Miracle-dz/UniFAR-FTUs huggingface dataset:
Characteristic disruptions of an excitable carbon cycle

Significance The great environmental disruptions of the geologic past remain enigmatic. Each one results in a temporary change in the oceans’ store of carbon. Although the causes remain controversial, these changes are typically interpreted as a proportionate response to an external input of carbon. This paper suggests instead that the magnitude of many disruptions is determined not by the strength of external stressors but rather by the carbon cycle’s intrinsic dynamics. Theory and observations indicate that characteristic disruptions are excited by carbon fluxes into the oceans that exceed a threshold. Similar excitations follow influxes that are either intense and brief or weak and long-lived, as long as they exceed the threshold. Mass extinction events are associated with influxes well above the threshold. The history of the carbon cycle is punctuated by enigmatic transient changes in the ocean’s store of carbon. Mass extinction is always accompanied by such a disruption, but most disruptions are relatively benign. The less calamitous group exhibits a characteristic rate of change whereas greater surges accompany mass extinctions. To better understand these observations, I formulate and analyze a mathematical model that suggests that disruptions are initiated by perturbation of a permanently stable steady state beyond a threshold. The ensuing excitation exhibits the characteristic surge of real disruptions. In this view, the magnitude and timescale of the disruption are properties of the carbon cycle itself rather than its perturbation. Surges associated with mass extinction, however, require additional inputs from external sources such as massive volcanism. Surges are excited when CO2 enters the oceans at a flux that exceeds a threshold. The threshold depends on the duration of the injection. For injections lasting a time ti≳10,000 y in the modern carbon cycle, the threshold flux is constant; for smaller ti, the threshold scales like ti−1. Consequently the unusually strong but geologically brief duration of modern anthropogenic oceanic CO2 uptake is roughly equivalent, in terms of its potential to excite a major disruption, to relatively weak but longer-lived perturbations associated with massive volcanism in the geologic past.
BAP1 Loss Is Associated with DNA Methylomic Repatterning in Highly Aggressive Class 2 Uveal Melanomas

Purpose: The strong association between BAP1 mutations and metastasizing Class 2 uveal melanoma (UM) suggests that epigenetic alterations may play a significant role in tumor progression. Thus, we characterized the impact of BAP1 loss on the DNA methylome in UM. Experimental Design: Global DNA methylation was analyzed in 47 Class 1 and 45 Class 2 primary UMs and in UM cells engineered to inducibly deplete BAP1. RNA-Seq was analyzed in 80 UM samples and engineered UM cells. Results: Hypermethylation on chromosome 3 correlated with downregulated gene expression at several loci, including 3p21, where BAP1 is located. Gene set analysis of hypermethylated and downregulated genes identified axon guidance and melanogenesis as deregulated pathways, with several of these genes located on chromosome 3. A novel hypermethylated site within the BAP1 locus was found in all Class 2 tumors, suggesting that BAP1 itself is epigenetically regulated. Highly differentially methylated probes were orthogonally validated using bisulfite sequencing, and they successfully distinguished Class 1 and Class 2 tumors in 100% of cases. In functional validation experiments, BAP1 knockdown in UM cells induced methylomic repatterning similar to UM tumors, enriched for genes involved in axon guidance, melanogenesis, and development. Conclusions: This study, coupled with previous work, suggests that the initial event in the divergence of Class 2 UM from Class 1 UM is loss of one copy of chromosome 3, followed by mutation of BAP1 on the remaining copy of chromosome 3, leading to the methylomic repatterning profile characteristic of Class 2 UMs.
Telomerase Reverse Transcriptase (TERT) in Action: Cross-Talking with Epigenetics

Telomerase, an RNA-dependent DNA polymerase with telomerase reverse transcriptase (TERT) as the catalytic component, is silent due to the tight repression of the TERT gene in most normal human somatic cells, whereas activated only in small subsets of cells, including stem cells, activated lymphocytes, and other highly proliferative cells. In contrast, telomerase activation via TERT induction is widespread in human malignant cells, which is a prerequisite for malignant transformation. It is well established that TERT/telomerase extends telomere length, thereby conferring sustained proliferation capacity to both normal and cancerous cells. The recent evidence has also accumulated that TERT/telomerase may participate in the physiological process and oncogenesis independently of its telomere-lengthening function. For instance, TERT is shown to interact with chromatin remodeling factors and to regulate DNA methylation, through which multiple cellular functions are attained. In the present review article, we summarize the non-canonical functions of TERT with a special emphasis on its cross-talk with epigenetics: How TERT contributes to epigenetic alterations in physiological processes and cancer, and how the aberrant epigenetics in turn facilitate TERT expression and function, eventually promoting cancer either initiation or progression or both. Finally, we briefly discuss clinical implications of the TERT-related methylation.
Extended long-term radiographic and functional comparison of tibial plateau leveling osteotomy vs tibial tuberosity advancement for cranial cruciate ligament rupture in the dog.

OBJECTIVE To report extended long-term outcomes of dogs with cranial cruciate ligament rupture treated by tibial plateau leveling osteotomy (TPLO) or tibial tuberosity advancement (TTA). STUDY DESIGN Retrospective clinical cohort study. ANIMALS Client-owned dogs with ≥3 years follow-up (118 dogs, 166 stifles). METHODS Records from June 2012 to May 2015 were reviewed. Follow-up examination and radiography were performed in dogs meeting the inclusion criteria. Measures of outcomes included a radiographic osteoarthritis score (preoperative, 8 weeks postoperative, and ≥3 years postoperative), the Canine Brief Pain Inventory, and the Canine Orthopedic Index. RESULTS Ninety-four dogs treated with TPLO (133 stifles) and 24 dogs treated with TTA (33 stifles) met the inclusion criteria. All dogs underwent meniscal release or partial medial meniscectomy. Osteoarthritis score progressed more after TTA (P = .003) and in dogs with bilateral surgery (P = .022). Long-term outcomes that were better after TPLO compared with TTA included average pain in the last 7 days (P = .007), interference with walking (P = .010), morning stiffness (P = .004), jumping (P = .003) and climbing (P = .040), limping during mild activities (P = .001), and overall quality of life (P = .045). CONCLUSION Osteoarthritis progressed more after TTA and in dogs with bilateral stifle surgery. Dogs treated with TPLO subjectively seemed to have less pain and fewer mobility issues. CLINICAL SIGNIFICANCE Tibial plateau leveling osteotomy provides a better long-term radiographic and functional outcome than TTA.
Experiences of Adults With Type 1 Diabetes Using Glucose Sensor–Based Mobile Technology for Glycemic Variability: Qualitative Study

Background Adults with type 1 diabetes (PWDs) face challenging self-management regimens including monitoring their glucose values multiple times a day to assist with achieving glycemic targets and reduce the risk of long-term diabetes complications. Recent advances in diabetes technology have reportedly improved glycemia, but little is known about how PWDs utilize mobile technology to make positive changes in their diabetes self-management. Objective The aim of this qualitative study was to explore PWDs’ experiences using Sugar Sleuth, a glucose sensor–based mobile app and Web-based reporting system, integrated with the FreeStyle Libre glucose monitor that provides feedback about glycemic variability. Methods We used a qualitative descriptive research design and conducted semistructured interviews with 10 PWDs (baseline mean glycated hemoglobin, HbA1c) 8.0%, (SD 0.45); 6 males and 4 females, aged 52 years (SD 15), type 1 diabetes (T1D) duration 31 years (SD 13), 40% (4/10, insulin pump) following a 14-week intervention during which they received clinical support and used Sugar Sleuth to evaluate and understand their glucose data. Audio-recorded interviews were transcribed, coded, and analyzed using thematic analysis and NVivo 11 (QSR International Pty Ltd). Results A total of 4 main themes emerged from the data. Participants perceived Sugar Sleuth as an Empowering Tool that served to inform lifestyle choices and diabetes self-management tasks, promoted preemptive self-care actions, and improved discussions with clinicians. They also described Sugar Sleuth as providing a Source of Psychosocial Support and offering relief from worry, reducing glycemic uncertainty, and supporting positive feelings about everyday life with diabetes. Participants varied in their Approaches to Glycemic Data: 40% (4/10) described using Sugar Sleuth to review data, understand glycemic cause and effect, and plan for future self-care. On the contrary, 60% (6/10) were reluctant to review past data; they described receiving benefits from the immediate numbers and trend arrows, but the app still prompted them to enter in the suspected causes of glucose excursions within hours of their occurrence. Finally, only 2 participants voiced Concerns About Use of Sugar Sleuth; they perceived the app as sometimes too demanding of information or as not attuned to the socioeconomic backgrounds of PWDs from diverse populations. Conclusions Results suggest that Sugar Sleuth can be an effective educational tool to enhance both patient-clinician collaboration and diabetes self-management. Findings also highlight the importance of exploring psychosocial and socioeconomic factors that may advance the understanding of PWDs’ individual differences when using glycemic technology and may promote the development of customized mobile tools to improve diabetes self-management.
Insulin Treatment Forces Arteriogenesis in Diabetes Mellitus by Upregulation of the Early Growth Response-1 (Egr-1) Pathway in Mice

The process of arteriogenesis is severely compromised in patients with diabetes mellitus (DM). Earlier studies have reported the importance of Egr-1 in promoting collateral outward remodeling. However, the role of Egr-1 in the presence of DM in outward vessel remodeling was not studied. We hypothesized that Egr-1 expression may be compromised in DM which may lead to impaired collateral vessel growth. Here, we investigated the relevance of the transcription factor Egr-1 for the process of collateral artery growth in diabetic mice. Induction of arteriogenesis by femoral artery ligation resulted in an increased expression of Egr-1 on mRNA and protein level but was severely compromised in streptozotocin-induced diabetic mice. Diabetes mellitus mice showed a significantly reduced expression of Egr-1 endothelial downstream genes Intercellular Adhesion Molecule-1 (ICAM-1) and urokinase Plasminogen Activator (uPA), relevant for extravasation of leukocytes which promote arteriogenesis. Fluorescent-activated cell sorting analyses confirmed reduced leukocyte recruitment. Diabetes mellitus mice showed a reduced expression of the proliferation marker Ki-67 in growing collaterals whose luminal diameters were also reduced. The Splicing Factor-1 (SF-1), which is critical for smooth muscle cell proliferation and phenotype switch, was found to be elevated in collaterals of DM mice. Treatment of DM mice with insulin normalized the expression of Egr-1 and its downstream targets and restored leukocyte recruitment. SF-1 expression and the diameter of growing collaterals were normalized by insulin treatment as well. In summary, our results showed that Egr-1 signaling was impaired in DM mice; however, it can be rescued by insulin treatment.
The Detection and Morphological Analysis of Circulating Tumor and Host Cells in Breast Cancer Xenograft Models

Hematogenous dissemination may occur early in breast cancer (BC). Experimental models could clarify mechanisms, but in their development, the heterogeneity of this neoplasia must be considered. Here, we describe circulating tumor cells (CTCs) and the metastatic behavior of several BC cell lines in xenografts. MDA-MB-231, BT-474, MDA-MB-453 and MDA-MB-468 cells were injected at the orthotopic level in immunocompromised mice. CTCs were isolated using a size-based method and identified by cytomorphological criteria. Metastases were detected by COX IV immunohistochemistry. CTCs were detected in 90% of animals in each model. In MDA-MB-231, CTCs were observed after 5 weeks from the injection and step wisely increased at later time points. In animals injected with less aggressive cell lines, the load of single CTCs (mean ± SD CTCs/mL: 1.8 ± 1.3 in BT-474, 122.2 ± 278.5 in MDA-MB-453, 3.4 ± 2.5 in MDA-MB-468) and the frequency of CTC clusters (overall 38%) were lower compared to MDA-MB-231 (946.9 ± 2882.1; 73%). All models had lung metastases, MDA-MB-453 and MDA-MB-468 had ovarian foci too, whereas lymph nodal involvement was observed in MDA-MB-231 and MDA-MB-468 only. Interestingly, CTCs showed morphological heterogeneity and were rarely associated to host cells. Orthotopic xenograft of BC cell lines offers valid models of hematogenous dissemination and a possible experimental setting to study CTC-blood microenvironment interactions.
Early Colonization of the Upper Genital Tract by Chlamydia muridarum Is Associated with Enhanced Inflammation Later in Infection

Chlamydia trachomatis is the most commonly reported bacterial sexually transmitted infection in the United States. Modeling infection in animals can be challenging, as mice naturally clear C. trachomatis when it is deposited in the lower genital tract. However, C. trachomatis can productively infect mice when the lower genital tract is bypassed and bacteria are deposited directly into the upper genital tract via transcervical inoculation. ABSTRACT Chlamydia trachomatis is the most commonly reported bacterial sexually transmitted infection in the United States. Modeling infection in animals can be challenging, as mice naturally clear C. trachomatis when it is deposited in the lower genital tract. However, C. trachomatis can productively infect mice when the lower genital tract is bypassed and bacteria are deposited directly into the upper genital tract via transcervical inoculation. Interestingly, the mouse-adapted Chlamydia species C. muridarum can infect mice both by transcervical inoculation and by natural ascension if introduced into the vaginal vault. In this study, we investigated whether the route of infection plays a role in the downstream immune responses to C. muridarum infection. We found that transcervical infection with C. muridarum results in higher bacterial burdens in the upper genital tract at earlier time points, correlating with levels of innate immune cells. When bacterial burdens were equivalent in intravaginally and transcervically infected mice at later time points, we observed substantially higher levels of adaptive immune cells in transcervically infected mice. Our data suggest that different routes of infection with the same organism can elicit different immune responses in the same tissue.
A new robotic tactile sensor with bio-mimetic structural colour inspired by Morpho butterflies

Since tactile perception and robotic manipulation play important roles in human survival, we propose a new method for developing robotic tactile sensors based on the structural colours of Morpho menelaus (a kind of Morpho butterfly). The first task is to fabricate a flexible bioinspired grating with a similar microstructure to the wings of Morpho menelaus using the transfer technique, onto the surfaces of polydimethylsiloxane (PDMS) films. The second task, depending on the angle of diffracted light, is to integrate the flexible diffraction grating with a polychromatic light source and a CCD camera, and then predict the position and magnitude of the contact force caused by a change in the diffraction pattern. The final task is to set up an experimental calibration platform and a marker point array with an interval of 1 mm for an image processing algorithm and a deep learning method to establish the relationship between the contact point position, and the magnitude of the force and diffraction pattern. The results showed that this tactile sensor has high sensitivity and resolution, with the position of the contact force of 1 mm. This practical application of the UR-5 manipulator verifies the feasibility of the prototype as a tactile sensor. This tactile sensing method may be widely used in robotics by miniaturising the design.
Comparing Pretransplant and Posttransplant Outcomes When Choosing a Transplant Center: Focus Groups and a Randomized Survey

Supplemental Digital Content is available in the text. Background. In response to calls for an increased focus on pretransplant outcomes and other patient-centered metrics in public reports of center outcomes, a mixed methods study evaluated how the content and presentation style of new information influences decision-making. The mixed methods design utilized qualitative and quantitative phases where the strengths of one method help address limitations of the other, and multiple methods facilitate comparing results. Methods. First, a series of organ-specific focus groups of kidney, liver, heart, and lung patients helped to develop and refine potential displays of center outcomes and understand patient perceptions. A subsequent randomized survey included adult internet users who viewed a single, randomly-selected variation of 6 potential online information displays. Multinomial regression evaluated the effects of graphical presentations of information on decision-making. Results. One hundred twenty-seven candidates and recipients joined 23 focus groups. Survey responses were analyzed from 975 adults. Qualitative feedback identified patient perceptions of uncertainty in outcome metrics, in particular pretransplant metrics, and suggested a need for clear guidance to interpret the most important metric for organ-specific patient mortality. In the randomized survey, only respondents who viewed a note indicating that transplant rate had the largest impact on survival chose the hospital with the best transplant rate over the hospital with the best posttransplant outcomes (marginal relative risk and 95% confidence interval, 1.161.501.95). Conclusions. The presentation of public reports influenced decision-making behavior. The combination of qualitative and quantitative research helped to guide and enhance understanding of the impacts of proposed changes in reported metrics.
Lasers in Surgery and Medicine

Yeachan Lee, Hyejin Kim, Namgue Hong, Jin‐Chul Ahn, and Hyun Wook Kang 1,3* Interdisciplinary Program of Biomedical Mechanical & Electrical Engineering, Pukyong National University, Busan, 48513, South Korea Department of Biomedical Science, College of Medicine, Dankook University, Cheonan, 31116, Republic of Korea Department of Biomedical Engineering and Center for Marine‐Integrated Biomedical Technology, Pukyong National University, Busan, 48513, South Korea
Cascade Impactor Equivalence Testing: Comparison of the Performance of the Modified Chi-Square Ratio Statistic (mCSRS) with the Original CSRS and EMA’s Average Bioequivalence Approach

The performances of three statistical approaches for assessing in vitro equivalence was evaluated with a set of 55 scenarios of realistic test (T) and reference (R) cascade impactor (CI) profiles (originally employed by the Product Quality Research Institute to evaluate the chi-square ratio statistic: CSRS) by comparing the outcomes against experts’ opinion (surrogate for the truth). The three methods were (A) a stepwise aerodynamic particle size distribution (APSD) equivalence test integrating population bioequivalence (PBE) testing of impactor-sized mass (ISM) with the CSRS (PBE-CSRS approach), previously suggested by the USFDA; (B) the combination of PBE testing of single actuation content and ISM with the newly suggested modified CSRS (PBE-mCSRS approach), a method employing reference variance scaling; and (C) EMA’s average bioequivalence (ABE approach). Based on Monte-Carlo simulations, both PBE-CSRS and ABE approaches resulted in high misclassification rates, the former with highest false-pass rate and the latter with highest false-fail rate at both ≥ 50% and ≥ 80% classification threshold values (the % of simulations or experts necessary to judge a given scenario as equivalent). Based on DeLong’s tests, the PBE-mCSRS approach showed significantly better overall agreement with experts’ opinion compared to the other approaches. Comparison of CSRS with mCSRS (both without PBE) suggested that the more discriminatory characteristics of the mCSRS method is based on the integration of variance scaling into the mCSRS method. Contrary to the ABE approach, the application of PBE-mCSRS approach for assessing APSD profiles of three dry powder inhaler (DPI) formulations supported the pharmacokinetic bioequivalence assessment of these formulations.
Regulation of Latency in the Human T Cell Leukemia Virus, HTLV-1.

The human T cell leukemia virus persists in vivo in 103 to 106 clones of T lymphocytes that appear to survive for the lifetime of the host. The plus strand of the provirus is typically transcriptionally silent in freshly isolated lymphocytes, but the strong, persistently activated cytotoxic T lymphocyte (CTL) response to the viral antigens indicates that the virus is not constantly latent in vivo. There is now evidence that the plus strand is transcribed in intense intermittent bursts that are triggered by cellular stress, modulated by hypoxia and glycolysis, and inhibited by polycomb repressive complex 1 (PRC1). The minus-strand gene hbz is transcribed at a lower, more constant level but is silent in a proportion of infected cells at a given time. Viral genes in the sense and antisense strands of the provirus play different respective roles in latency and de novo infection: Expression of the plus-strand gene tax is essential for de novo infection, whereas hbz appears to facilitate survival of the infected T cell clone in vivo. Expected final online publication date for the Annual Review of Virology Volume 6 is September 30, 2019. Please see http://www.annualreviews. org/page/journal/pubdates for revised estimates.