Non-perturbative Landau gauge and infrared critical exponents in QCD

We discuss Faddeev-Popov quantization at the non-perturbative level and show that Gribov's prescription of cutting off the functional integral at the Gribov horizon does not change the Schwinger-Dyson equations, but rather resolves an ambiguity in the solution of these equations. We note that Gribov's prescription is not exact, and we therefore turn to the method of stochastic quantization in its time-independent formulation, and recall the proof that it is correct at the non-perturbative level. The non-perturbative Landau gauge is derived as a limiting case, and it is found that it yields the Faddeev-Popov method in Landau gauge with a cut-off at the Gribov horizon, plus a novel term that corrects for over-counting of Gribov copies inside the Gribov horizon. Non-perturbative but truncated coupled Schwinger-Dyson equations for the gluon and ghost propagators $D(k)$ and $G(k)$ in Landau gauge are solved asymptotically in the infrared region. The infrared critical exponents or anomalous dimensions, defined by $D(k) \sim 1/(k^2)^{1 + a_D}$ and $G(k) \sim 1/(k^2)^{1 + a_G}$ are obtained in space-time dimensions $d = 2, 3, 4$. Two possible solutions are obtained with the values, in $d = 4$ dimensions, $a_G = 1, a_D = -2$, or $a_G = [93 - (1201)^{1/2}]/98 \approx 0.595353, a_D = - 2a_G$.Comment: 26 pages. Modified 2.25.02 to update references and to clarify Introduction and Conclusio

Oncogenic Transformation of Mammary Epithelial Cells by Transforming Growth Factor Beta Independent of Mammary Stem Cell Regulation

BackgroundTransforming growth factor beta (TGFβ) is transiently increased in the mammary gland during involution and by radiation. While TGFβ normally has a tumour suppressor role, prolonged exposure to TGFβ can induce an oncogenic epithelial to mesenchymal transition (EMT) program in permissive cells and initiate the generation of cancer stem cells. Our objective is to mimic the transient exposure to TGFβ during involution to determine the persistent effects on premalignant mammary epithelium

Epidemiological Modeling of SARS-CoV-2 in White-tailed Deer (\u3cem\u3eOdocoileus virginianus\u3c/em\u3e) Reveals Conditions for Introduction and Widespread Transmission

Emerging infectious diseases with zoonotic potential often have complex socioecological dynamics and limited ecological data, requiring integration of epidemiological modeling with surveillance. Although our understanding of SARS-CoV-2 has advanced considerably since its detection in late 2019, the factors influencing its introduction and transmission in wildlife hosts, particularly white-tailed deer (Odocoileus virginianus), remain poorly understood. We use a Susceptible-Infected-Recovered-Susceptible epidemiological model to investigate the spillover risk and transmission dynamics of SARS-CoV-2 in wild and captive white-tailed deer populations across various simulated scenarios. We found that captive scenarios pose a higher risk of SARS-CoV-2 introduction from humans into deer herds and subsequent transmission among deer, compared to wild herds. However, even in wild herds, the transmission risk is often substantial enough to sustain infections. Furthermore, we demonstrate that the strength of introduction from humans influences outbreak characteristics only to a certain extent. Transmission among deer was frequently sufficient for widespread outbreaks in deer populations, regardless of the initial level of introduction. We also explore the potential for fence line interactions between captive and wild deer to elevate outbreak metrics in wild herds that have the lowest risk of introduction and sustained transmission. Our results indicate that SARS-CoV-2 could be introduced and maintained in deer herds across a range of circumstances based on testing a range of introduction and transmission risks in various captive and wild scenarios. Our approach and findings will aid One Health strategies that mitigate persistent SARS-CoV-2 outbreaks in white-tailed deer populations and potential spillback to humans

Reliability Exercise of Ultrasound Salivary Glands in Sjögren's Disease:An International Web Training Initiative

INTRODUCTION: Major salivary gland ultrasonography (SGUS) demonstrated its good metric properties as an outcome measure for diagnosing primary Sjögren's disease (SD). The objective was to assess SGUS reliability among sonographers with different levels of experience, using web training.METHODS: Sonographers from expert centers participated in the reliability exercise. Before exercises, training was done by videoconferencing. Reliability of the two most experienced sonographers (MES) was assessed and then compared to other sonographers. Intra-reader and inter-reader reliability of SGUS items were assessed by computing Cohen's κ coefficients.RESULTS: All sets were read twice by all 14 sonographers within a 4-month interval. Intra-reader reliability of MES was almost perfect for homogeneity, substantial for Outcome Measures in Rheumatology (OMERACT) scoring system (OMERACTss). Among LES (less experienced sonographers), reliability was moderate to almost perfect for homogeneity, fair to moderate for OMERACTss, and fair to almost perfect for binary OMERACTss. Inter-reader reliability between MES was almost perfect for homogeneity, substantial for diagnosis, moderate for OMERACTss, and substantial for binary OMERACTss. Compared to MES, reliabilities of LES were moderate to almost perfect for both homogeneity and diagnosis, only fair to moderate for OMERACTss, but increased in binary OMERACTss.CONCLUSIONS: Videoconferencing training sessions in an international reliability exercise could be an excellent tool to train experienced and less-experienced sonographers. SGUS homogeneity items is useful to distinguish normal from abnormal salivary glands parenchyma independently of diagnosis. Structural damage evaluations by OMERACT scoring system is a new comprehensive score to diagnose patients with SD and could be easily used by sonographers in a binary method.</p

The origins of estrogen receptor alpha-positive and estrogen receptor alpha-negative human breast cancer

Current hormonal therapies have benefited millions of patients with breast cancer. Their success, however, is often temporary and limited to a subset of patients whose tumors express estrogen receptor alpha (ER). The therapies are entirely ineffective in ER-negative disease. Recent studies suggest that there are many biological pathways and alterations involved in determining whether ER is expressed and how it is regulated during breast cancer evolution. Improving hormonal therapies, in addition to perfecting current strategies, will also target these newly discovered pathways and alterations, and others yet to be found. The present commentary will briefly highlight a few important observations and unanswered questions regarding ER status and growth regulation during breast cancer evolution, which hopefully will help to stimulate new thinking and progress in this important area of medial research

2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153772/1/acr24131.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153772/2/acr24131_am.pd

Identifying Mist1 regulated genes in pancreatic acinar cell homeostasis and carcinogenesis

Early embryogenesis requires cell fate decisions that define the body axes and establish progenitor cell pools. However, development does not cease once lineages are specified. Instead, cells continue to undergo specific maturation events where changes in their transcriptome ensure that essential gene products are available to carry out unique physiological functions. For example, secretory pancreatic acinar cells mature post-natally to handle an extensive protein synthetic load, to establish an organized cell polarity and to orchestrate efficient cell-cell communication. One transcriptional effector that has been implicated in regulating these maturation events is MIST1, a secretory cell-restricted transcription factor. Mist1 deficient acinar cells fail to establish an apical-basal organization, fail to properly position zymogen granules, and fail to generate intercellular communication, making the injured exocrine organ highly susceptible to pancreatic disease. In an effort to test whether MIST1 directly induces and maintains the mature acinar cell phenotype, Cre-mediated Mist1 gene expression was activated in adult Mist1 deficient mice. Induction of Mist1 rapidly restored wildtype acinar gene expression patterns and produced dramatic changes in cellular phenotypes, including the generation of apical-basal polarity, increased zymogen granule size, reorganization of the actin cytoskeletal network, restoration of intercellular communication and recovery of regulated exocytosis function. These studies provide direct evidence that the injured adult exocrine pancreas can be remodeled in vivo and that MIST1 actively controls maturation processes, opening new therapeutic avenues for repairing damaged organs prior to developing pancreatic disease. Indeed, forced expression of Mist1 in a KrasG12D -induced mouse model of pancreatic carcinogenesis suppressed pre-cancerous lesion formation as well as the accompanying stromal response. These results suggest that maintaining MIST1 activity in KrasG12D-expressing acinar cells can partially mitigate the transformation activity of oncogenic KRAS. Future therapeutics that target Mist1 transcriptional networks may show promising efficacy in combating pancreatic cancer

Abstract A76: A novel <i>in vivo</i> model for pancreatic restructuring and suppression of transformation

Abstract Our studies are focused on the identification and prevention of the initial transformation events associated with pancreatic ductal adenocarcinoma (PDA) development, an extremely lethal malignancy with poor prognosis and ineffective treatments. PDA initiates through activating mutations in the KRAS proto-oncogene (KrasG12D) and recent studies from our laboratory have determined that targeted expression of an endogenous KrasG12D allele in pancreatic acinar cells is sufficient to produce PDA precursor lesions (PanINs). These results suggest that PDA arises via acinar cells undergoing a process of acinar-to-ductal metaplasia (ADM) which is characterized by a loss of acinar cell properties with the acquisition of duct-like characteristics. Several studies indicate that the process of ADM requires inactivation of the acinar-specific transcription factor Mist1, since Mist1 null (Mist1KO) mice display accelerated ADM and PanIN formation upon KrasG12D expression. Additionally, acinar cell polarity is disrupted in Mist1KO mice with diffuse zymogen granule organization and mis-localization of nuclei. These results suggest that Mist1 has a key role in suppressing PDA formation by maintaining the acinar cell differentiation program. To identify the downstream genes affected by the absence of Mist1, we have generated an inducible Mist1 transgenic mouse line (LSL-Mist1myc) in which constitutive Mist1 expression is activated through Cre-mediated recombination. When LSL-Mist1myc mice are crossed to Mist1Cre-ER mice, Mist1myc expression can be induced in acinar cells upon Tamoxifen (TM) addition. Analysis of Mist1Cre-ER/Cre-ER; LSL-Mist1myc mice confirmed that exogenous Mist1myc expression is detected as early as 6 hours post-TM. Time course studies in a Mist1KO background revealed that nuclear and zymogen granule organization can be restored within 24 hours of Cre activation. We conclude that Mist1 actively controls pancreatic acinar cell organization and that induction of Mist1 in Mist1KO mice leads to complete reorganization of pancreatic tissues. Our current efforts are focused on establishing how Mist1 negatively regulates ADM and PanIN formation and to identify Mist1 targets that negatively regulate Kras-induced pancreas metaplasia and transformation. Citation Information: Cancer Res 2009;69(23 Suppl):A76.</jats:p

Abstract A71: Distinct functions of epithelial growth factor receptor (EGFR) pathways in pancreatic acinar cell differentiation and initiation of pancreatic ductal adenocarcinoma

Abstract Significance: Pancreatic ductal adenocarcinoma (PDA) is one of the most fatal malignancies, partially due to the lack of early detection methods. Background: Efforts to understand the early stages of PDA progression have led to identification of Kras mutations as the initiating event and pancreatic intraepithelial neoplasias (PanINs) as one of the cellular precursors of PDA. Recently, several labs have demonstrated that PanINs can be generated from pancreatic acinar cells upon expression of Kras mutants in mouse models. This dramatic shift from differentiated acinar cells to duct-like PanIN cells, generally termed acinar-ductal metaplasia (ADM), is accelerated by loss of Mist1, an acinar-restricted basic helix-loop-helix transcription factor. Despite this recent progress, the transcription and signaling networks that regulate ADM remain largely unknown. Results: To study these networks, we employed a collagen-based 3-dimensional (3D) culture model of ADM, where primary acinar cells can be transformed into duct-like cysts when treated with transforming growth factor-alpha (TGF-α). A similar acinar-to-ductal conversion was observed with primary acinar cells that express the KrasG12D mutant. Initial characterization of the ADM process revealed that the MAPK pathway is required in both settings. However, EGFR activity is required for TGF-α-induced conversion but not for KrasG12D-induced conversion. Consistent with previous data generated from mouse models, loss of Mist1 accelerates KrasG12D-induced conversion to ductal cysts in vitro. This accelerated ADM formation can be reversed by inhibition of EGFR, without affecting the basal level conversion induced by KrasG12D, suggesting that loss of Mist1 promotes transformation through an EGFR-dependent pathway. Further investigation has revealed that Mist1 directly activates transcription of the epidermal growth factor (EGF) gene, which encodes a classic ligand of EGFR. Conclusion: These data suggest that EGFR has a complex role in this ADM model. EGFR activity either promotes maintenance of acinar differentiation, or cooperates with KrasG12D-induced transformation, possibly depending on the functional specificity of different ligands. Citation Information: Cancer Res 2009;69(23 Suppl):A71.</jats:p