Clinical effects of fasting therapy for treating Type-2 Diabetes Mellitus and Fibromyalgia

There is large empirical and observational evidence that medically supervised modified fasting is efficacious in the treatment of metabolic syndrome and chronic pain syndromes. Beneficial effects of fasting are attributed to distinct anti-inflammatory effects and the deceleration of chronic degenerative pathways, accompanied by enhancement of health-related lifestyle modification and mood enhancement. Recently, there is increasing international use and demand of fasting therapy within the concept of integrative medicine, e.g. in the U.S. and China. The goal of the studies that make up this dissertation is to evaluate the clinical effects of fasting therapy with controlled pilot trials, hence, contribute to the evaluation of fasting therapy as a health-promoting complementary treatment. In the first study, we evaluated the effects of a Traditional Chinese Medicine (TCM) herbal decoction combined with short-term fasting over 5 days (energy intake < 550 kcal/day) on the therapeutic response in type 2 diabetes mellitus (T2DM) patients. Both groups showed improvement of glycemic control, but with combination therapy a more pronounced glucoregulatory and metabolic effect including the reduced use of anti-diabetic medication could be found after three months. These results point to a putative beneficial effect of a combination approach of fasting and traditional herbal Chinese Medicine in T2DM treatment. To further explore the clinical effect of fasting therapy on T2DM, in the second study, we investigated the mid-term (four months) metabolic response of prolonged fasting (7 days, energy intake < 300 kcal/day) in patients with T2DM within a randomized controlled outpatient study. Fasting led to greater weight decrease, reduction of abdominal circumference, significant decrease of blood pressure and increased quality-of-life. However, only non-significant improvements were observed for HbA1c, insulin and HOMA-index. These results suggest that prolonged fasting is feasible and might have beneficial clinical effects on T2DM. The effectiveness should be proven in larger confirmatory trials. In the third study, we conducted a controlled pilot study to compare the therapeutic effects on fibromyalgia treated with conventional rheumatological inpatient care (RT) versus integrative medicine (IM) including fasting therapy. Findings indicate that a multimodal IM treatment with fasting therapy might be superior to CM in the short term and not inferior in the mid-term. Beyond, we published a narrative review summarizing the current state of fasting therapy for treating and preventing diseases.Daten aus Beobachtungsstudien und langjährige Erfahrung von Anwendern legen nahe, daß medizinisch überwachtes therapeutisches Fasten (periodisches Fasten, „Heilfasten, very low calorie diet“) bei der Behandlung von Metabolischem Syndrom sowie chronischen Schmerzsyndromen des Bewegungsapparates eine wirksame Maßnahme darstellt. Zugeschrieben werden dem Fasten eine antiinflammatorische Wirkung, die Verlangsamung von chronisch degenerativen Prozessen sowie die Induzierung von gesundheitsfördernder Lebensstiländerung und stimmungsaufhellende Effekte. Inzwischen wird Fasten international zunehmend eingesetzt, u.a. Auch im Rahmender der Integrativen Medizin in den USA und China. Ziel der kontrollierten Pilotstudien dieser Dissertation ist es, die klinischen Effekte einer Fastenbehandlung zu evaluieren und damit zur Einschätzung des Fastens als gesundheitsfördernder komplementärmedizinischer Behandlung beizutragen. In der ersten Studie untersuchten wir die kombinierte Wirkung einer additiven Phytotherapie nach Empfehlungen der Traditionellen Chinesischen Medizin (TCM) im Zusammenhang mit einem kurzzeitigen, 5-tägigen Fasten mit Energieaufnahme <550 kcal / Tag bei Patienten mit Typ-2-Diabetes mellitus (T2DM). Es zeigte sich in beiden Gruppen eine Verbesserung metabolischer und glukoregulatorischer Parameter, in der Kombinationstherapie aber mit stärkerer Ausprägung einschließlich eines reduzierter Bedarfs an Antidiabetika nach drei Monaten. Ein integrativer Behandlungsansatz, der die Standard-T2DM Behandlung, VLCD und ein TCM-Dekokt umfasst, könnte somit vorteilhafte Wirkungen haben. In einer weiteren randomisiert-kontrollierten Studie untersuchten wir die mittelfristige (vier Monate) metabolische Reaktion auf ein ambulantes periodisches Fasten über 7 Tage nach der Buchinger Technik (Energieaufnahme ca. 300 kcal/Tag durch Säfte) bei Patienten mit T2DM. Das Fasten führte im Vergleich zur Kontrollgruppe mit konventioneller Ernährungsberatung zu Gewichtsabnahme, Verringerung des abdominalen Umfangs, signifikanter Senkung des Blutdrucks und erhöhter Lebensqualität. Es wurden jedoch nur nicht signifikante Verbesserungen für HbA1c, Insulin und HOMA-Index beobachtet. Diese Ergebnisse legen nahe, dass verlängertes Fasten positive klinische Auswirkungen auf T2DM haben könnte und somit als gut durchführbare Therapieergänzung in größeren konfirmatorischen Studien weiter evaluiert werden sollte. In einer dritten Untersuchung verglichen wir in einer kontrollierten Pilotstudie die therapeutischen Effekte der rheumatologisch-stationären Komplex Therapie (RT) mit denen der integrativen Medizin (IM), einschließlich des Schwerpunktes einer stationären Fastentherapie mit begleitender Mind Body Medizin bei Patienten mit Fibromyalgie Syndrom. Die Ergebnisse deuten darauf hin, dass eine multimodale IM-Behandlung mit Fasten-Therapie und Mind Body Medizin der CM kurzfristig überlegen und mittelfristig nicht unterlegen sein könnte. Darüber hinaus veröffentlichten wir einen narrativen Review Artikel, zur aktuellen Studienlage bezüglich der Wirksamkeit von Fastenbehandlungen zur Behandlung und Vorbeugung von Erkrankungen

Identification and experimental validation of key m6A modification regulators as potential biomarkers of osteoporosis

Osteoporosis (OP) is a severe systemic bone metabolic disease that occurs worldwide. During the coronavirus pandemic, prioritization of urgent services and delay of elective care attenuated routine screening and monitoring of OP patients. There is an urgent need for novel and effective screening diagnostic biomarkers that require minimal technical and time investments. Several studies have indicated that N6-methyladenosine (m6A) regulators play essential roles in metabolic diseases, including OP. The aim of this study was to identify key m6A regulators as biomarkers of OP through gene expression data analysis and experimental verification. GSE56815 dataset was served as the training dataset for 40 women with high bone mineral density (BMD) and 40 women with low BMD. The expression levels of 14 major m6A regulators were analyzed to screen for differentially expressed m6A regulators in the two groups. The impact of m6A modification on bone metabolism microenvironment characteristics was explored, including osteoblast-related and osteoclast-related gene sets. Most m6A regulators and bone metabolism-related gene sets were dysregulated in the low-BMD samples, and their relationship was also tightly linked. In addition, consensus cluster analysis was performed, and two distinct m6A modification patterns were identified in the low-BMD samples. Subsequently, by univariate and multivariate logistic regression analyses, we identified four key m6A regulators, namely, METTL16, CBLL1, FTO, and YTHDF2. We built a diagnostic model based on the four m6A regulators. CBLL1 and YTHDF2 were protective factors, whereas METTL16 and FTO were risk factors, and the ROC curve and test dataset validated that this model had moderate accuracy in distinguishing high- and low-BMD samples. Furthermore, a regulatory network was constructed of the four hub m6A regulators and 26 m6A target bone metabolism-related genes, which enhanced our understanding of the regulatory mechanisms of m6A modification in OP. Finally, the expression of the four key m6A regulators was validated in vivo and in vitro, which is consistent with the bioinformatic analysis results. Our findings identified four key m6A regulators that are essential for bone metabolism and have specific diagnostic value in OP. These modules could be used as biomarkers of OP in the future

AIO2: Online Correction of Object Labels for Deep Learning with Incomplete Annotation in Remote Sensing Image Segmentation

While the volume of remote sensing data is increasing daily, deep learning in Earth Observation faces lack of accurate annotations for supervised optimization. Crowdsourcing projects such as OpenStreetMap distribute the annotation load to their community. However, such annotation inevitably generates noise due to insufficient control of the label quality, lack of annotators, frequent changes of the Earth's surface as a result of natural disasters and urban development, among many other factors. We present Adaptively trIggered Online Object-wise correction (AIO2) to address annotation noise induced by incomplete label sets. AIO2 features an Adaptive Correction Trigger (ACT) module that avoids label correction when the model training under- or overfits, and an Online Object-wise label Correction (O2C) methodology that employs spatial information for automated label modification. AIO2 utilizes a mean teacher model to enhance training robustness with noisy labels to both stabilize the training accuracy curve for fitting in ACT and provide pseudo labels for correction in O2C. Moreover, O2C is implemented online without the need to store updated labels every training epoch. We validate our approach on two building footprint segmentation datasets with different spatial resolutions. Experimental results with varying degrees of building label noise demonstrate the robustness of AIO2. Source code will be available at https://github.com/zhu-xlab/AIO2.git

Electrical impedance performance of metal dry bioelectrode with different surface coatings

To improve the electrical impedance performance of bioelectrodes, a novel metal dry bioelectrodes with different coating layers are developed with laser micromilling and electroplating technology. Based on the analysis of the coating layer on the bioelectrode surface, the effect of different coating layers on the electrical impedance performance of bioelectrodes is investigated. The results show that the silver content increases with electroplating time when the silver layer is coated on the bioelectrode surface. However, the decrease of silver layer weight is observed with much longer electroplating time, and the optimal electroplating time is 20 min. Compared with the uncoated bioelectrode, the bioelectrode coated with silver layer exhibits much lower impedance value and better impedance stability. Especially, when the silver-coated bioelectrode is subsequently coated with silver-silver chloride layer, the lowest impedance value and best impedance stability are obtained

Novel dry metal electrode with tilted microstructure fabricated with laser micromilling process

A novel dry metal electrodes with tilted microstructure arrays was fabricated with laser micromilling process by adjusting the incident angle of the laser beam. After discussing the laser fabrication process for dry metal electrodes, the effects of the laser incident angle, width of unscanned area, laser output power, and scanning times on the shape and size of the microstructures are further discussed. Our experimental results show that the tilted angle of the surface microstructures of the dry metal electrodes depended on the laser incident angle. The heights of the surface microstructures of dry metal electrodes were greatly increased by increases of the laser output power and scanning times. Compared with vertical microstructure arrays, the developed dry metal electrodes with 60° tilted angle microstructure arrays demonstrated much lower impedances

IGFBPL1 Regulates Axon Growth through IGF-1-mediated Signaling Cascades

Activation of axonal growth program is a critical step in successful optic nerve regeneration following injury. Yet the molecular mechanisms that orchestrate this developmental transition are not fully understood. Here we identified a novel regulator, insulin-like growth factor binding protein-like 1 (IGFBPL1), for the growth of retinal ganglion cell (RGC) axons. Expression of IGFBPL1 correlates with RGC axon growth in development, and acute knockdown of IGFBPL1 with shRNA or IGFBPL1 knockout in vivo impaired RGC axon growth. In contrast, administration of IGFBPL1 promoted axon growth. Moreover, IGFBPL1 bound to insulin-like growth factor 1 (IGF-1) and subsequently induced calcium signaling and mammalian target of rapamycin (mTOR) phosphorylation to stimulate axon elongation. Blockage of IGF-1 signaling abolished IGFBPL1-mediated axon growth, and vice versa, IGF-1 required the presence of IGFBPL1 to promote RGC axon growth. These data reveal a novel element in the control of RGC axon growth and suggest an unknown signaling loop in the regulation of the pleiotropic functions of IGF-1. They suggest new therapeutic target for promoting optic nerve and axon regeneration and repair of the central nervous system

Homoharringtonine exhibits potent anti-tumor effect and modulates DNA epigenome in acute myeloid leukemia by targeting SP1/TET1/5hmC

Homoharringtonine, a plant alkaloid, has been reported to suppress protein synthesis and has been approved by the US Food and Drug Administration for the treatment of chronic myeloid leukemia. Here we show that in acute myeloid leukemia (AML), homoharringtonine potently inhibits cell growth/viability and induces cell cycle arrest and apoptosis, significantly inhibits disease progression in vivo, and substantially prolongs survival of mice bearing murine or human AML. Strikingly, homoharringtonine treatment dramatically decreases global DNA 5-hydroxymethylcytosine abundance through targeting the SP1/TET1 axis, and TET1 depletion mimics homoharringtonine’s therapeutic effects in AML. Our further 5hmC-seq and RNA-seq analyses, followed by a series of validation and functional studies, suggest that FLT3 is a critical down-stream target of homoharringtonine/SP1/TET1/5hmC signaling, and suppression of FLT3 and its downstream targets (e.g. MYC) contributes to the high sensitivity of FLT3-mutated AML cells to homoharringtonine. Collectively, our studies uncover a previously unappreciated DNA epigenome-related mechanism underlying the potent antileukemic effect of homoharringtonine, which involves suppression of the SP1/TET1/5hmC/FLT3/MYC signaling pathways in AML. Our work also highlights the particular promise of clinical application of homoharringtonine to treat human AML with FLT3 mutations, which accounts for more than 30% of total cases of AML