Factors associated with having less than 20 natural teeth in rural adults: a cross-sectional study

BACKGROUND: Some systematic reviews have consistently indicated a positive link between Metabolic syndrome, impairedfasting glucose, all-cause or circulatory disease-related mortality, general health, periodontitis, and toothloss. This study was to examine the prevalence of number of remaining teeth <20 and associated risk factors among adults in a rural area of Taiwan. METHODS: A community-based, cross-sectional study was conducted in southwestern coastal Taiwan in 2013; 6680 residents aged 20–64 years were studied. Oral hygiene, substance use, dietary habits, and metabolic syndrome were explored as potential risk factors for number of remaining teeth <20 using logistic regression analysis. RESULTS: The mean number of remaining teeth was 24.6 (SD = 7.4), and 16.3 % (n = 1085) of the participants had number of remaining teeth <20. Men had significantly less frequent use of dental floss, unhealthy dietary habits, more substance use and metabolic syndrome than did women (p <0.001). However, women tended to have fewer teeth than men (p <0.001). After adjusting for potential confounders, older age (odds ratio [OR] = 4.56, 95 % confidence interval [CI]: 3.74–5.55), female (OR = 1.88, 95 % CI: 1.56–2.25), less education (OR = 2.40, 95 % CI: 1.90–3.02), infrequent use of dental floss (OR = 1.94, 95 % CI: 1.66–2.27), substance use (OR = 1.32, 95 % CI: 1.09–1.59), and number of metabolic syndrome components (OR = 1.10, 95 % CI: 1.04–1.16) were independently associated with a higher risk of number of remaining teeth <20. CONCLUSIONS: Number of remaining teeth <20 was highly prevalent among rural adults. In addition to unmodifiable factors, infrequent use of dental floss, substance use, and metabolic syndrome were risk factors associated with tooth loss

Safety, tolerability, and efficacy of subcutaneous efgartigimod in patients with chronic inflammatory demyelinating polyradiculoneuropathy (ADHERE): a multicentre, randomised-withdrawal, double-blind, placebo-controlled, phase 2 trial

Background: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disease of the peripheral nervous system that can lead to severe disability from muscle weakness and sensory disturbances. Around a third of patients do not respond to currently available treatments, and many patients with a partial response have residual neurological impairment, highlighting the need for effective alternatives. Efgartigimod alfa, a human IgG1 antibody Fc fragment, has demonstrated efficacy and safety in patients with generalised myasthenia gravis. We evaluated the safety, tolerability, and efficacy of subcutaneous efgartigimod PH20 in adults with CIDP. Methods: ADHERE, a multistage, double-blind, placebo-controlled trial, enrolled participants with CIDP from 146 clinical sites from Asia-Pacific, Europe, and North America. Participants with evidence of clinically meaningful deterioration entered an open-label phase of weekly 1000 mg subcutaneous efgartigimod PH20 for no longer than 12 weeks (stage A). Those with confirmed evidence of clinical improvement (ECI; treatment responders) entered a randomised-withdrawal phase of 1000 mg subcutaneous efgartigimod PH20 weekly treatment versus placebo for a maximum of 48 weeks (stage B). Participants were randomised (1:1) through interactive response technology and stratified by their adjusted Inflammatory Neuropathy Cause and Treatment (aINCAT) score change during stage A and their most recent CIDP medication within 6 months before screening. Investigators, the clinical research organisation, and participants were masked to the treatment. The primary endpoint in stage A, evaluated in the stage A safety population, was confirmed ECI (≥1 points aINCAT decrease, ≥4 points [centile metric] Inflammatory Rasch-built Overall Disability Scale increase, or ≥8 kPa grip strength increase after four injections and two consecutive visits). The primary endpoint in stage B, evaluated in the modified intention-to-treat population, was the risk of relapse (time to first aINCAT increase of ≥1 points). ADHERE is registered with ClinicalTrials.gov (NCT04281472) and EudraCT (2019-003076-39) and is completed. Findings: Between April 15, 2020, and May 11, 2023, 629 participants were screened; 322 (114 female, 208 male) entered stage A, of whom 214 (66%, 95% CI 61·0-71·6) had confirmed ECI. In stage B, 221 participants were randomised (79 female, 142 male; 111 to subcutaneous efgartigimod PH20, 110 to placebo). Subcutaneous efgartigimod PH20 significantly reduced the risk of relapse versus placebo (hazard ratio 0·39 [95% CI 0·25-0·61]; p<0·0001). 31 (27·9% [19·6-36·3]) participants given subcutaneous efgartigimod PH20 had a relapse versus 59 (53·6% [44·3-63·0]) given placebo. In stage A, treatment-emergent adverse events (TEAEs) occurred in 204 (63%) participants and serious TEAEs in 21 (7%). In stage B, TEAEs occurred in 71 (64%) participants on subcutaneous efgartigimod PH20 and 62 (56%) participants on placebo, and serious TEAEs in six (5%) on subcutaneous efgartigimod PH20 and six (5%) on placebo. Three deaths occurred: two in stage A (one non-related and one unlikely related to treatment) and one in stage B (placebo group). Interpretation: ADHERE showed the efficacy of subcutaneous efgartigimod PH20 in reducing the risk of relapse versus placebo in people with CIDP who responded to treatment. Further studies are needed to provide data on the longer-term effects of efgartigimod alfa and how it compares with currently available treatment options. Funding: argenx

Refuse Whenever You Feel Unsafe: Improving Safety in LLMs via Decoupled Refusal Training

This study addresses a critical gap in safety tuning practices for Large Language Models (LLMs) by identifying and tackling a refusal position bias within safety tuning data, which compromises the models' ability to appropriately refuse generating unsafe content. We introduce a novel approach, Decoupled Refusal Training (DeRTa), designed to empower LLMs to refuse compliance to harmful prompts at any response position, significantly enhancing their safety capabilities. DeRTa incorporates two novel components: (1) Maximum Likelihood Estimation (MLE) with Harmful Response Prefix, which trains models to recognize and avoid unsafe content by appending a segment of harmful response to the beginning of a safe response, and (2) Reinforced Transition Optimization (RTO), which equips models with the ability to transition from potential harm to safety refusal consistently throughout the harmful response sequence. Our empirical evaluation, conducted using LLaMA3 and Mistral model families across six attack scenarios, demonstrates that our method not only improves model safety without compromising performance but also surpasses well-known models such as GPT-4 in defending against attacks. Importantly, our approach successfully defends recent advanced attack methods (e.g., CodeAttack) that have jailbroken GPT-4 and LLaMA3-70B-Instruct. Our code and data can be found at https://github.com/RobustNLP/DeRTa

Hypoxia-induced Slug SUMOylation enhances lung cancer metastasis

Abstract Background The Slug-E-cadherin axis plays a critical role in non-small-cell lung cancers (NSCLCs) where aberrant upregulation of Slug promotes cancer metastasis. Now, the post-translational modifications of Slug and their regulation mechanisms still remain unclear in lung cancer. Hence, exploring the protein linkage map of Slug is of great interest for investigating the scenario of how Slug protein is regulated in lung cancer metastasis. Methods The Slug associated proteins, Ubc9 and SUMO-1, were identified using yeast two-hybrid screening; and in vitro SUMOylation assays combined with immunoprecipitation and immunoblotting were performed to explore the detail events and regulations of Slug SUMOylation. The functional effects of SUMOylation on Slug proteins were examined by EMSA, reporter assay, ChIP assay, RT-PCR, migration and invasion assays in vitro, tail vein metastatic analysis in vivo, and also evaluated the association with clinical outcome of NSCLC patients. Results Slug protein could interact with Ubc9 and SUMO-1 and be SUMOylated in cells. Amino acids 130–212 and 33–129 of Slug are responsible for its binding to Ubc9 and protein inhibitor of activated STAT (PIAS)y, respectively. SUMOylation could enhance the transcriptional repression activity of Slug via recruiting more HDAC1, resulting in reduced expression of downstream Slug target genes and enhanced lung cancer metastasis. In addition, hypoxia could increase Slug SUMOylation through attenuating the interactions of Slug with SENP1 and SENP2. Finally, high expression Slug and Ubc9 levels were associated with poor overall survival among NSCLC patients. Conclusions Ubc9/PIASy-mediated Slug SUMOylation and subsequent HDAC1 recruitment may play a crucial role in hypoxia-induced lung cancer progression, and these processes may serve as therapeutic targets for NSCLC

Construction of intracellular asymmetry and asymmetric division in Escherichia coli

AbstractThe design principle of establishing an intracellular protein gradient for asymmetric cell division is a long-standing fundamental question. While the major molecular players and their interactions have been elucidated via genetic approaches, the diversity and redundancy of natural systems complicate the extraction of critical underlying features. Here, we take a synthetic cell biology approach to construct intracellular asymmetry and asymmetric division in Escherichia coli, in which division is normally symmetric. We demonstrate that the oligomeric PopZ from Caulobacter crescentus can serve as a robust polarized scaffold to functionalize RNA polymerase. Furthermore, by using another oligomeric pole-targeting DivIVA from Bacillus subtilis, the newly synthesized protein can be constrained to further establish intracellular asymmetry, leading to asymmetric division and differentiation. Our findings suggest that the coupled oligomerization and restriction in diffusion may be a strategy for generating a spatial gradient for asymmetric cell division.</jats:p

Additional file 14: of Hypoxia-induced Slug SUMOylation enhances lung cancer metastasis

Figure S14. The levels of ubiquitinated and acetylated Slug. (a) To identify the ubiquitination sites of Slug, HEK293T cells were cotransfected with plasmids encoding different 3xFlag-tagged Slug mutants and Myc-tagged ubiquitin and were then treated with the proteasome inhibitor MG132 (10 μM for 6 h). Immunoprecipitation of the Slug protein using anti-Flag antibodies was analyzed by immunoblotting with anti-Flag antibodies. The asterisk and arrowhead indicate Slug modified and not modified by ubiquitin, respectively. (b) The acetylation of Slug. Different 3xFlag-tagged Slug mutants were transfected into HEK293T cells in the presence or absence of the sirtuin deacetylase inhibitor NAM and the HDAC inhibitor TSA. Acetylation of Slug was evaluated via immunoprecipitation and western blot analysis. Asterisk indicated acetylated Slug. (PDF 113 kb

Additional file 5: of Hypoxia-induced Slug SUMOylation enhances lung cancer metastasis

Figure S5. Structure of the Slug/PIASy/Ubc9/SUMO-1 complex. (a) Schematic showing the regions of Slug that interact with PIASy, Ubc9, and SUMO. Slug is 268 amino acids in length and contains a SNAG repression domain at its N-terminus and five zinc finger (ZnF) domains at its C-terminus. ND means no detection. (b) A 3D structure of Slug/PIASy/Ubc9/SUMO-1 complex was generated using prediction software (orange, Slug; purple, PIASy; green, Ubc9; gray, SUMO-1). A rotated view of this complex is shown in the lower panel. (PDF 127 kb