cBAF complex components and MYC cooperate early in CD8+ T cell fate.

The identification of mechanisms to promote memory T (Tmem) cells has important implications for vaccination and anti-cancer immunotherapy1-4. Using a CRISPR-based screen for negative regulators of Tmem cell generation in vivo5, here we identify multiple components of the mammalian canonical BRG1/BRM-associated factor (cBAF)6,7. Several components of the cBAF complex are essential for the differentiation of activated CD8+ T cells into T effector (Teff) cells, and their loss promotes Tmem cell formation in vivo. During the first division of activated CD8+ T cells, cBAF and MYC8 frequently co-assort asymmetrically to the two daughter cells. Daughter cells with high MYC and high cBAF display a cell fate trajectory towards Teff cells, whereas those with low MYC and low cBAF preferentially differentiate towards Tmem cells. The cBAF complex and MYC physically interact to establish the chromatin landscape in activated CD8+ T cells. Treatment of naive CD8+ T cells with a putative cBAF inhibitor during the first 48 h of activation, before the generation of chimeric antigen receptor T (CAR-T) cells, markedly improves efficacy in a mouse solid tumour model. Our results establish cBAF as a negative determinant of Tmem cell fate and suggest that manipulation of cBAF early in T cell differentiation can improve cancer immunotherapy.

Wavelength extension beyond 3†µm in a Ho3+/Pr3+ co-doped AlF3-based fiber laser.

In this Letter, we report continuous-wave (CW) lasers with wavelengths beyond 3 µm in homemade Ho3+/Pr3+ co-doped AlF3-based glass fibers. The laser cavity was established through the integration of a dichroic mirror (DM, HR@3-3.1 µm) positioned at the pump end and a partial reflectivity (PR) fiber Bragg grating (FBG) situated at the laser emission end. The FBGs in AlF3-based glass fibers were fabricated by a fs laser direct-writing method, and the resonant wavelengths were 3.009, 3.036, and 3.064 µm, respectively. Under the pump of 1.15 µm laser, a maximum unsaturated output power of 1.014 W was obtained at 3.009 µm with an overall laser efficiency of 11.8% and FWHM bandwidth of 0.88 nm. Furthermore, in order to enhance the optical-thermal stability, the FBG was heat-treated at 200°C for 30 min, and a higher output power of 1081 mW (348 mW without heat treatment) at 3.036 µm was achieved. To the best of our knowledge, this is the first demonstration of 3-3.1 µm lasers by using FBGs in Ho3+/Pr3+ co-doped AlF3-based fibers.

Enhanced and Sustainable Removal of Indoor Formaldehyde by Naturally Porous Bamboo Activated Carbon Supported with MnOx: Synergistic Effect of Adsorption and Oxidation.

Novel bamboo activated carbon (BAC) catalysts decorated with manganese oxides (MnOx) were prepared with varying MnOx contents through a facile one-step redox reaction. Due to the physical anchoring effect of the natural macropore structure for catalyst active components, homogeneous MnOx nanoparticles (NPs), and high specific surface area over catalyst surface, the BAC@MnOx-N (N = 1, 2, 3, 4, 5) catalyst shows encouraging adsorption and catalytic oxidation for indoor formaldehyde (HCHO) removal at room temperature. Dynamic adsorption and catalytic activity experiments were conducted. The higher Smicro (733 m2/g) and Vmicro/Vt (82.6%) of the BAC@MnOx-4 catalyst could facilitate its excellent saturated and breakthrough adsorption capacity (5.24 ± 0.42 mg/g, 2.43 ± 0.22 mg/g). The best performer against 2 ppm HCHO is BAC@MnOx-4 catalyst, exhibiting a maximum HCHO removal efficiency of 97% for 17 h without any deactivation as RH = 0, which is higher than those of other MnOx-based catalysts. The average oxidation state and in situ DRIFTS analysis reveal that abundant oxygen vacancies on the BAC@MnOx-4 catalyst could be identified as surface-active sites of decomposing HCHO into the intermediate species (dioxymethylene and formate). This study provides a potential approach to deposit MnOx nanoparticles onto the BAC surface, and this hybrid BAC@MnOx material is promising for indoor HCHO removal at room temperature.

Efficient 2075-nm laser emission from Ho3+-doped fluorotellurite glass in a compact all-fiber structure.

In this Letter, we report an Ho3+-doped fluorotellurite glass all-fiber laser at 2075 nm. The gain fiber is pumped in-band with a 1976-nm fiber laser and connected by fusion splicing. A high-quality fusion splicing point with a loss of < 0.1 dB was obtained by finely adjusting the splicing power and offset. In addition, by optimizing the writing parameters, a third-order fiber Bragg grating (FBG) with a reflectivity of 98% was achieved at 2075 nm using the femtosecond laser direct-writing method. Using the FBG as the laser cavity mirror and a relatively short 28-cm-long home-made Ho3+-doped fluorotellurite fiber as the laser medium, a laser with a maximum unsaturated output power of 7.33 W was obtained, and the corresponding slope efficiency was as high as 93.4%. The first, to the best of our knowledge, demonstration of the fluorotellurite glass all-fiber ∼2.1-µm laser presented in this work may pave the way for a high-power 2.1-µm fiber laser with a compact structure.

Direct femtosecond laser inscription of Bragg gratings in Ho3+/Pr3+ co-doped AlF3-based glass fibers for a 2.86†µm laser.

In this Letter, we report the fabrication of fiber Bragg gratings (FBGs) in home-made Ho3+/Pr3+ co-doped single-cladding fluoroaluminate (AlF3) glass fibers and its application in watt-level lasing at the mid-infrared (MIR) wavelength of 2.86 µm. The FBGs were inscribed using an 800 nm femtosecond (fs) laser direct-writing technique. The FBG properties were investigated for different pulse energies, inscription speeds, grating orders, and transversal lengths. A second-order FBG with a high reflectivity of 99% was obtained at one end of a 16.5-cm-long gain fiber. Under 1150 nm laser pumping, this fiber yielded a power exceeding 1 W at 2863.9 nm with an overall laser efficiency of 17.7%. The fiber laser showed a FWHM bandwidth of 0.46 nm and long-term spectral stability.

Tuning Bulk O2 and Nonbonding Oxygen State for Reversible Anionic Redox Chemistry in P2-Layered Cathodes.

Improving the reversibility of oxygen redox is quite significant for layered oxides cathodes in sodium-ion batteries. Herein, we for the first time simultaneously tune bulk O2 and nonbonding oxygen state for reversible oxygen redox chemistry in P2-Na0.67 Mn0.5 Fe0.5 O2 through a synergy of Li2 TiO3 coating and Li/Ti co-doping. O2- is oxidized to molecular O2 and peroxide (O2 )n- (n<2) during charging. Molecular O2 derived from transition metal (TM) migration is related to the superstructure ordering induced by Li doping. The synergy mechanism of Li2 TiO3 coating and Li/Ti co-doping on the two O-redox modes is revealed. Firstly, Li2 TiO3 coating restrains the surface O2 and inhibits O2 loss. Secondly, nonbonding Li-O-Na enhances the reversibility of O2- →(O2 )n- . Thirdly, Ti doping strengthens the TM-O bond which fixes lattice oxygen. The cationic redox reversibility is also enhanced by Li/Ti co-doping. The proposed insights into the oxygen redox reversibility are insightful for other oxide cathodes.

2 µm lasing from Tm3+-doped PbO-PbF2-Bi2O3-Ga2O3 glass microspheres.

Whispering gallery mode (WGM) lasers at ∼2µm are demonstrated in PbO-PbF2-Bi2O3-Ga2O3 (PBG) heavy metal oxyfluoride glass microspheres. A 793 nm diode laser is used to pump the PBG microsphere and achieve single-mode and multimode WGM lasing. The fluorescence spectra of Tm3+-doped PBG glasses are measured under 793 nm diode laser pumping. The maximum absorption and emission cross sections of Tm3+:3F4→3H6 are calculated to be 8.23×10-21 and 4.42×10-20cm2, respectively. The experimental results indicate that these PBG glass microspheres could become an important photonic component for infrared laser applications.

22.7 W mid-infrared supercontinuum generation in fluorotellurite fibers.

In this Letter, we demonstrate 22.7 W mid-infrared (MIR) supercontinuum (SC) generation in all-solid fluorotellurite fibers. All-solid fluorotellurite fibers based on ${{\rm TeO}_2} {\text -} {{\rm BaF}_2}{\text -}{{\rm Y}_2}{{\rm O}_3}$TeO2-BaF2-Y2O3 and ${{\rm TeO}_2}$TeO2 modified fluoroaluminate glasses are fabricated by using a rod-in-tube method. By using a 0.6 m long fluorotellurite fiber with a core diameter of 11 µm as the nonlinear medium and a high-power 1.93-2.5 µm SC fiber laser as the pump source, we obtain 22.7 W SC generation from 0.93 to 3.95 µm in the fiber for a pump power of 39.7 W. The 10 dB bandwidth is about 1633 nm, and the corresponding spectral range is from 1890 to 3523 nm. The optical-to-optical conversion efficiency is about 57.2%. Our results show that all-solid fluorotellurite fibers are promising nonlinear media for constructing high-power MIR SC light sources.

Hematopoietic stem cells: self-renewal and expansion.

: Hematopoietic stem cells (HSCs) are a unique population of cells with the remarkable ability to replenish themselves through self-renewal and to give rise to differentiated cell lineages. Though having been discovered more than 50 years ago, and having been widely used in bone marrow transplantation to treat blood disorders including leukemia, expansion of HSCs remains an unmet task, thus affecting its more effective usage in clinical practice. PURPOSE OF REVIEW: The purpose of this review article is to summarize past efforts in ex-vivo HSC expansion and to compare recent advances in expanding murine and human HSCs by targeting the N-methyladenosine (mA) pathway. RECENT FINDINGS: Unlike past many efforts that mainly target single or limited pathways and often lead to lineage bias or expansion of progenitor cells or limited long-term HSCs (LT-HSCs), the blocking the degradation of mA pathway has an advantage of stabilizing hundreds of key factors required for maintaining HSCs, thus resulting in expansion of functional LT-HSCs. SUMMARY: The new approach of targeting the mA pathway has a promising application in clinical HSC-based transplantation.

Study on the influence path of public participation in marine ecotourism under the perspective of conspicuous consumption - Analysis of fsQCA based on VBN theory.

Marine ecological tourism has become a popular topic in recent years, and the public's conspicuous consumption behavior is also a hot topic studied by many scholars. How to explore and stimulate the public's conspicuous consumption behavior in marine ecological tourism is an important issue that we need to address. Based on the "value-belief-norm" (VBN) theory and using the fuzzy set Qualitative Comparative Analysis (fsQCA) method, this article analyzes 462 valid samples collected through a questionnaire to explore whether the combination of VBN theory's conditional elements affects the public's conspicuous consumption behavior in marine ecological tourism. The study found that the path of public conspicuous consumption behavior has the characteristics of "different paths leading to the same destination," that is, the combination of conditional elements from different dimensions can stimulate the goal of public conspicuous consumption behavior, and a single-dimensional conditional element is not a necessary condition to increase public conspicuous consumption behavior. Environmental values, such as biosphere values and altruistic values, significantly affect the public's conspicuous consumption behavior.

Effects of strength training on functional ambulation following knee replacement: a systematic review, meta-analysis, and meta-regression.

Strength training is recommended by the American Physical Therapy Association to improve muscle strength, mobility, and balance following knee replacement. Few studies have focused on the direct effects of strength training on functional ambulation, and potential dose-response relationships between strength training parameters and the effect remain unclear. The aim of this systematic review, meta-analysis, and meta-regression was to evaluate the effects of strength training on functional ambulation following knee replacement (KR). We also aimed to explore potential dose-response relationships between strength training parameters and performance in functional ambulation. A systematic literature search of eight online databases was performed on March 12, 2023, for randomized controlled trials evaluating the effects of strength training on functional ambulation by six-minute walk test (6MWT) or timed-up and go test (TUG) after KR. Data were pooled by random-effect meta-analyses and presented as weighted mean difference (WMD). A random-effect meta-regression was performed for four predetermined training parameters, namely, duration (weeks), frequency (sessions per week), volume (time per session), and initial time (after surgery) separately to explore dose-response relationships with WMD. Fourteen trials encompassing 956 participants were included in our study. Meta-analyses showed an improvement in 6MWT performance after strength training (WMD: 32.15, 95% CI 19.44-44.85) and a decrease in time to complete TUG (WMD: - 1.92, 95% CI - 3.43 to - 0.41). Meta-regression revealed a dose-response relationship only between volume and 6MWT, with a decreasing trend (P = 0.019, 95% CI - 1.63 to - 0.20). Increasing trends of improvement in 6MWT and TUG were observed with increasing training duration and frequency. A slight decreasing trend of improvement was observed in 6MWT with postponed initial time, while an opposite trend was observed in TUG. Based on existing studies, moderate-certainty evidence suggests that strength training could increase 6MWT distance, and low-certainty evidence shows that strength training could decrease the time to complete TUG after KR. Meta-regression results only suggested a dose-response relationship between volume and 6MWT with a decreasing trend.Registration: PROSPERO: CRD42022329006.

Exploring the Rules of Related Parameters in Transcutaneous Electrical Nerve Stimulation for Cancer Pain Based on Data Mining.

INTRODUCTION: This study aims to investigate the regularity of related parameters in the treatment of cancer pain using transcutaneous electrical nerve stimulation (TENS). METHODS: A comprehensive literature search was conducted in databases such as PubMed, Cochrane Library, Embase, Web of Science, OVID, CNKI, CBM, VIP, and WANNGFANG from inception up to December 2022. A database was established, and data mining techniques were applied to analyze the relevant TENS parameters. RESULTS: A total of 27 articles were included, encompassing nine current frequencies, four retention times, four treatment frequencies, and two wave types. On the basis of the analysis of parameter association rules, the most closely related parameter combination for clinical TENS in the treatment of cancer pain was a current frequency of 2/100 Hz, a treatment frequency of once a day, a retention time of 30 min, and the dilatational wave. Moreover, the study involved 22 acupuncture points distributed along 13 meridians. According to the analysis of acupuncture point association rules, Hegu (LI04), Zusanli (ST36), and Sanyinjiao (SP06) were the most closely related acupuncture points and could be used in combination for clinical TENS in cancer pain treatment. Furthermore, cluster analysis was conducted on acupuncture points with a frequency ≥ 5, resulting in three categories: the first category included Sanyinjiao (SP06), Zusanli (ST36), Hegu (LI04), Jiaji point, and Neiguan (PC06); the second category included Ashi point; and the third category included Back shu point. CONCLUSION: In the treatment of cancer pain using TENS, it is recommended to use a current frequency of 2/100 Hz, a treatment frequency of once a day, a retention time of 30 min, and the dilatational wave. The electrode positions were primarily selected from Ashi point, Back shu point, Sanyinjiao (SP06), Zusanli (ST36), Hegu (LI04), Jiaji point, and Neiguan (PC06) to achieve the best analgesic effect.

World Health Organization survey on the level of integration of traditional Chinese medicine in Chinese health system rehabilitation services.

Background: To meet the growing global demand for rehabilitation services, the World Health Organization (WHO) launched Rehabilitation 2030. This study was commissioned by the WHO to investigate the integration degree of traditional Chinese medicine (TCM) in Chinese health system rehabilitation services and the demand for TCM rehabilitation in China. Methods: Twenty TCM rehabilitation experts and relevant government administrators were invited to complete the questionnaire between September 2019 and January 2022. The development of traditional, complementary, and integrative medicine (TCI) rehabilitation in China was assessed primarily based on six different health system components. Results: 26 policies, regulations, and national strategic plans related to TCI rehabilitation were issued by relevant government departments since 2002; notably, 14 policies related to TCI rehabilitation development were intensively introduced from 2016 to 2021. These policies cover the three main areas of financing, infrastructure development, and service delivery. The National Administration of Traditional Chinese Medicine's investment in TCM clinical capacity infrastructure and scientific research in 2019-2021 increased by 66% compared to 2010-2012, and the average number of TCM hospitals with rehabilitation departments in 2020 increased by 6.5% compared to 2018. The proportion of community health service centers providing TCM services in primary medical and health institutions has increased by 30.8% over the past 10 years. Conclusion: Long-term continuous policies, substantial financial investment, and expansion of the scope of TCI rehabilitation services in primary care institutions have effectively contributed to the rapid development of TCI rehabilitation. However, human resources and financing mechanisms for TCI rehabilitation need further improvement.

Effects of Liuzijue Qigong Posture on Aerodynamics of Phonation in Healthy Volunteers.

OBJECTIVES: To verify the possible function of Liuzijue Qigong (LQG), a kind of traditional Chinese health exercise, in improving phonation. METHODS: A total of 30 healthy volunteers (10 males, 20 females) without voice disorders were included. The subjects were asked to have phonation tasks at the sitting and LQG postures. Aerodynamic, electroglottographic, and acoustic parameters were measured. Expiratory Volume (FVC); Subglottic Pressure at comfortable phonation (SGP), Glottal Resistance (GR), Glottal Efficiency (GE); Contact Quotient (CQ), Mean Flow (MF), Fundamental frequency (F0), Mean Sound Pressure Level (SPL); Phonation Threshold Pressure (PTP); and Maximum Phonation Time (MPT) were measured and analyzed. RESULTS: In total subjects, the analysis showed a significant increase in FVC (P = 0.020), SGP (P = 0.043), F0 (P = 0.021), and PTP (P = 0.000) at the LQG posture when compared with the sitting posture, and there is no difference in CQ, MF, SPL, GR, GE, and MPT. CONCLUSIONS: The results showed LQG posture increased the respiratory support and glottal closure, while induced the respiratory system and vocal system in coordination to improve phonation. It is logical to postulate that LQG has potential in the management of voice disorders with glottal closure insufficiency.

Traditional Chinese Medicine and Sarcopenia: A Systematic Review.

Sarcopenia has become a key challenge for healthy aging in older adults. However, it remains unclear whether traditional Chinese medicine can effectively treat sarcopenia. This systematic review analyzes the current evidence for the effect of traditional Chinese medicine (TCM) on sarcopenia. We searched for articles regarding sarcopenia treated by TCM in Cochrane library, PubMed, SinoMed, Web of Science, Embase, and the China National Knowledge Infrastructure (from inception until 10 December 2021). Two researchers independently screened the literature in accordance with the inclusion and exclusion criteria designed by PICOS principles. The risk of bias was assessed by the Cochrane Risk of Bias (ROB) tool. The quality of evidence was assessed by the grading of recommendations, assessment, development, and evaluation (GRADE). Participants' characteristics, interventions, and the relevant results of the included studies were extracted and synthesized in a narrative way. The total number of participants in the 21 included studies was 1,330. Most of the studies evaluated physical function (n = 20) and muscle strength (n = 18), and a small number of studies (n = 6) assessed muscle mass. Overall, it was found that TCM had a positive impact on muscle strength (grip strength, chair stand test) and physical function (6-m walking speed, timed up and go test, sit and reach) in patients with sarcopenia, inconsistent evidence of effects on muscle mass. However, the small sample size of the included studies led to imprecision in the results, and the presence of blinding of the studies, allocation concealment, and unreasonable problems with the control group design made the results low grade. Among these results, the quality of evidence for grip strength (n = 10) was of medium grade, and the quality of evidence related to the remaining indicators was of low grade. This systematic review showed that traditional Chinese Qigong exercises and Chinese herbal medicine have a positive and important effect on physical performance and muscle strength in older adults with sarcopenia. Future high-quality multicenter randomized controlled trials (RCTs) with large samples are needed to determinate whether acupuncture and other therapies are effective in treating sarcopenia.

Ditangquan exercises based on safe-landing strategies prevent falls and injury among older individuals with sarcopenia.

Background: Sarcopenia is the age-related loss of skeletal muscle mass and function; it is a risk factor for falls among older individuals. Few studies have focused on training such individuals to adopt a safe-landing strategy that would protect them from fall-related injuries. Ditangquan is a traditional Chinese martial art comprising movements that conform to the principles of safe landing. This study aims to investigate the effectiveness of Ditangquan in preventing fall-related injuries among older individuals with sarcopenia. Methods: A total of 70 participants (21 males and 49 females with sarcopenia) between 60 and 80 years of age were recruited from three local communities and randomly assigned to the Ditangquan exercise group (DG) or the control group (CG) in a 1:1 ratio. Three times a week for 24 weeks, both the DG and CG received an hour of conventional exercise and an hour of Ditangquan exercise based on safe landing. Primary outcomes were the modified falls efficacy scale (MFES), the number of falls, and fall injuries; the secondary outcome was the Timed Up & Go (TUG) test. Results: The DG had significantly fewer falls (1 vs. 8, P = 0.028) and fall injuries (0 vs. 6, P = 0.025) than the CG. Furthermore, at the end of the study, the DG had a significantly improved MFES (mean difference: 32.17 scores; 95% CI: 21.32, 43.02; P <0.001) and TUGT (mean difference: -4.94 s; 95% CI: -7.95, -1.93; P = 0.002) as compared with the CG. Conclusion: Ditangquan exercise based on the safe-landing strategy effectively improves the functional mobility of the elderly, reduces the occurrence of falls and injuries, and increases the individual's confidence in preventing falls.

Therapeutic Effects of Traditional Chinese Exercises on Musculoskeletal Pain: A Systematic Review and Meta-Analysis.

Background: The number of patients with musculoskeletal pain, which seriously affects people's quality of life, has increased. Traditional Chinese exercises are accepted and practiced to strengthen the body. Objective: This study aims to explore the efficacy of traditional Chinese exercises for the treatment of musculoskeletal pain. Methods: A comprehensive search of randomized controlled trials (RCTs) related to traditional Chinese exercises on patients with musculoskeletal pain was completed using PubMed, SinoMed, CNKI, VIP, and Wanfang Med Online databases. All RCTs published until February 2021 were considered. Two researchers independently screened the literature according to the predesigned inclusion and exclusion criteria, and data was extracted and assessed for their risk of bias via the Cochrane collaboration tool. Meta-analysis was performed using RevMan5.2 and Rx64 4.0.2 software. Results: A total of 45 RCT studies with 3178 patients were included. Traditional Chinese exercises were able to effectively alleviate patients with musculoskeletal pain (MD = -1.54, 95% confidence interval (-1.88, -1.19), P < 0.01). Among them, the Yi Jin Jing exercise was superior to other exercises, while Wu Qin Xi showed no significant effects. Besides, traditional Chinese exercises had significant positive effects on the dysfunction and stiffness of the waist and knee joints. Traditional Chinese exercises could effectively relieve the clinical symptoms of patients with musculoskeletal pain. Particularly, the Yi Jin Jing exercise presented the most significant positive effect on pain reduction.

Effects of Wuqinxi in the Patients with Chronic Low Back Pain: A Randomized Controlled Trial.

Low back pain (LBP) is one of the major concerns of the current health care. The guidelines for chronic LBP recommend traditional Chinese exercise as an effective treatment. As one of the representatives of traditional Chinese exercise, Wuqinxi has been famous in China for its effects on improving health and treating chronic diseases for thousands of years. The objectives of the study were to assess the effects of Wuqinxi in the patients with chronic LBP on pain intensity, trunk muscle strength, and quality of life. The primary outcome measure was assessed by the Short-Form McGill Pain Questionnaire (SF-MPQ), including the Visual Analog Scale (VAS) and Present Pain Intensity (PPI) as the subtables. The effects of Wuqinxi on the quality of life were also assessed by the Short-Form Health Survey (SF-36) and the Pittsburgh Sleep Quality Index (PSQI) from physical component summary (PCS), mental component summary (MCS), and sleep quality. Besides, the electrical activities of the rectus abdominis (RA), obliquus externus abdominis (OEA), lumbar erector spinae (ES), and multifidus (MF) were assessed by integrated electromyogram (iEMG) after the end of the intervention. Both the groups showed statistically significant improvement in SF-MPQ, SF-36, PSQI, and iEMG at 12 weeks and 24 weeks when compared with baseline (P < 0.05). However, Wuqinxi demonstrated better effects in SF-MPQ and MCS after 24 weeks of intervention compared with the general exercise (P < 0.05). The patients in the Wuqinxi group (WQXG) also showed a significantly higher iEMG on OEA than the general exercise group (GEG) in 30°/s and 90°/s (P < 0.05). Our results showed that Wuqinxi had better effects on chronic LBP for a long time compared with general exercise, including pain intensity and quality of life. Thus, Wuqinxi should be recognized as a possible standalone therapy and self-management skill in chronic LBP, which is suitable for long-term practice.

ß-Catenin and Associated Proteins Regulate Lineage Differentiation in Ground State Mouse Embryonic Stem Cells.

Mouse embryonic stem cells (ESCs) cultured in defined medium resemble the pre-implantation epiblast in the ground state, with full developmental capacity including the germline. ß-Catenin is required to maintain ground state pluripotency in mouse ESCs, but its exact role is controversial. Here, we reveal a Tcf3-independent role of ß-catenin in restraining germline and somatic lineage differentiation genes. We show that ß-catenin binds target genes with E2F6 and forms a complex with E2F6 and HMGA2 or E2F6 and HP1γ. Our data indicate that these complexes help ß-catenin restrain and fine-tune germ cell and neural developmental potential. Overall, our data reveal a previously unappreciated role of ß-catenin in preserving lineage differentiation integrity in ground state ESCs.

Overcoming Wnt-ß-catenin dependent anticancer therapy resistance in leukaemia stem cells.

Leukaemia stem cells (LSCs) underlie cancer therapy resistance but targeting these cells remains difficult. The Wnt-ß-catenin and PI3K-Akt pathways cooperate to promote tumorigenesis and resistance to therapy. In a mouse model in which both pathways are activated in stem and progenitor cells, LSCs expanded under chemotherapy-induced stress. Since Akt can activate ß-catenin, inhibiting this interaction might target therapy-resistant LSCs. High-throughput screening identified doxorubicin (DXR) as an inhibitor of the Akt-ß-catenin interaction at low doses. Here we repurposed DXR as a targeted inhibitor rather than a broadly cytotoxic chemotherapy. Targeted DXR reduced Akt-activated ß-catenin levels in chemoresistant LSCs and reduced LSC tumorigenic activity. Mechanistically, ß-catenin binds multiple immune-checkpoint gene loci, and targeted DXR treatment inhibited expression of multiple immune checkpoints specifically in LSCs, including PD-L1, TIM3 and CD24. Overall, LSCs exhibit distinct properties of immune resistance that are reduced by inhibiting Akt-activated ß-catenin. These findings suggest a strategy for overcoming cancer therapy resistance and immune escape.