Fat mass and obesity-associated protein (FTO) affects midpalatal suture bone remodeling during rapid maxillary expansion.

BACKGROUND: The fat mass and obesity-associated protein (FTO) is an RNA demethylase that contributes to several physiological processes. Nonetheless, the impact of FTO on bone remodeling in the midpalatal suture while undergoing rapid maxillary expansion (RME) remains unclear. METHODS: First, to explore the expression of FTO in the midpalatal suture during RME, six rats were randomly divided into two groups: Expansion group and Sham group (springs without being activated). Then, suture mesenchymal stem cells (SuSCs) were isolated as in vitro model. The expression of FTO was knocked down by small interfering RNA to study the effect of FTO on the osteogenic differentiation of SuSCs. Finally, to evaluate the function of FTO in the process of bone remodeling in the midpalatal suture, ten rats were randomly divided into two groups: FB23-2 group (10 µM, a small molecule inhibitor of FTO) and DMSO group (control). RESULTS: Increased arch width and higher expression of OCN and FTO in the midpalatal area were observed in expansion group (P < .05). In the in vitro model, the mRNA expression levels of Runx2, Bmp2, Col1a1, Spp1, and Tnfrsf11b were decreased (P < .05) upon knocking down FTO. Additionally, the protein levels of RUNX2 and OPN were also decreased (P < 0.05). Adding FB23-2, a small-molecule inhibitor targeting FTO, to the medium of SuSCs caused a decrease in the mRNA expression levels of Runx2, Bmp2, Col1a1, Spp1, and Tnfrsf11b (P < 0.05). There was a statistically significant difference in evaluating the expression of OCN and OPN on the palatal suture between the FB23-2 and DMSO groups (P < .05). LIMITATION: The molecular mechanisms by which FTO regulates SuSCs osteogenesis remain to be elucidated. The FTO conditional knock out mouse model can be established to further elucidate the role of FTO during RME. CONCLUSION: FTO contributes to the osteogenic differentiation of SuSCs and plays a promoting role in midpalatal suture bone remodeling during the RME.

THE USE OF DENTAL PATIENT-REPORTED OUTCOMES AMONG COMPARATIVE OBSERVATIONAL STUDIES IN ORTHODONTICS: A METHODOLOGICAL STUDY.

OBJECTIVE: To identify and summarize the presence and characteristics of dental patient-reported outcomes (dPROs) and dental patient-reported outcome measures (dPROMs) within comparative observational studies published in 5 leading orthodontic journals. METHODS: Electronic searching was performed to identify intervention (therapeutic or preventive) related comparative observational studies published in selected journals between 2015 and 2021. Two authors extracted the characteristics of each included study independently and in duplicate and summarized the dPROs and dPROMs used in these studies. All dPROs were classified into 2 general types (oral health-related quality of life [OHRQoL] and others), while dPROMs were divided into 3 categories (single-item questionnaires, generic multiple-item questionnaires, and specific multiple-item questionnaires). In addition, dPROMs were examined, if they evaluated the 4 dimensions of OHRQoL (oral function, orofacial pain, orofacial appearance, and psychosocial impact). RESULTS: A total of 683 observational studies were eligible and included of which 117 (17.1%) used dPROs and dPROMs. Seven different dPROs (OHRQoL, patients' satisfaction with treatment, preferences, concerns, compliance, duration, and unwanted events) and 33 different dPROMs (including 8 single-item questionnaires, 11 generic multiple-item questionnaires, and 14 specific multiple-item questionnaires) were identified in these studies. OHRQoL was the most commonly used dPRO (92/117, 78.6%), while Oral Health Impact Profile 14 (OHIP-14) was the most frequently used dPROM (20/92, 21.7%). In terms of study design, cross-sectional studies had the highest proportion of dPRO usage (62/148, 41.9%), followed by cohort studies (63/505, 12.5%) and case-control studies (1/30, 3.3%). CONCLUSIONS: Only one-sixth of comparative observational studies published in leading orthodontic journals could reflect patients' perspectives. Observational studies in orthodontics need to provide more patient-important information through the use of dPROs and dPROMs.

THE USE OF DENTAL PATIENT-REPORTED OUTCOMES AMONG RANDOMIZED CONTROLLED TRIALS IN ORTHODONTICS: A METHODOLOGICAL STUDY.

OBJECTIVE: To identify and summarize the use and characteristics of dental patient-reported outcomes (dPROs) and dental patient-reported outcome measures (dPROMs) within randomized controlled trials (RCTs) published in 5 leading orthodontic journals. METHODS: A manual search was conducted to identify intervention (therapeutic or preventive) related RCTs published in selected journals between 2015 and 2021. Two authors extracted the characteristics of each included trial, as well as all outcomes and outcome measures used in these trials independently and in duplicate. Thereafter, the use of dPROs and dPROMs was identified and summarized. We classified all dPROs into 2 general types (oral health-related quality of life [OHRQoL] and others) and dPROMs into 3 categories (single-item questionnaires, generic multiple-item questionnaires, and specific multiple-item questionnaires). We also identified whether these dPROMs assessed 4 dimensions of OHRQoL (Oral Function, Orofacial Pain, Orofacial Appearance, and Psychosocial Impact). RESULTS: From 4631 examined articles, a total of 315 RCTs were included, of which 76 (24.1%) used dPROs and dPROMs. Eight different dPROs (OHRQoL, patients' satisfaction with treatment, difficulty, compliance, preference, efficacy, duration, and unwanted events) and 34 different dPROMs (including 13 single-item questionnaires, 7 generic multiple-item questionnaires, and 14 specific multiple-item questionnaires) were identified in these trials. OHRQoL was the most commonly used dPRO (n = 71; 93.4%), followed by patients' satisfaction with treatment (n = 10; 13.2%), patient-reported difficulty (n = 5; 6.6%), and patient-reported compliance (n = 4, 5.3%). The 4 most frequently used dPROMs were pain measured with 10 mm Visual Analogue Scale (n = 20; 24.1%), pain measured with Numerical Rating Scale (n = 11; 13.3%), the Feldmann's Questionnaire (2007) (n = 6; 7.2%), and the Oral Health Impact Profile 14 (n = 5; 6.0%). CONCLUSION: Only about one-fourth of RCTs published in leading orthodontic journals can reflect patients' perspectives. OHRQoL was the most commonly used dPRO in these trials. Substantial heterogeneity exists among dPROMs used for OHRQoL assessment. Efforts are needed from researchers, reviewers, editors and other stakeholders to promote the wide and standardized use of dPROs in orthodontic research.

Correction to: Short-term dietary restriction in old mice rejuvenates the aging-induced structural imbalance of gut microbiota.

In the original publication of the article, the alphabets in figures were published in upper case and mismatched with the figure legends. The corrected figures and figure legends are given in this Correction.

Short-term dietary restriction in old mice rejuvenates the aging-induced structural imbalance of gut microbiota.

The world's aging population is growing rapidly. Incidences of multiple pathologies, such as abdominal obesity, cardiovascular and cerebrovascular diseases, type 2 diabetes, and malignant neoplasms, increase sharply with age. Aged individuals possess a significantly shifted composition of gut microbiota, which is suggested to play important roles in aging associated pathologies. Whether the existing shifted structural composition of microbiota in aged populations can be reverted non-pharmacologically has not been studied so far. Here, we show an intestinal flora imbalance in old C57BL/6J mice with a remarkable dominant proportion of microbes promoting lipid metabolism and inflammation. Intriguingly, short-term (2 months) dietary restriction was enough to significantly revert the imbalance of intestinal flora in aged mice toward a more balanced structural composition as shown in young mice. Our study provides the first evidence that short-term dietary restriction in old mice can restore the already dysfunctional aged gut microbiota. Our study provides the first evidence that short-term dietary restriction in old mice can restore the already dysfunctional aged gut microbiota, which may help ameliorate aging-related disorders plaguing the vast elderly population.

Effect of Graphene on the Performance of Silicon-Carbon Composite Anode Materials for Lithium-Ion Batteries.

(Si/graphite)@C and (Si/graphite/graphene)@C were synthesized by coating asphalt-cracked carbon on the surface of a Si-based precursor by spray drying, followed by heat treatment at 1000 °C under vacuum for 2h. The impact of graphene on the performance of silicon-carbon composite-based anode materials for lithium-ion batteries (LIBs) was investigated. Transmission electron microscopy (TEM) and selected area electron diffraction (SAED) images of (Si/graphite/graphene)@C showed that the nano-Si and graphene particles were dispersed on the surface of graphite, and thermogravimetric analysis (TGA) curves indicated that the content of silicon in the (Si/graphite/graphene)@C was 18.91%. More bituminous cracking carbon formed on the surface of the (Si/graphite/graphene)@C due to the large specific surface area of graphene. (Si/Graphite/Graphene)@C delivered first discharge and charge capacities of 860.4 and 782.1 mAh/g, respectively, initial coulombic efficiency (ICE) of 90.9%, and capacity retention of 74.5% after 200 cycles. The addition of graphene effectively improved the cycling performance of the Si-based anode materials, which can be attributed to the reduction of electrochemical polarization due to the good structural stability and high conductivity of graphene.

Dietary restriction rescues 5-fluorouracil-induced lethal intestinal toxicity in old mice by blocking translocation of opportunistic pathogens.

Chemotherapy remains a major treatment for malignant tumors, yet the application of standard dose intensity chemotherapy is limited due to the side effects of cytotoxic drugs, especially in old populations. The underlying mechanisms of cytotoxicity and strategies to increase the safety and tolerance of chemotherapy remain to be explored. Using 5-fluorouracil (5-FU), a cornerstone chemotherapeutic drug, we demonstrate that the main cause of death in ad libitum (AL) fed mice after 5-FU chemotherapy was infection caused by translocation of intestinal opportunistic pathogens. We show that these opportunistic pathogens greatly increase in the intestine after chemotherapy, which was closely related to loss of intestinal lysozyme. Of note, two weeks of dietary restriction (DR) prior to chemotherapy significantly protected the loss of lysozyme and increased the content of the beneficial Lactobacillus genera, resulting in a substantial inhibition of intestinal opportunistic pathogens and their translocation. The rescue effect of DR could be mimicked by Lysozyme or Lactobacillus gavage. Our study provides the first evidence that DR achieved a comprehensive protection of the intestinal physical, biological and chemical barriers, which significantly improved the overall survival of 5-FU-treated mice. Importantly, the above findings were more prominent in old mice. Furthermore, we show that patients over 65 years old have enriched opportunistic pathogens in their gut microbiota, especially after 5-FU based chemotherapy. Our study reveals important mechanisms for the poor chemotherapy tolerance of the elderly population, which can be significantly improved by short-term DR. This study generates new insights into methods for improving the chemotherapeutic prognosis by increasing the chemotherapy tolerance and safety of patients with malignant tumors.

Effect of Post-transplant Dietary Restriction on Hematopoietic Reconstitution and Maintenance of Reconstitution Capacity of Hematopoietic Stem Cells.

Hematopoietic cell transplantation (HCT) is an important therapy for many hematological malignancies as well as some non-malignant diseases. Post-transplant hematopoiesis is affected by multiple factors, and the mechanisms of delayed post-transplant hematopoiesis remain poorly understood. Patients undergoing HCT often suffer from significantly reduced food intake due to complications induced by preconditioning treatments. Here, we used a dietary restriction (DR) mouse model to study the effect of post-transplant dietary reduction on hematopoiesis and hematopoietic stem cells (HSCs). We found that post-transplant DR significantly inhibited both lymphopoiesis and myelopoiesis in the primary recipient mice. However, when bone marrow cells (BMCs) from the primary recipient mice were serially transplanted into secondary and tertiary recipient mice, the HSCs derived from the primary recipient mice, which were exposed to post-transplant DR, exhibited a much higher reconstitution capacity. Transplantation experiments with purified HSCs showed that post-transplant DR greatly inhibited hematopoietic stem cell (HSC) expansion. Additionally, post-transplant DR reshaped the gut microbiotas of the recipient mice, which inhibited inflammatory responses and thus may have contributed to maintaining HSC function. Our findings may have important implications for clinical work because reduced food intake and problems with digestion and absorption are common in patients undergoing HCT.

Dietary Restriction Attenuates Inflammation and Protects Mouse Skin from High-Dose Ultraviolet B Irradiation.

Ultraviolet B (UVB) radiation may influence the occurrence or even worsen cutaneous disorders from inflammatory to neoplastic disorders. Dietary restriction (DR) is a well-known regimen that can retard aging-associated pathologies, and is shown by us and others that it can significantly inhibit inflammation under various conditions, including in both undisturbed and stressed settings. It is unknown whether DR could act as a nonpharmacological factor to protect skin against UVB-induced damage. In this study, we performed 30% DR to mice 1 week before UVB irradiation (798.6 mJ/cm2). Remarkably, continuous DR significantly ameliorated UVB-induced skin damage and histological changes, associated with a great reduction in the inflammatory responses in the skin. Intriguingly, refed DR mice with ad libitum diet even 24 hours postirradiation reinflamed the inflammatory responses and induced significantly strong damage to the skin. Together, this study provides the first experimental evidence that DR greatly protects mouse skin from high dose of UVB irradiation, which if translatable could have great implications in human beings.

Gut microbiota mediates the inhibition of lymphopoiesis in dietary-restricted mice by suppressing glycolysis.

Dietary restriction (DR) is one of the most robust interventions shown to extend health-span and remains on the forefront of anti-aging intervention studies, though conflicting results have been shown on its effect on lifespan both in rodents and primates. The severe inhibitory effects on the lymphoid lineage by DR remains one of its major negative downsides which reduces its overall beneficial effects on organismal health. Yet, the underlying mechanism of how DR suppresses the lymphoid system remains to be explored. Here, we show that antibiotic ablation of gut microbiota significantly rescued the inhibition of lymphopoiesis by DR. Interestingly, glycolysis in lymphocytes was significantly down-regulated in DR mice and pharmacological inhibition of glycolysis reverted this rescue effect of lymphopoiesis in DR mice with ablated gut microbiota. Furthermore, DR remarkably reconstructed gut microbiota with a significant increase in butyrate-producing bacterial taxa and in expression of But, a key gene involved in butyrate synthesis. Moreover, supplemental butyrate feeding in AL mice suppressed glycolysis in lymphoid cells and mimicked the inhibition of lymphopoiesis in AL mice. Together, our study reveals that gut microbiota mediates the inhibition on lymphopoiesis via down-regulation of glycolysis under DR conditions, which is associated with increased butyrate-synthesis. Our study uncovered a candidate that could potentially be targeted for ameliorating the negative effects of DR on lymphopoiesis, and therefore may have important implications for the wider application of DR and promoting healthy aging.

Dietary restriction increases protective gut bacteria to rescue lethal methotrexate-induced intestinal toxicity.

Methotrexate (MTX) is a typical chemotherapeutic drug that is widely used in the treatment of various malignant diseases as well as autoimmune diseases, with gastrointestinal toxicity being its most prominent complication which could have a significant effect on the prognosis of patients. Yet effective ways to alleviate such complications remains to be explored. Here we show that 30% dietary restriction (DR) for 2 weeks dramatically increased the survival rate of 2-month-old female mice after lethal-dose MTX exposure. DR significantly reduced intestinal inflammation, preserved the number of basal crypt PCNA-positive cells, and protected the function of intestinal stem cells (ISCs) after MTX treatment. Furthermore, ablating intestinal microbiota by broad-spectrum antibiotics completely eliminated the protective effect achieved by DR. 16S rRNA gene deep-sequencing analysis revealed that short-term DR significantly increased the Lactobacillus genus, with Lactobacillus rhamnosus GG gavage partially mimicking the rescue effect of DR on the intestines of ad libitum fed mice exposed to lethal-dose MTX. Together, the current study reveals that DR could be a highly effective way to alleviate the lethal injury in the intestine after high-dose MTX treatment, which is functionally mediated by increasing the protective intestinal microbiota taxa in mice. Keywords: Dietary restriction, Methotrexate, Gut microbiota, Intestinal stem cells, intestinal toxicity.

Long-term mid-onset dietary restriction rejuvenates hematopoietic stem cells and improves regeneration capacity of total bone marrow from aged mice.

Currently, the world's aging population is expanding rapidly, leading to a rise in aged hematopoietic cell transplantation (HCT) recipients and aged donors. However, the age of donors is negatively related to the prognosis after transplantation due to functional decline in hematopoietic stem cells (HSCs) during aging. Previously, we showed that an early-onset dietary restriction (DR) significantly retards early aging of HSCs. However, the effects of a mid-onset DR on HSCs remain unknown. In the current study, we performed 30% DR in 15- to 18-month-old mice (equivalent to 50-60 human years) for short-term (4 months) and long-term (9 months). We show that DR reduces and rectifies the imbalance of the HSC pool in aged mice. Short-term DR improves hematopoietic reconstitution in purified HSC transplantations, but not in bone marrow transplantations. Intriguingly, long-term mid-onset DR improves the hematopoietic regeneration of aging HSCs with a particular enhancement of lymphoid outputs even in total bone marrow transplantation settings. Mechanistically, long-term DR rejuvenates the aberrantly regulated mitochondrial pathways in aging HSCs and is accompanied by increased quiescence and reduced DNA damage signaling in HSCs. Short-term DR showed a similar trend of rescuing these aging hallmarks but to a much lesser extent. Together, the current study suggests that mid-onset DR ameliorates the function of aging HSCs and long-term DR even improved hematopoietic reconstitution in bone marrow transplantation, which could potentially have considerable implications in HCT of humans when only old donors are available.

High Canonical Wnt/ß-Catenin Activity Sensitizes Murine Hematopoietic Stem and Progenitor Cells to DNA Damage.

Aging is characterized by the accumulation of DNA damage and a decrease in stem cell functionality, yet molecular mechanisms that limit the maintenance of stem cells in response to DNA damage remain to be delineated. Here we show in mouse models that DNA damage leads to a transient over-activation of Wnt signaling in hematopoietic stem cells (HSCs), and that high activity of canonical Wnt/ß-catenin signaling sensitizes HSCs to DNA damage induced by X-irradiation which results in preferential maintenance of HSCs with low levels of Wnt signaling. The study shows that genetic or chemical activation of canonical Wnt signaling enhances radiosensitivity of HSCs while inhibition of Wnt signaling decreases it. Together, these results indicate that levels of Wnt signaling activity mediate heterogeneity in the sensitivity of HSCs to DNA damage induced depletion. These findings could be relevant for molecular alterations and selection of stem cells in the context of DNA damage accumulation during aging and cancer formation.

Wnt Signaling Mediates the Aging-Induced Differentiation Impairment of Intestinal Stem Cells.

Stem cell aging underlies aging-associated disorders, such as steeply increased incidences of tumors and impaired regeneration capacity upon stress. However, whether and how the intestinal stem cells age remains largely unknown. Here we show that intestinal stem cells derived from 24-month-old mice hardly form typical organoids with crypt-villus structures, but rather mainly form big, rounded cysts devoid of differentiated cell types, which mimics the culturing of heterozygous APC-deficient cells from the APCmin mouse line. Further analysis showed that cultured crypts derived from aged mice exhibited reduced expression levels of differentiation genes and higher expression of Wnt target genes. Lowering the concentration of R-spondin-1 in the culture system significantly reduced formation of rounded cysts, accompanied by an increased formation of organoids from crypts derived from old mice. We are the first to uncover that intestinal stem cells derived from old mice harbor significant deficiency in differentiation that can be partially rescued through a reduction in R-spondin-1 exposure. This could be highly relevant to intestinal tumor development and the reduced regeneration potential observed in the aged population. Our study provides the first experimental evidence that an over-responsiveness to Wnt/beta-catenin signaling of aged intestinal stem cells mediates the aging-induced deficiency in differentiation, and could serve as a potential target to ameliorate aging-associated intestinal pathologies.

The Use of Functionalized Silk Fibroin Films as a Platform for Optical Diffraction-Based Sensing Applications.

A set of biocompatible, biodegradable, and biofunctionalizable diffractive optical elements (DOEs) using silk proteins as the building materials is reported. The diffraction pattern of a DOE is highly sensitive to the surrounding environment and the structural integrity, offering numerous opportunities for biosensing applications.