Miracle-dz/UniFAR-FTUs huggingface dataset:
A new tool for the action potential repolarization dynamic analysis: Application to the discrimination of diabetic and control cells

In CinC2015 we have shown that the dynamics of the action potential (AP) repolarization could be tracked throughout the stimulation course. Despite some valuable outcomes, the populations of interest (control, Ctrl, and streptozotocin-induced, STZ, diabetic mice) could not be significantly distinguished in term of dynamics because of the global extracted feature. In this study, the computation of new features for each repolarization percentage allows an accurate and meaningful characterization of the two groups leading to a significant classification. APs in isolated left ventricular cardiomyocytes obtained from Ctrl and STZ mice were measured by patch-clamp. The progressive changes in AP repolarization for individual cells were tested on a set of 100 consecutive excitations at 2Hz pacing rate. The corresponding repolarizations are stacked in a matrix decomposed with a new approach. Observations are modeled as a sum of vectors multiplied by specific polynomial functions. This approach is similar to the Singular Value Decomposition (SVD), but the corresponding scalars are replaced by these functions. Model unknowns are estimated by using an alternated least square algorithm. Finally, the mean of the polynomial first derivative is computed for each repolarization percentage as a representative feature. A Wilcoxon signed rank test (p<0.05) has been applied on the features from the two groups. We can observe a significant difference in the late repolarization phase (70%–95% repolarization), with a singular behavior in correspondence with the AP profile shoulder onset (80%).
Antiaging therapy: a prospective hypothesis

This hypothesis proposes a new prospective approach to slow the aging process in older humans. The hypothesis could lead to developing new treatments for age-related illnesses and help humans to live longer. This hypothesis has no previous documentation in scientific media and has no protocol. Scientists have presented evidence that systemic aging is influenced by peculiar molecules in the blood. Researchers at Albert Einstein College of Medicine, New York, and Harvard University in Cambridge discovered elevated titer of aging-related molecules (ARMs) in blood, which trigger cascade of aging process in mice; they also indicated that the process can be reduced or even reversed. By inhibiting the production of ARMs, they could reduce age-related cognitive and physical declines. The present hypothesis offers a new approach to translate these findings into medical treatment: extracorporeal adjustment of ARMs would lead to slower rates of aging. A prospective “antiaging blood filtration column” (AABFC) is a nanotechnological device that would fulfill the central role in this approach. An AABFC would set a near-youth homeostatic titer of ARMs in the blood. In this regard, the AABFC immobilizes ARMs from the blood while blood passes through the column. The AABFC harbors antibodies against ARMs. ARM antibodies would be conjugated irreversibly to ARMs on contact surfaces of the reaction platforms inside the AABFC till near-youth homeostasis is attained. The treatment is performed with the aid of a blood-circulating pump. Similar to a renal dialysis machine, blood would circulate from the body to the AABFC and from there back to the body in a closed circuit until ARMs were sufficiently depleted from the blood. The optimal application criteria, such as human age for implementation, frequency of treatments, dosage, ideal homeostasis, and similar concerns, should be revealed by appropriate investigations. If AABFC technology undergoes practical evaluations and gains approval, it would hold future promises such as: 1) prolonged lifespans; 2) slowed age-related illnesses such as low bone mass, weak muscular systems, diabetes, arthritis, Alzheimer’s disease, and impaired memory in the elderly; 3) reduced health expenses; 4) reduced cosmetic surgeries performed on the elderly; 5) healthier astronauts in extended outer space journeys; 6) reduced financial burden of advanced care for the elderly imposed upon both government and society; and 7) rejuvenating effects in healthy, non-aged individuals.
Reconciling concepts, theory, and empirical patterns surrounding cascade reinforcement

Reinforcement is a critically important process in speciation. It has been credited with often completing speciation, and it is unique in that natural selection directly favors the evolution of reproductive isolating barriers. Reinforcement occurs when selection favors increased prezygotic isolation between two lineages in order to avoid maladaptive hybridization in areas of sympatry (Noor 1999; Servedio and Noor 2003; Coyne and Orr 2004). The classic signature of reinforcement is reproductive character displacement (RCD), where prezygotic isolation is heightened between two lineages in areas of sympatry relative to areas of allopatry. Reinforcement was once considered controversial primarily due to theoretical difficulties (Felsenstein 1981; Spencer et al. 1986; reviewed in Noor 1999, and Coyne and Orr, 2004). However, a wealth of empirical cases demonstrating reinforcement along with renewed theoretical treatments of the process of reinforcement (Liou and Price 1994; Kelly and Noor 1996; Servedio 2000; Kirkpatrick and Ravigne 2002) has led to the conclusion that reinforcement can and does occur in nature. One consequence of reinforcement is that—by altering reproductive isolating traits—reinforcement may also lead to prezygotic isolation among populations within species. Hence, like ecological and sexual selection, reinforcement can have incidental effects upon reproductive isolation (RI). In fact, reinforcement might be particularly likely to have such incidental effects precisely because it alters reproductive isolating traits among species in areas of sympatry. The process whereby increased prezygotic isolation among populations evolves as an incidental effect of reinforcement has been referred to as “cascade reinforcement” (Ortiz-Barrientos et al. 2009) and as “reproductive character displacement speciation” (Hoskin and Higgie 2010). In this special column, we use the term cascade reinforcement. The idea has been recognized sporadically throughout the history of reinforcement (Zouros and Dentremont 1980; Howard 1993), but has recently received renewed attention (Ortiz-Barrientos et al. 2009; … Email: fuller{at}life.illinois. edu.
Dynamic m6A modification regulates local translation of mRNA in axons

Abstract N 6-methyladenosine (m6A) is a reversible modification in mRNA and has been shown to regulate processing, translation and decay of mRNA. However, the roles of m6A modification in neuronal development are still not known. Here, we found that the m6A eraser FTO is enriched in axons and can be locally translated. Axon-specific inhibition of FTO by rhein, or compartmentalized siRNA knockdown of Fto in axons led to increases of m6A levels. GAP-43 mRNA is modified by m6A and is a substrate of FTO in axons. Loss-of-function of this non-nuclear pool of FTO resulted in increased m6A modification and decreased local translation of axonal GAP-43 mRNA, which eventually repressed axon elongation. Mutation of a predicted m6A site in GAP-43 mRNA eliminated its m6A modification and exempted regulation of its local translation by axonal FTO. This work showed an example of dynamic internal m6A demethylation of non-nuclear localized mRNA by the demethylase FTO. Regulation of m6A modification of axonal mRNA by axonal FTO might be a general mechanism to control their local translation in neuronal development.
Aviation fuel tracer simulation: Model intercomparison and implications

An upper limit for aircraft‐produced perturbations to aerosols and gaseous exhaust products in the upper troposphere and lower stratosphere (UT/LS) is derived using the 1992 aviation fuel tracer simulation performed by eleven global atmospheric models. Key findings are that subsonic aircraft emissions: 1) have not be responsible for the observed water vapor trends at 40°N; 2) could be a significant source of soot mass near 12 km, but not at 20 km, 3) might cause a noticeable increase in the background sulfate aerosol surface area and number densities (but not mass density) near the northern mid‐latitude tropopause, and 4) could provide a global, annual mean top of the atmosphere radiative forcing up to +0.006 W/m² and −0.013 W/m² due to emitted soot and sulfur, respectively.
Proanthocyanidin Synthesis in Chinese Bayberry (Myrica rubra Sieb. et Zucc.) Fruits

Proanthocyanidins (PAs) are distributed widely in Chinese bayberry fruit and have been associated with human health benefits, but molecular and biochemical characterization of PA biosynthesis remains unclear. Here, two genes encoding key PA biosynthetic enzymes, anthocyanidin reductase (ANR) and leucoanthocyanidin reductase (LAR) were isolated in bayberry fruit. MrANR was highly expressed at the early stage of fruit development when soluble PAs accumulated at high levels. Meanwhile, the transcript abundance of both MrANR and MrLAR observed at the late stage was paralleled with the high amounts of insoluble PAs. LC-MS/MS showed that PAs in developing Chinese bayberry fruits were comprised predominantly of epigallocatechin-3-O-gallate terminal subunits, while the extension subunits were a mixture of epigallocatechin-3-O-gallate, epigallocatechin and catechin. Recombinant MrANR protein converted cyanidin to a mixture of epicatechin and catechin, and delphinidin to a mixture of epigallocatechin and gallocatechin in vitro. Recombinant MrLAR was active with leucocyanidin as substrate to produce catechin. Ectopic expression of MrANR in tobacco reduced anthocyanin levels but increased PA accumulation. The catechin and epicatechin contents in transgenic flowers overexpressed MrANR were significantly higher than those of wild-type. However, overexpression of MrLAR in tobacco led to an increase in catechin levels but had no impact on PA contents. Quantitative real time PCR revealed that the loss of anthocyanin in transgenic flowers overexpressed MrANR or MrLAR is probably attributed to decreased expression of tobacco chalcone isomerase (CHI) gene. Our results not only reveal in vivo and in vitro functions for ANR and LAR but also provide a resource for understanding the mechanism of PA biosynthesis in Chinese bayberry fruit.
Predictors of COPD in symptomatic smokers and ex-smokers seen in primary care

Even in subjects at high risk of chronic obstructive pulmonary disease (COPD), the diagnosis is often missed due to lack of awareness of symptoms and risk factors. The objective of this study was to identify predictors of a diagnosis of COPD in symptomatic current and ex-smokers seen in a primary care setting. General practitioners (n = 241) consecutively recruited subjects ≥ 35 years, with tobacco exposure, at least one respiratory symptom (i.e. cough, sputum, wheeze, dyspnoea and/or recurrent lower respiratory tract infections), and no previous diagnosis of obstructive airways disease. Information on age, smoking status, body mass index (BMI) and dyspnoea (Medical Research Council (MRC) dyspnoea scale) was obtained. Individuals with airway obstruction (i.e. forced expiratory volume in 1 second (FEV1)/forced vital capacity ratio (FVC) < 0.70) at initial spirometry had a diagnostic spirometry after administration of a bronchodilator. COPD was defined as the presence of symptoms, tobacco exposure and persistent airflow limitation. The most prevalent symptoms were cough (72%) and dyspnoea (48%). Of 3875 (50% females, mean age 57 years) subjects screened, 700 (18.1%) were diagnosed with COPD. Multivariate logistic regression analysis revealed that increasing age 50–59 years (OR 2.4, 95% CI 1.8–3.3), 60–69 years (OR 4.1, 95% CI 3.1–5.5), ≥70 years (OR 5.7, 95% CI 4.2–7.8), BMI < 25 (OR 2.3, 95% CI 1.9–2.7), being current smoker (OR 1.2, 95% CI 1.01–1.5), self-reported dyspnoea (OR 1.7, 95% CI 1.4–2.0), wheeze (OR 1.9, 95% CI 1.5–2.3) and sputum (OR 1.4, 95% CI 1.1–1.7) were associated with a significantly higher risk of being diagnosed with COPD. No association was found between gender, cough and recurrent respiratory tract infections and a diagnosis of COPD. Among symptomatic smokers and ex-smokers seen in primary care, self-reported sputum production, wheeze, dyspnoea and low BMI identify a subgroup with a higher likelihood of COPD.
Carbon content and C:N ratio of transparent exopolymeric particles (TEP) produced by bubbling exudates of diatoms

The carbon content of transparent exopolymeric particles (TEP) was measured in the laboratory in particles produced by bubbling exudates of the diatom Thalassiosira weissflogii, grown under nitrogen non-limited conditions (N:P = 7). The carbon content of these particles (TEP-C) appears to vary as a function of their size according to TEP-C = 0.25 × 10 -6 r 2.55 (μg C TEP -1 ), where r is the equivalent spherical radius of the TEP particle (μm). This relationship implies that TEP are fractal aggregates having a fractal dimension D = 2.55. When this value was applied to historical TEP size spectra from a coastal area (Kattegat, Denmark), TEP carbon concentration in the surface mixed layer was on the order of 230 ± 150 μg C l -1 . This is high relative to other sources of particulate organic carbon (e.g. phytoplankton) and depending on TEP turnover rates, suggests that TEP is an important pathway for dissolved organic carbon in coastal seas. The carbon to nitrogen ratio of TEP was measured from particles formed by bubbling exudates of the diatoms T. weissflogii, Skeletonema costatum, Chaetoceros neogracile and C. affinis. Each of these diatom species was grown under various N:P ratios, from N-non-limited to N-limited conditions. While the C:N ratio of the diatom cells grown under N-limited conditions was high (C:N ≥ 14), the TEP aggregates formed by coagulation of the extracellular release produced by these cells exhibited a C:N ratio relatively constant (C:N = 7.3 ± 2.6) and apparently independent from that of the cells.
Quantifying rigidity of Parkinson's disease in relation to laxative treatment: a service evaluation

Aim To estimate whether laxatives prescribed for constipation in Parkinson's disease (PD) could moderate rigidity. Constipation predates diagnosis of PD by decades. Deposition of misfolded protein may begin in the gut, driven by dysbiosis. Successive antimicrobial exposures are associated with cumulative increase in rigidity, and rigidity has biological gradients on circulating leukocyte‐subset counts. Methods Retrospective service evaluation, in a gut/brain axis clinic, yielded an interrupted time series, relating maintenance laxative and other medication to rigidity, in consecutive outpatients identified by inclusion and exclusion criteria. Objective assessment of rigidity was used to bring greater sensitivity to change, validated against subjective gold standard (UPDRS). Results There were 1493 measurements of torque required to extend (flexor rigidity) and flex (extensor rigidity) the forearm in 79 PD patients over 374 person‐years. Both were strongly associated with UPDRS (P < 0.001 and P = 0.008, respectively). Before exhibition of laxative, flexor rigidity increased by 6% (95% CI 1, 10) per year, plateauing at −2% (−4, 1) per year after, with no shift at initiation. Change in slope was significant (P = 0.002), and manifest in those naïve to antiparkinsonian medication. The change was replicated for individual laxative classes (bulk, osmotic, enterokinetic). There was no temporal change in extensor rigidity. Limited experience with a quanylate cyclase‐C receptor agonist (17 patients, 6 person‐years) indicated a large and significant step down in flexor and extensor rigidity, of 19% (1, 34) and 16% (6, 24) respectively (P = 0.04 and <0.001). Conclusions Maintenance laxative usage was associated with apparent stemming of the temporal increase in rigidity in PD, adding to indicative evidence of a continuing role of gastrointestinal dysbiosis in pathogenesis.
Disease activity in and quality of life of patients with psoriatic arthritis mutilans: the Nordic PAM Study

Objective: To describe the social status and health-related quality of life of patients with psoriatic arthritis mutilans (PAM) in the Nordic countries. Method: Patients with at least one mutilated joint confirmed by radiology were studied. Disease activity involving joints and skin, physician-assessed disease activity, and patient’s education and work status were recorded. Data from the 36-item Short Form Health Survey, Health Assessment Questionnaire and Dermatology Life Quality Index questionnaire were gathered and correlated with disease duration, pain, and general well-being (visual analogue scale). The controls were 58 Swedish patients with long-standing psoriatic arthritis sine PAM. Results: Sixty-seven patients were included. Patients with PAM had a protracted disease history (33 ± 14 years) and disease onset at a relatively early age (30 ± 12 years). Overall inflammatory activity at inclusion was mild to moderate. The mean number of mutilated joints was 8.2 and gross deformity was found in 16% of patients. Forty per cent were treated with biological and 32% with conventional synthetic disease-modifying anti-rheumatic drugs. Forty-two per cent had retired early or were on sick leave. Impaired functional capacity with little or no ability to perform self-care or everyday tasks was reported by 21% of the patients. Patients between 45 and 60 years of age reported the most impaired quality of life in comparison to the control group. Conclusion: PAM seriously affects social functioning. Whether early recognition of PAM and new forms of therapy can improve disease outcome and quality of life remains to be studied.
Applications of Raman Spectroscopy

This thesis is devoted to exploring experimental applications of Raman spectroscopy. The ability of Raman spectroscopy to investigate the vibrational modes of a molecule was explored in several studies. The work included using Raman spectroscopy to examine the molecular configuration of proteins, the relative amounts of certain molecules present in a nanoporous material, the enhanced scattering properties of nano-structures and finding the local temperature of nanowire materials. The primary research project presented in this thesis focused on determining the structural conformation of lysozyme in a variety of contact lens solutions and the relation to its functionality. Protein activity was established by the use of micrococcal assays. The two multipurpose solutions tested, BioTrue and ReNu, as well as a neutralized hydrogen peroxide solution, ClearCare, showed no indications of major structural alterations in the lysozyme when exposed to the separate solutions. The assay experimental data indicated a consistently high protein activity during exposure to the various solutions. Both the data indicating a native structural conformation and high degree functionality result in the conclusion that the multipurpose solutions do not denature lysozyme during a regular cleaning cycle. The non-neutralized ClearCare and the other hydrogen peroxide solution, UltraCare (both neutralized and non-neutralized), demonstrated signs of lysozyme denaturation within a time period of a typical cleaning cycle, due to structural changes to the protein. However, the functionality of non-neutralized UltraCare and ClearCare (by the micrococcal assay) were both found to remain relatively high, seemingly contradicting the structural indications of denaturation. This discrepancy between the structure and function of the proteins may be attributed to the irreversible process of aggregation that occurs at the high concentrations of protein which are require to produce a strong Raman signal. However, the relatively lower concentration of lysozyme used in the assay experiments better reflect the true amounts found in the tear film. Thus, the conclusion can be made that if lysozyme is denatured by the majority of the solutions, they are only reversibly denatured, posing minimal risks when reintroduced back into the eye. The only contact lens solution that may pose the potential for inducing an inflammatory response to permanently denatured lysozyme is following exposure to neutralized UltraCare. The exact reason for this permanent denaturation seems to be from the components of the neutralizing tablet, but this requires further investigation. Raman spectroscopy was also employed in several additional research projects for other graduate groups. The first side project involved the use of heptane to wash away only
Toward an integrated map of genetic interactions in cancer cells

Cancer genomes often harbor hundreds of molecular aberrations. Such genetic variants can be drivers or passengers of tumorigenesis and, as a side effect, create new vulnerabilities for potential therapeutic exploitation. To systematically identify genotype-dependent vulnerabilities and synthetic lethal interactions, forward genetic screens in different genetic backgrounds have been conducted. We devised MINGLE, a computational framework that integrates CRISPR/Cas9 screens originating from many different libraries and laboratories to build genetic interaction maps. It builds on analytical approaches that were established for genetic network discovery in model organisms. We applied this method to integrate and analyze data from 85 CRISPR/Cas9 screens in human cancer cell lines combining functional data with information on genetic variants to explore the relationships of more than 2.1 million gene-background relationships. In addition to known dependencies, our analysis identified new genotype-specific vulnerabilities of cancer cells. Experimental validation of predicted vulnerabilities associated with aberrant Wnt/β-catenin signaling identified GANAB and PRKCSH as new positive regulators of Wnt/β-catenin signaling. By clustering genes with similar genetic interaction profiles, we drew the largest genetic network in cancer cells to date. Our scalable approach highlights how diverse genetic screens can be integrated to systematically build informative maps of genetic interactions in cancer, which can grow dynamically as more data is included.
Gravin regulates centrosome function through PLK1

We propose to understand how the mitotic kinase PLK1 drives chromosome segregation errors, with a specific focus on Gravin, a PLK1 scaffold. In both three-dimensional primary prostate cancer cell cultures that are prone to Gravin depletion and Gravin short hairpin RNA (shRNA)–treated cells, an increase in cells containing micronuclei was noted in comparison with controls. To examine whether the loss of Gravin affected PLK1 distribution and activity, we utilized photokinetics and a PLK1 activity biosensor. Gravin depletion resulted in an increased PLK1 mobile fraction, causing the redistribution of active PLK1, which leads to increased defocusing and phosphorylation of the mitotic centrosome protein CEP215 at serine-613. Gravin depletion further led to defects in microtubule renucleation from mitotic centrosomes, decreased kinetochore-fiber integrity, increased incidence of chromosome misalignment, and subsequent formation of micronuclei following mitosis completion. Murine Gravin rescued chromosome misalignment and micronuclei formation, but a mutant Gravin that cannot bind PLK1 did not. These findings suggest that disruption of a Gravin–PLK1 interface leads to inappropriate PLK1 activity contributing to chromosome segregation errors, formation of micronuclei, and subsequent DNA damage.