Base of Tongue Squamous Cell Carcinoma With Metastasis to the Mandibular Symphysis: A Case Report.

Squamous cell carcinoma (SCC) is the most common malignancy of the oropharynx (OP). Treatment of OP SCC includes chemotherapy, radiation, and/or surgery. OP SCC can spread via direct extension, lymphatics, or hematogenously. Although rare, distant metastases can occur in OP SCC. The most common sites of metastasis include the lungs, bone, and liver. Other less common sites include the skin, bone marrow, brain, kidneys, eyes, and heart. Patients who present with distant metastases usually have a poor prognosis. Sites of bone metastases from more common to less common include the spine, skull, ribs, and axial bones. In this article, we discuss a patient who presents with HPV+ base of tongue SCC with metastases to the lungs and mandible symphysis. Base of tongue SCC metastasizing to the mandible symphysis is a rarely reported location of metastasis.

Spatial Disparities of COVID-19 Cases and Fatalities in United States Counties.

This paper examines the spatial and temporal trends in county-level COVID-19 cases and fatalities in the United States during the first year of the pandemic (January 2020-January 2021). Statistical and geospatial analyses highlight greater impacts in the Great Plains, Southwestern and Southern regions based on cases and fatalities per 100,000 population. Significant case and fatality spatial clusters were most prevalent between November 2020 and January 2021. Distinct urban-rural differences in COVID-19 experiences uncovered higher rural cases and fatalities per 100,000 population and fewer government mitigation actions enacted in rural counties. High levels of social vulnerability and the absence of mitigation policies were significantly associated with higher fatalities, while existing community resilience had more influential spatial explanatory power. Using differences in percentage unemployment changes between 2019 and 2020 as a proxy for pre-emergent recovery revealed urban counties were hit harder in the early months of the pandemic, corresponding with imposed government mitigation policies. This longitudinal, place-based study confirms some early urban-rural patterns initially observed in the pandemic, as well as the disparate COVID-19 experiences among socially vulnerable populations. The results are critical in identifying geographic disparities in COVID-19 exposures and outcomes and providing the evidentiary basis for targeting pandemic recovery.

Urban-rural differences in COVID-19 exposures and outcomes in the South: A preliminary analysis of South Carolina.

As the COVID-19 pandemic moved beyond the initial heavily impacted and urbanized Northeast region of the United States, hotspots of cases in other urban areas ensued across the country in early 2020. In South Carolina, the spatial and temporal patterns were different, initially concentrating in small towns within metro counties, then diffusing to centralized urban areas and rural areas. When mitigation restrictions were relaxed, hotspots reappeared in the major cities. This paper examines the county-scale spatial and temporal patterns of confirmed cases of COVID-19 for South Carolina from March 1st-September 5th, 2020. We first describe the initial diffusion of the new confirmed cases per week across the state, which remained under 2,000 cases until Memorial Day weekend (epi week 23) then dramatically increased, peaking in mid-July (epi week 29), and slowly declining thereafter. Second, we found significant differences in cases and deaths between urban and rural counties, partially related to the timing of the number of confirmed cases and deaths and the implementation of state and local mitigations. Third, we found that the case rates and mortality rates positively correlated with pre-existing social vulnerability. There was also a negative correlation between mortality rates and county resilience patterns, as expected, suggesting that counties with higher levels of inherent resilience had fewer deaths per 100,000 population.

Genetic manipulation of primary human natural killer cells to investigate the functional and oncogenic roles of PRDM1.

Extra-nodal natural killer/T-cell lymphoma, nasal type (ENKTCL) is a highly aggressive lymphoma, where the tumor suppressor gene (TSG) PRDM1 is frequently lost/inactivated. We employed two different CRISPR/Cas9 approaches to generate PRDM1-/- primary NK cells to study its role in NK-cell homeostasis. PRDM1-/- NK cells showed a marked increase in cloning efficiency, higher proliferation rate and less apoptosis compared with their wild type counterparts. Gene expression profiling demonstrated a marked enrichment in pathways associated with proliferation, cell cycle, MYC, MYB and TCR/NK signaling in PRDM1-/- NK cells, but pathways associated with normal cellular functions including cytotoxic functions were down-regulated, suggesting that the loss of PRDM1 shifted NK cells toward proliferation and survival rather than the performance of its normal functions. We were also able to further modify a PRDM1 deleted clone to introduce heterozygous deletions of common TSG in ENKTCL such as TP53, DDX3X, or PTPN6. We have established an in vitro model to elucidate the major pathways through which PRDM1 mediates its homeostatic control of NK-cells. This approach can be applied to the study of other relevant genetic lesions and oncogenic collaborations in lymphoma pathogenesis.

Exploring Themes and Bias in Art using Machine Learning Image Analysis.

Machine learning and computer vision have been applied for image recognition of art objects such as paintings, sculpture images etc. In particular, deep learning methods for image classification in art have been used to improve user engagement by providing access to accurately labelled and classified art objects. As an increasing number of notable museums turn towards creating open access collections, alternatives to the use of laborious human annotating methods are needed. This paper focuses on the Open Access initiative of The Metropolitan Museum of Art (The Met) which was launched in 2017 in an effort to expand The Met's reach and presence. The museum now provides a select dataset of information on more than 470,000 artworks in its collection for unrestricted commercial and noncommercial use. However, with a widely accessible collection, the Met now faces the problem of how to enhance the user experience via access to accurately labelled art. This paper focuses on machine learning methods with applicability to automated classification of images obtained from The Met's online collection. We aimed to: 1) Compare three different convolutional neural networks ResNet 50, ResNet 101, and Inception-ResNet-V2 using human annotated data, 2) Add transparency and interpretability to our models by using Gradient-weighted Class Activation Maps (Grad-CAMs) and to explore bias in gender labels and 3) Implement a multi-label classification model using ResNet 50. Future work would include the use of unsupervised clustering methods/auto-encoders to explore additional themes in the data. Other extensions of this work would include exploring methods to implement fine grained visual categorization, to mitigate bias, and to address the limitations associated with culture and stylistic interpretations. Deep learning techniques for art image classification may also help detect consistent features of bias in human annotated art.

Proteolysis of methylated SOX2 protein is regulated by L3MBTL3 and CRL4DCAF5 ubiquitin ligase.

SOX2 is a dose-dependent master stem cell protein that controls the self-renewal and pluripotency or multipotency of embryonic stem (ES) cells and many adult stem cells. We have previously found that SOX2 protein is monomethylated at lysine residues 42 and 117 by SET7 methyltransferase to promote SOX2 proteolysis, whereas LSD1 and PHF20L1 act on both methylated Lys-42 and Lys-117 to prevent SOX2 proteolysis. However, the mechanism by which the methylated SOX2 protein is degraded remains unclear. Here, we report that L3MBTL3, a protein with the malignant-brain-tumor (MBT) methylation-binding domain, is required for SOX2 proteolysis. Our studies showed that L3MBTL3 preferentially binds to the methylated Lys-42 in SOX2, although mutation of Lys-117 also partially reduces the interaction between SOX2 and L3MBTL3. The direct binding of L3MBTL3 to the methylated SOX2 protein leads to the recruitment of the CRL4DCAF5 ubiquitin E3 ligase to target SOX2 protein for ubiquitin-dependent proteolysis. Whereas loss of either LSD1 or PHF20L1 destabilizes SOX2 protein and impairs the self-renewal and pluripotency of mouse ES cells, knockdown of L3MBTL3 or DCAF5 is sufficient to restore the protein levels of SOX2 and rescue the defects of mouse ES cells caused by LSD1 or PHF20L1 deficiency. We also found that retinoic acid-induced differentiation of mouse ES cells is accompanied by the enhanced degradation of the methylated SOX2 protein at both Lys-42 and Lys-117. Our studies provide novel insights into the mechanism by which the methylation-dependent degradation of SOX2 protein is controlled by the L3MBTL3-CRL4DCAF5 ubiquitin ligase complex.

Proliferating cell nuclear antigen interacts with the CRL4 ubiquitin ligase subunit CDT2 in DNA synthesis-induced degradation of CDT1.

During DNA replication or repair, the DNA polymerase cofactor, proliferating cell nuclear antigen (PCNA), homotrimerizes and encircles the replicating DNA, thereby acting as a DNA clamp that promotes DNA polymerase processivity. The formation of the PCNA trimer is also essential for targeting the replication-licensing protein, chromatin-licensing, and DNA replication factor 1 (CDT1), for ubiquitin-dependent proteolysis to prevent chromosomal DNA re-replication. CDT1 uses its PCNA-interacting peptide box (PIP box) to interact with PCNA, and the CRL4 E3 ubiquitin ligase subunit CDT2 is recruited through the formation of PCNA-CDT1 complexes. However, it remains unclear how CDT1 and many other PIP box-containing proteins are marked for degradation by the CRL4CDT2 ubiquitin ligase during DNA replication or damage. Here, using recombinant protein expression coupled with site-directed mutagenesis, we report that CDT2 and PCNA directly interact and this interaction depends on the presence of a highly conserved, C-terminal PIP box-like region in CDT2. Deletion or mutation of this region abolished the CDT2-PCNA interaction between CDT2 and PCNA both in vitro and in vivo Moreover, PCNA-dependent CDT1 degradation in response to DNA damage and replication during the cell cycle requires an intact PIP box in CDT2. The requirement of the PIP boxes in both CDT2 and its substrate CDT1 suggests that the formation of the PCNA trimeric clamp around DNA during DNA replication and repair may bring together CDT1 and CRL4CDT2 ubiquitin E3 ligase to target CDT1 for proteolysis in a DNA synthesis-dependent manner.

LSD1 demethylase and the methyl-binding protein PHF20L1 prevent SET7 methyltransferase-dependent proteolysis of the stem-cell protein SOX2.

The pluripotency-controlling stem-cell protein SRY-box 2 (SOX2) plays a pivotal role in maintaining the self-renewal and pluripotency of embryonic stem cells and also of teratocarcinoma or embryonic carcinoma cells. SOX2 is monomethylated at lysine 119 (Lys-119) in mouse embryonic stem cells by the SET7 methyltransferase, and this methylation triggers ubiquitin-dependent SOX2 proteolysis. However, the molecular regulators and mechanisms controlling SET7-induced SOX2 proteolysis are unknown. Here, we report that in human ovarian teratocarcinoma PA-1 cells, methylation-dependent SOX2 proteolysis is dynamically regulated by the LSD1 lysine demethylase and a methyl-binding protein, PHD finger protein 20-like 1 (PHF20L1). We found that LSD1 not only removes the methyl group from monomethylated Lys-117 (equivalent to Lys-119 in mouse SOX2), but it also demethylates monomethylated Lys-42 in SOX2, a reaction that SET7 also regulated and that also triggered SOX2 proteolysis. Our studies further revealed that PHF20L1 binds both monomethylated Lys-42 and Lys-117 in SOX2 and thereby prevents SOX2 proteolysis. Down-regulation of either LSD1 or PHF20L1 promoted SOX2 proteolysis, which was prevented by SET7 inactivation in both PA-1 and mouse embryonic stem cells. Our studies also disclosed that LSD1 and PHF20L1 normally regulate the growth of pluripotent mouse embryonic stem cells and PA-1 cells by preventing methylation-dependent SOX2 proteolysis. In conclusion, our findings reveal an important mechanism by which the stability of the pluripotency-controlling stem-cell protein SOX2 is dynamically regulated by the activities of SET7, LSD1, and PHF20L1 in pluripotent stem cells.

Minimotif Miner 3.0: database expansion and significantly improved reduction of false-positive predictions from consensus sequences.

Minimotif Miner (MnM available at http://minimotifminer.org or http://mnm.engr.uconn.edu) is an online database for identifying new minimotifs in protein queries. Minimotifs are short contiguous peptide sequences that have a known function in at least one protein. Here we report the third release of the MnM database which has now grown 60-fold to approximately 300,000 minimotifs. Since short minimotifs are by their nature not very complex we also summarize a new set of false-positive filters and linear regression scoring that vastly enhance minimotif prediction accuracy on a test data set. This online database can be used to predict new functions in proteins and causes of disease.

The external K+ concentration and mutations in the outer pore mouth affect the inhibition of kv1.5 current by Ni2+.

By examining the consequences both of changes of [K+]o and of point mutations in the outer pore mouth, our goal was to determine if the mechanism of the block of Kv1.5 ionic currents by external Ni2+ is similar to that for proton block. Ni2+ block is inhibited by increasing [K+]o, by mutating a histidine residue in the pore turret (H463Q) or by mutating a residue near the pore mouth (R487V) that is the homolog of Shaker T449. Aside from a slight rightward shift of the Q-V curve, Ni2+ had no effect on gating currents. We propose that, as with Ho+, Ni2+ binding to H463 facilitates an outer pore inactivation process that is antagonized by Ko+ and that requires R487. However, whereas Ho+ substantially accelerates inactivation of residual currents, Ni2+ is much less potent, indicating incomplete overlap of the profiles of these two metal ions. Analyses with Co2+ and Mn2+, together with previous results, indicate that for the first-row transition metals the rank order for the inhibition of Kv1.5 in 0 mM Ko+ is Zn2+ (KD approximately 0.07 mM) > or = Ni2+) (KD approximately 0.15 mM) > Co2+ (KD approximately 1.4 mM) > Mn2+ (KD > 10 mM).