Fusobacterium nucleatum, a Gram‐negative oral anaerobe, is a significant contributor to colorectal cancer. Using an in vitro cancer progression model, we discover that F. nucleatum stimulates the ...growth of colorectal cancer cells without affecting the pre‐cancerous adenoma cells. Annexin A1, a previously unrecognized modulator of Wnt/β‐catenin signaling, is a key component through which F. nucleatum exerts its stimulatory effect. Annexin A1 is specifically expressed in proliferating colorectal cancer cells and involved in activation of Cyclin D1. Its expression level in colon cancer is a predictor of poor prognosis independent of cancer stage, grade, age, and sex. The FadA adhesin from F. nucleatum up‐regulates Annexin A1 expression through E‐cadherin. A positive feedback loop between FadA and Annexin A1 is identified in the cancerous cells, absent in the non‐cancerous cells. We therefore propose a “two‐hit” model in colorectal carcinogenesis, with somatic mutation(s) serving as the first hit, and F. nucleatum as the second hit exacerbating cancer progression after benign cells become cancerous. This model extends the “adenoma‐carcinoma” model and identifies microbes such as F. nucleatum as cancer “facilitators”.
Synopsis
Fusobacterium nucleatum specifically stimulates colorectal carcinoma cells by inducing the Wnt/β‐catenin modulator Annexin A1. This supports a model where driver mutations serve as the first, and microbial infection as the second “hit” to promote cancer progression.
Fusobacterium nucleatum stimulates colorectal cancer cells without affecting precancerous adenoma cells.
Annexin A1 is specifically expressed in colorectal cancer cells and is a predictor of poor prognosis.
The Fusobacterium nucleatum FadA adhesin up‐regulates Annexin A1 expression through E‐cadherin.
A positive feedback loop between FadA and Annexin A1 is specifically present in cancer cells.
Fusobacterium nucleatum specifically stimulates colorectal carcinoma cells by inducing the Wnt/β‐catenin modulator Annexin A1. This supports a model where driver mutations serve as the first, and microbial infection as the second “hit” to promote cancer progression.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
MicroRNAs (miRNAs) have been known to affect various biological processes by repressing expression of specific genes. Here we describe an essential function of the miR-34/449 family during ...differentiation of epithelial cells. We found that miR-34/449 suppresses the cell-cycle machinery in vivo and promotes cell-cycle exit, thereby allowing epithelial cell differentiation. Constitutive ablation of all six members of this miRNA family causes derepression of multiple cell cycle-promoting proteins, thereby preventing epithelial cells from exiting the cell cycle and entering a quiescent state. As a result, formation of motile multicilia is strongly inhibited in several tissues such as the respiratory epithelium and the fallopian tube. Consequently, mice lacking miR-34/449 display infertility as well as severe chronic airway disease leading to postnatal death. These results demonstrate that miRNA-mediated repression of the cell cycle is required to allow epithelial cell differentiation.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Background With an aging population, fragility fractures including injuries to the proximal humerus continue to rise in the United States. The purpose of this study was to investigate recent trends ...in the incidence and treatment of proximal humerus fractures (PHFs) in a cross-sectional elderly population. Methods Medicare data from 2005 to 2012 were queried to identify patients treated for PHF. Associated patient demographics, hospitalization data, treatment, and revision status were obtained. Statistical analyses were performed to identify significant trends in treatment. Results There were 259,506 PHFs recorded, with 79% occurring in female patients. In all age groups, nonoperative treatment of PHF was the most common method (67%). Within the surgical group, open reduction with internal fixation was most frequently used, and total shoulder arthroplasty (TSA) or reverse total shoulder arthroplasty (RTSA) was the least common (11%). However, although the overall rate of surgical intervention remained constant, there was a significant increase in treatment with TSA from 3% in 2005 to 17% in 2012. In particular, RTSA represented 89% of all TSAs for PHF in 2011. All surgical treatment options demonstrated high 2-year survival rates without revision surgery (97%). Conclusion Recent trends show that in the elderly population, nonoperative management remains the most common treatment for PHFs. Within the surgically treated cohort, there has been an increase in treatment with arthroplasty including RTSA, with a low rate of early revisions. There are excellent survival rates in all surgically treated PHFs, but long-term data will be required to fully evaluate the viability of these surgical options.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The COVID-19 pandemic caused a critical public health crisis worldwide, and policymakers are using lockdowns to control the virus. However, there has been a noticeable increase in aggressive social ...behaviors that threaten social stability. Lockdown measures might negatively affect mental health and lead to an increase in aggressive emotions. Discovering the relationship between lockdown and increased aggression is crucial for formulating appropriate policies that address these adverse societal effects. We applied natural language processing (NLP) technology to internet data, so as to investigate the social and emotional impacts of lockdowns. This research aimed to understand the relationship between lockdown and increased aggression using NLP technology to analyze the following 3 kinds of aggressive emotions: anger, offensive language, and hate speech, in spatiotemporal ranges of tweets in the United States. We conducted a longitudinal internet study of 11,455 Twitter users by analyzing aggressive emotions in 1,281,362 tweets they posted from 2019 to 2020. We selected 3 common aggressive emotions (anger, offensive language, and hate speech) on the internet as the subject of analysis. To detect the emotions in the tweets, we trained a Bidirectional Encoder Representations from Transformers (BERT) model to analyze the percentage of aggressive tweets in every state and every week. Then, we used the difference-in-differences estimation to measure the impact of lockdown status on increasing aggressive tweets. Since most other independent factors that might affect the results, such as seasonal and regional factors, have been ruled out by time and state fixed effects, a significant result in this difference-in-differences analysis can not only indicate a concrete positive correlation but also point to a causal relationship. In the first 6 months of lockdown in 2020, aggression levels in all users increased compared to the same period in 2019. Notably, users under lockdown demonstrated greater levels of aggression than those not under lockdown. Our difference-in-differences estimation discovered a statistically significant positive correlation between lockdown and increased aggression (anger: P=.002, offensive language: P<.001, hate speech: P=.005). It can be inferred from such results that there exist causal relations. Understanding the relationship between lockdown and aggression can help policymakers address the personal and societal impacts of lockdown. Applying NLP technology and using big data on social media can provide crucial and timely information for this effort.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The cyclin-dependent kinase 1 (Cdk1) drives cell division. To uncover additional functions of Cdk1, we generated knockin mice expressing an analog-sensitive version of Cdk1 in place of wild-type ...Cdk1. In our study, we focused on embryonic stem cells (ESCs), because this cell type displays particularly high Cdk1 activity. We found that in ESCs, a large fraction of Cdk1 substrates is localized on chromatin. Cdk1 phosphorylates many proteins involved in epigenetic regulation, including writers and erasers of all major histone marks. Consistent with these findings, inhibition of Cdk1 altered histone-modification status of ESCs. High levels of Cdk1 in ESCs phosphorylate and partially inactivate Dot1l, the H3K79 methyltransferase responsible for placing activating marks on gene bodies. Decrease of Cdk1 activity during ESC differentiation de-represses Dot1l, thereby allowing coordinated expression of differentiation genes. These analyses indicate that Cdk1 functions to maintain the epigenetic identity of ESCs.
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•Mice expressing analog-sensitive Cdk1 allow identification of Cdk1 substrates•Many Cdk1 substrates in ESCs are chromatin-bound at poised or transcribed genes•Cdk1 phosphorylates a large number of epigenetic regulators•Cdk1 phosphorylates and inactivates H3K79 methyltransferase Dot1l
Cdk1 drives mitotic entry and progression. Michowski et al. generated mice expressing analog-sensitive Cdk1. The authors found that in embryonic stem cells, Cdk1 phosphorylates a large number of epigenetic regulators and controls the global epigenetic landscape. Decreased Cdk1 activity during differentiation allows coordinated expression of differentiation genes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Chemotherapy employs anti-cancer drugs to stop the growth of cancerous cells, but one common obstacle to the success is the development of chemoresistance, which leads to failure of the previously ...effective anti-cancer drugs. Resistance arises from different mechanistic pathways, and in this critical review, we focus on the Fanconi Anemia (FA) pathway in chemoresistance. This pathway has yet to be intensively researched by mainstream cancer researchers. This review aims to inspire a new thrust toward the contribution of the FA pathway to drug resistance in cancer. We believe an indepth understanding of this pathway will open new frontiers to effectively treat drug-resistant cancer.
Epigenetic predisposition is thought to critically contribute to adult-onset disorders, such as retinal neurodegeneration. The histone methyltransferase, enhancer of zeste homolog 2 (Ezh2), is ...transiently expressed in the perinatal retina, particularly enriched in retinal ganglion cells (RGCs). We previously showed that embryonic deletion of Ezh2 from retinal progenitors led to progressive photoreceptor degeneration throughout life, demonstrating a role for embryonic predisposition of Ezh2-mediated repressive mark in maintaining the survival and function of photoreceptors in the adult. Enrichment of Ezh2 in RGCs leads to the question if Ezh2 also mediates gene expression and function in postnatal RGCs, and if its deficiency changes RGC susceptibility to cell death under injury or disease in the adult. To test this, we generated mice carrying targeted deletion of Ezh2 from RGC progenitors driven by Math5-Cre (mKO). mKO mice showed no detectable defect in RGC development, survival, or cell homeostasis as determined by physiological analysis, live imaging, histology, and immunohistochemistry. Moreover, RGCs of Ezh2 deficient mice revealed similar susceptibility against glaucomatous and acute optic nerve trauma-induced neurodegeneration compared to littermate floxed or wild-type control mice. In agreement with the above findings, analysis of RNA sequencing of RGCs purified from Ezh2 deficient mice revealed few gene changes that were related to RGC development, survival and function. These results, together with our previous report, support a cell lineage-specific mechanism of Ezh2-mediated gene repression, especially those critically involved in cellular function and homeostasis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Geographical research using historical maps has progressed considerably as the digitalization of topological maps across years provides valuable data and the advancement of AI machine learning models ...provides powerful analytic tools. Nevertheless, analysis of historical maps based on supervised learning can be limited by the laborious manual map annotations. In this work, we propose a semi-supervised learning method that can transfer the annotation of maps across years and allow map comparison and anthropogenic studies across time. Our novel two-stage framework first performs style transfer of topographic map across years and versions, and then supervised learning can be applied on the synthesized maps with annotations. We investigate the proposed semi-supervised training with the style-transferred maps and annotations on four widely-used deep neural networks (DNN), namely U-Net, fully-convolutional network (FCN), DeepLabV3, and MobileNetV3. The best performing network of U-Net achieves Formula: see text and Formula: see text trained on style-transfer synthesized maps, which indicates that the proposed framework is capable of detecting target features (bridges) on historical maps without annotations. In a comprehensive comparison, the Formula: see text of U-Net trained on Contrastive Unpaired Translation (CUT) generated dataset (Formula: see text) achieves 57.3 % than the comparative score (Formula: see text) of the least valid configuration (MobileNetV3 trained on CycleGAN synthesized dataset). We also discuss the remaining challenges and future research directions.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Previous studies have demonstrated that patients with abnormal spinopelvic motion are at increased risk of dislocation. However, little is known about the effect of hip offset on dislocation risk ...following total hip arthroplasty (THA) in patients with abnormal spinopelvic motion. The purpose of this study is to investigate the prevalence of under-restored hip offset and spinopelvic abnormalities in a series of THA patients treated for recurrent instability.
This is a retrospective review of consecutive patients treated for hip instability following primary THA (THA+I) from 2012 to 2020. Patient demographics, surgical variables, and radiographic parameters were recorded. THA+I patients were compared to an age-matched and gender-matched control THA population without hip instability (THA). Univariate analyses were performed to compare differences between groups.
Thirty-three THA+I patients (44 hips) were compared to 44 THA patients (44 hips). THA+I patients had a higher prevalence of spinopelvic pathology (odds ratio OR 7.80, 95% confidence interval CI 2.59-23.50, P < .001). The majority of acetabular components were placed within the Lewinnek safe zone (86.4% THA+I vs 72.7% THA; P = .119). THA+I patients were at greater risk of markedly under-restored hip offset (Δoffset ≤ 3 mm; OR 6.34, 95% CI 2.20-18.30, P = .001) and small (<32 mm) femoral head diameter (OR 4.38, 95% CI 1.53-12.53, P = .006) compared to THA patients.
Lumbar degenerative disease and under-restoration of hip offset were present in a high proportion of patients with hip instability. Although multiple factors may contribute to THA instability, these data suggest that restoration of offset is essential, particularly in patients with spinopelvic pathology, and may be more important than historically described acetabular targets.
Level III.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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