, isolated and grown at different temperatures for hundreds of generations, from an octocoral species. We exposed replicates of different genotypes to increasing temperature and measured their population dynamics and physiology. We found broad thermal tolerance of this symbiont species, but also found significant variation among genotypes, although this was unrelated to the historical temperature at which they were grown.
At present, noninvasive fibrosis markers are not available for the assessment of liver fibrosis in children with chronic hepatitis C. Sixty-three children with chronic hepatitis C were included. Changes in Wisteria floribunda agglutinin-positive Mac-2 binding protein (M2BPGi) levels were evaluated in l3 of 27 treatment-naive patients during the natural course of disease (median 4, range 3–6 years). Changes during treatment were evaluated in 27 of 36 patients for 4 (2–9) years of posttreatment follow-up. There were significant differences in the levels of M2BPGi between control group and HCV F0 group (P = 0.002) and between control group and HCV F1 group (P < 0.001). Receiver operating characteristic curve analysis showed that to discriminate stage F1 fibrosis from F0, the cut-off value was 0.95 for M2BPGi with a sensitivity of 52%, specificity of 90%, and area under the curve of 0.687. A substantial decrease in M2BPGi levels by treatment was shown from 0.98 ± 0.57 at pretreatment to 0.42 ± 0.15 at posttreatment (P < 0.001) in the 27 treated patients. Our study shows new findings that M2BPGi may be useful to predict the presence of a mild degree of fibrosis in children with chronic hepatitis C, and such mild fibrosis may be quickly resolved by treatment.
ADNP and POGZ are two top-ranking risk factors for autism spectrum disorder and intellectual disability, but how they are linked to these neurodevelopmental disorders is largely unknown. Both ADNP and POGZ are chromatin regulators, which could profoundly affect gene transcription and cellular function in the brain. Using post-mortem tissue from patients with autism spectrum disorder, we found diminished expression of ADNP and POGZ in the prefrontal cortex, a region highly implicated in neurodevelopmental disorders. To understand the functional role of these neurodevelopmental disorder risk factors, we used viral-based gene transfer to investigate how Adnp or Pogz deficiency in mouse prefrontal cortex affects behavioural, transcriptomic and synaptic function. Mice with prefrontal cortex deficiency of Adnp or Pogz exhibited specific impairment of cognitive task performance. RNA-sequencing revealed that Adnp or Pogz deficiency induced prominent upregulation of overlapping genes enriched in neuroinflammation, similar to the elevation of pro-inflammatory genes in humans with neurodevelopmental disorders. Concomitantly, Adnp or Pogz deficiency led to the significant increase of pro-phagocytic microglial activation in prefrontal cortex, as well as the significant decrease of glutamatergic transmission and postsynaptic protein expression. These findings have uncovered the convergent functions of two top risk factors for autism spectrum disorder and intellectual disability in prefrontal cortex, providing a mechanism linking chromatin, transcriptional and synaptic dysregulation to cognitive deficits associated with neurodevelopmental disorders.
Introduction The diagnosis of tall cell variant papillary thyroid carcinoma (TCV-PTC) corresponds to the feature of “aggressive histology” within the framework of the American Thyroid Association (ATA) Risk of Recurrence (ROR) guidelines. Using the current World Health Organization (WHO) definition for TCV-PTC (tall cells with height at least twice the width, distribution ≥ 30%), we examined the impact of this diagnosis on disease-free survival (DFS). Methods The study cohort consisted of 347 patients treated for primary papillary thyroid carcinoma (PTC). Current ATA guidelines were followed for the extent of surgery and the administration of adjuvant radioiodine therapy. Clinical surveillance included ultrasound examination and biochemical parameters according to ATA standards. The outcome was measured as time from surgery to first disease recurrence (DR) versus time from surgery until the last documented disease-free encounter (no evidence of disease, NED). Disease-free patients with fewer than 6 months of follow-up were excluded from this cohort. Structural recurrences are documented by histology or cytology whereas biochemical recurrences are documented by rising serum thyroglobulin in the absence of structural disease. All slides on all patients were examined by two pathologists with the substantial interobserver agreement (Kappa = 73%). The primary tumors are categorically classified either as 1) TCV-PTC (definition above), 2) Papillary thyroid carcinoma with tall cell features (PTC-TCF) (≥ 10% < 30% tall cells), or 3) Control (< 10% tall cells). Tumor size is categorized as either 1) ≤ 10 mm, 2) 11-29 mm, or 3) ≥ 30 mm. Degree of ETE is categorized as either intrathyroidal, microscopic ETE, histologic spread to strap muscles, or pT4 disease. Results 185 patients are classified as TCV-PTC (≥ 30% tall cells), 62 as PTC-TCF (≥ 10% < 30% tall cells), and 100 as control group (< 10% tall cells). TCV-PTC is associated with ≥ 30 mm size (p =.0246) and invasion of strap muscles and/or pT4 (p =.0325). There was no relationship between TCV-PTC and aggressive lymph node (ALN) status defined by ATA. Overall follow-up ranged from two months (one patient death) to 203 months (mean 40.8, median 33.0). DR occurred in 61 patients (mean 31.4 months, range 0 –184, 59 structural recurrences, 2 biochemical recurrences). Three models for TCV-PTC were examined: Model 1 - Tall cells ≥ 10% versus control, Model 2 - TCV-PTC versus TCF-PTC versus control, and Model 3 - TCV-PTC versus control. Kaplan Meier curves demonstrated decreased DFS with ALN status (p =.0001), ETE (p =.0295), and TCV-PTC (Model 1, p =.041). On multivariate analysis, TCV-PTC (Model 1) remained significantly predictive when adjusted for ALN (p =.0059). ETE dropped out of the model. Conclusion TCV-PTC is significantly associated with larger tumors and a greater degree of ETE. The diagnosis of TCV-PTC significantly impacts DFS at the 10% cut-point on multivariate analysis.
Social withdrawal is the behavioral tendency to remove oneself from social situations - a tendency that often contributes to reductions in individuals' mental health. The current study evaluated the links between different motivations for social withdrawal (shyness, unsociability, social avoidance) and indices of psychosocial adjustment in a Norwegian sample of emerging adults. Participants were N = 194 Norwegian university students who completed self-report measures of life satisfaction, loneliness, and depressive symptoms, as well as withdrawal motivations. Among the results, a newly translated version of the Social Preference Scale-Revised (SPS-R) was validated for use in Norway. Findings showed that shyness was uniquely and positively associated with loneliness and depressive symptoms, as well as lower life satisfaction, whereas social avoidance was positively associated with depressive symptoms. Unsociability was uniquely linked to lower levels of loneliness and depressive symptoms. Findings provide novel information about the psychosocial correlates of social withdrawal motivations during emerging adulthood in the under-explored cultural context of Norway. Understanding nuances in the correlates of different motivations may aid in the development of culturally and developmentally sensitive interventions.
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• Center for Hearing and Deafness