Dual targeting of CD19 and CD22 with bicistronic CAR-T cells in patients with relapsed/refractory large B-cell lymphoma.

Relapse after CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy for large B-cell lymphoma (LBCL) is commonly ascribed to antigen loss or CAR-T exhaustion. Multiantigen targeting and programmed cell death protein-1 blockade are rational approaches to prevent relapse. Here, we test CD19/22 dual-targeting CAR-T (AUTO3) plus pembrolizumab in relapsed/refractory LBCL (NCT03289455). End points include toxicity (primary) and response rates (secondary). Fifty-two patients received AUTO3 and 48/52 received pembrolizumab. Median age was 59 years (range, 27-83), 46/52 had stage III/ IV disease and median follow-up was 21.6 months. AUTO3 was safe; grade 1-2 and grade 3 cytokine release syndrome affected 18/52 (34.6%) and 1/52 (1.9%) patients, neurotoxicity arose in 4 patients (2/4, grade 3-4), and hemophagocytic lymphohistiocytosis affected 2 patients. Outpatient administration was tested in 20 patients, saving a median of 14 hospital days per patient. Overall response rates were 66% (48.9%, complete response [CR]; 17%, partial response). Median duration of remission (DOR) for CR patients was not reached and for all responding patients was 8.3 months (95% confidence interval [CI]: 3.0-not evaluable). 54.4% (CI: 32.8-71.7) of CR patients and 42.6% of all responding patients were projected to remain progression-free at ≥12 months. AUTO3 ± pembrolizumab for relapsed/refractory LBCL was safe and delivered durable remissions in 54.4% of complete responders, associated with robust CAR-T expansion. Neither dual-targeting CAR-T nor pembrolizumab prevented relapse in a significant proportion of patients, and future developments include next-generation-AUTO3, engineered for superior expansion in vivo, and selection of CAR binders active at low antigen densities.

Distinct neural networks derived from galanin-containing nociceptors and neurotensin-expressing pruriceptors.

Pain and itch are distinct sensations arousing evasion and compulsive desire for scratching, respectively. It's unclear whether they could invoke different neural networks in the brain. Here, we use the type 1 herpes simplex virus H129 strain to trace the neural networks derived from two types of dorsal root ganglia (DRG) neurons: one kind of polymodal nociceptors containing galanin (Gal) and one type of pruriceptors expressing neurotensin (Nts). The DRG microinjection and immunosuppression were performed in transgenic mice to achieve a successful tracing from specific types of DRG neurons to the primary sensory cortex. About one-third of nuclei in the brain were labeled. More than half of them were differentially labeled in two networks. For the ascending pathways, the spinothalamic tract was absent in the network derived from Nts-expressing pruriceptors, and the two networks shared the spinobulbar projections but occupied different subnuclei. As to the motor systems, more neurons in the primary motor cortex and red nucleus of the somatic motor system participated in the Gal-containing nociceptor-derived network, while more neurons in the nucleus of the solitary tract (NST) and the dorsal motor nucleus of vagus nerve (DMX) of the emotional motor system was found in the Nts-expressing pruriceptor-derived network. Functional validation of differentially labeled nuclei by c-Fos test and chemogenetic inhibition suggested the red nucleus in facilitating the response to noxious heat and the NST/DMX in regulating the histamine-induced scratching. Thus, we reveal the organization of neural networks in a DRG neuron type-dependent manner for processing pain and itch.

The Intermode Polariton Parametric Scattering Laser in a Strong Coupled Microcavity Via Two-Photon Absorption.

Exciton-polaritons, hybrid quasiparticles from the strong coupling of excitons and cavity photons in semiconductor microcavities, offer a platform for exploring quantum coherence and nonlinear optical properties. The unique polariton parametric scattering (PPS) laser is of interest for its potential in quantum technologies and nonlinear devices. However, direct resonant excitation of polaritons in strong-coupling microcavities is challenging. This study proposes an innovative two-photon absorption (TPA) pump mechanism to address this. We observe TPA-driven PPS lasing in a strongly coupled microcavity at room temperature. High K-value exciton injections promote coherent stimulated emission of polariton scattering through intermode channels. Angle-resolved spectra confirm a TPA process, showing evolution from pump-state to signal-state. Hanbury Brown-Twiss measurement of second-order correlation g2(τ) of signal state indicates a phase transition from a classical thermal state to a quantum coherent state. Theoretical modeling provides insights into the physical mechanisms of PPS. Our work advances nonlinear phenomena exploration in strongly coupled light-matter systems, contributing to quantum polaritonics and nonlinear optics.

ß-Ga2O3 Air-Channel Field-Emission Nanodiode with Ultrahigh Current Density and Low Turn-On Voltage.

Field-emission nanodiodes with air-gap channels based on single ß-Ga2O3 nanowires have been investigated in this work. With a gap of ∼50 nm and an asymmetric device structure, the proposed nanodiode achieves good diode characteristics through field emission in air at room temperature. Measurement results show that the nanodiode exhibits an ultrahigh emission current density, a high enhancement factor of >2300, and a low turn-on voltage of 0.46 V. More impressively, the emission current almost keeps constant over a wide range (8 orders of magnitude) of air pressures below 1 atm. Meanwhile, the fluctuation in field-emission current is below 8.7% during long-time monitoring, which is better than the best reported field-emission device based on ß-Ga2O3 nanostructures. All of these results indicate that ß-Ga2O3 air-gapped nanodiodes are promising candidates for vacuum electronics that can also operate in air.

Transcription factor-like 5 is a potential DNA- and RNA-binding protein essential for maintaining male fertility in mice.

Transcription factor-like 5 (TCFL5) is a testis-specific protein that contains the basic helix-loop-helix domain, but the in vivo functions of TCFL5 remain unknown. Herein, we generated CRISPR/Cas9-mediated knockout mice to dissect the function of TCFL5 in mouse testes. Surprisingly, we found that it was difficult to generate homozygous mice with the Tcfl5 deletion as the heterozygous males (Tcfl5+/-) were infertile. However, we did observe markedly abnormal phenotypes of spermatids and spermatozoa in the testes and epididymides of Tcfl5+/- mice. Mechanistically, we demonstrated that TCFL5 transcriptionally and post-transcriptionally regulated a set of genes participating in male germ cell development via TCFL5 ChIP-DNA and eCLIP-RNA high-throughput sequencing. We also identified a known RNA-binding protein, FXR1, as an interacting partner of TCFL5 that may coordinate the transition and localization of TCFL5 in the nucleus. Collectively, we herein report for the first time that Tcfl5 is haploinsufficient in vivo and acts as a dual-function protein that mediates DNA and RNA to regulate spermatogenesis. This article has an associated First Person interview with the first author of the paper.

Multidimensional influencing factors of postpartum depression based on the perspective of the entire reproductive cycle: evidence from western province of China.

OBJECTIVE: China has a serious burden of Postpartum depression (PPD). In order to improve the current situation of high burden of PPD, this study explores the factors affecting PPD from the multidimensional perspectives with physiology, family support and social support covering the full-time chain of pre-pregnancy-pregnancy-postpartum. METHODS: A follow-up survey was conducted in the Qujing First People's Hospital of Yunnan Province from 2020 to 2022, and a total of 4838 pregnant women who underwent antenatal checkups in the hospital were enrolled as study subjects. Mothers were assessed for PPD using the Edinburgh Postnatal Depression Scale (EPDS), and logistic regression was used to analyse the level of mothers' postnatal depression and identify vulnerability characteristics. RESULTS: The prevalence of mothers' PPD was 46.05%, with a higher prevalence among those who had poor pre-pregnancy health, had sleep problems during pregnancy, and only had a single female fetus. In the family support dimension, only family care (OR = 0.52, 95% CI 0.42-0.64) and only other people care(OR = 0.78, 95% CI 0.64-0.96) were the protective factors of PPD. The experience risk of PPD was higher among mothers who did not work or use internet. CONCLUSION: The PPD level in Yunnan Province was significantly higher than the global and Chinese average levels. Factors affecting mothers' PPD exist in all time stages throughout pregnancy, and the influence of family support and social support on PPD shouldn't be ignored. There is an urgent need to extend the time chain of PPD, move its prevention and treatment forward and broaden the dimensions of its intervention.

Spiky Artificial Peroxidases with V-O-Fe Pair Sites for Combating Antibiotic-Resistant Pathogens.

With the sharp rise of antibiotic-resistant pathogens worldwide, it is of enormous importance to create new strategies for combating pathogenic bacteria. Here, we create an iron oxide-based spiky artificial peroxidase (POD) with V-O-Fe pair sites (V-Fe2 O3 ) for combating methicillin-resistant Staphylococcus aureus (MRSA). The experimental studies and theoretical calculations demonstrate that the V-Fe2 O3 can achieve the localized "capture and killing" bifunction from the spiky morphology and massive reactive oxygen species (ROS) production. The V-Fe2 O3 can reach nearly 100 % bacterial inhibition over a long period by efficiently oxidizing the lipid membrane. Our wound disinfection results identify that the V-Fe2 O3 can not only efficiently eliminate MRSA and their biofilm but also accelerate wound recovery without causing noticeable inflammation and toxicity. This work offers essential insights into the critical roles of V-O-Fe pair sites and localized "capture and killing" in biocatalytic disinfection and provides a promising pathway for the de novo design of efficient artificial peroxidases.

Influencing factors of two-way social support for the old adults in China: A cross-sectional study.

This study aims to investigate the status and influencing factors of two-way social support among old adults. A cross-sectional study of 408 convenient samples of old adults was conducted using socio-demographic questionnaire, Brief 2-Way Social Support Scale, Modified Barthel index, General Well-being Schedule, Family APGAR Index, and Lubben Social Network Scale 6. The two-way social support score for old adults in China was (43.74±7.86), with the receiving and giving social support scoring (22.80±4.06) and (20.94±4.52), respectively. The multiple linear regression analysis revealed that family care, residence place, socioeconomic status, and social network were associated with both receiving and giving social support. Chronic diseases and religious beliefs were related to receiving social support, while gender, general well-being, and residence form were related to giving social support. Tailored interventions based on the distinct influencing factors are needed to enhance old adults' social support both as recipients and providers.

Heterogeneously integrated InGaN-based green microdisk light-emitters on Si (100).

Heterogeneous integration of nitrides on Si (100) is expected to open the door to the new possibilities for this material system in the fields of high-speed integrated photonics and information processing. In this work, GaN epitaxial layer grown on the patterned sapphire substrate is transferred onto Si (100) by a combination of wafer bonding, laser lift-off and chemical mechanical polishing (CMP) processes. The GaN epilayer transferred is uniformly thinned down to 800 nm with a root mean square surface roughness as low as 2.33 Å. The residual stress within the InGaN quantum wells transferred is mitigated by 79.4% after the CMP process. Accordingly, its emission wavelength exhibits a blue shift of 8.8 nm, revealing an alleviated quantum-confined Stark effect. Based on this platform, an array of microcavities with diverse geometrics and sizes are fabricated, by which optically-pumped green lasing at ∼505.8 nm is achieved with a linewidth of ∼0.48 nm from ∼12 µm microdisks. A spontaneous emission coupling factor of around 10-4 is roughly estimated based on the light output characteristics with increasing the pumping densities. Lasing behaviors beyond the threshold suggest that the microdisk suffers less thermal effects as compared to its undercut counterparts. The electrically-injected microdisks are also fabricated, with a turn-on voltage of ∼2.0 V and a leakage current as low as ∼2.4 pA at -5 V. Being compatible with traditional semiconductor processing techniques, this work provides a feasible solution to fabricate large-area heterogeneously integrated optoelectronic devices based on nitrides.

3D surface reconstruction of transparent objects using laser scanning with a four-layers refinement process.

Acquiring the 3D geometry of objects has been an active research topic, wherein the reconstruction of transparent objects poses a great challenge. In this paper, we present a fully automatic approach for reconstructing the exterior surface of a complex transparent scene. Through scanning a line laser by a galvo-mirror, images of the scene are captured from two viewing directions. Due to the light transmission inside the transparent object, the captured feature points and the calibrated laser plane can produce large number of 3D point candidates with large incorrect points through direct triangulation. Various situations of laser transmission inside the transparent object are analyzed and the reconstructed 3D laser point candidates are classified into two types: first-reflection points and non-first-reflection points. The first-reflection points means the first reflected laser points on the front surface of measured objects. Then, a novel four-layers refinement process is proposed to extract the first-reflection points step by step from the 3D point candidates through optical geometric constraints, including (1) Layer-1 : fake points removed by single camera, (2) Layer-2 : ambiguity points removed by the dual-camera joint constraint, (3) Layer-3 : retrieve the missing first-reflection exterior surface points by fusion and (4) Layer-4 : severe ambiguity points removed by contour-continuity. Besides, a novel calibration model about this imaging system is proposed for 3D point candidates reconstruction through triangulation. Compared with traditional laser scanning method, we pulled in the viewing angle information of the second camera and a novel four-layers refinement process is adopted for reconstruction of transparent objects. Various experiments on real objects demonstrate that proposed method can successfully extract the first-reflection points from the candidates and recover the complex shapes of transparent and semitransparent objects.

Transparent dual-band ultraviolet photodetector based on graphene/p-GaN/AlGaN heterojunction.

Versatile applications have driven a desire for dual-band detection that enables seeing objects in multiple wavebands through a single photodetector. In this paper, a concept of using graphene/p-GaN Schottky heterojunction on top of a regular AlGaN-based p-i-n mesa photodiode is reported for achieving solar-/visible-blind dual-band (275 nm and 365 nm) ultraviolet photodetector with high performance. The highly transparent graphene in the front side and the polished sapphire substrate at the back side allows both top illumination and back illumination for the dual band detection. A system limit dark current of 1×10-9 A/cm2 at a negative bias voltage up to -10 V has been achieved, while the maximum detectivity obtained from the detection wavebands of interests at 275 nm and 365 nm are ∼ 9.0 ×1012 cm·Hz1/2/W at -7.5 V and ∼8.0 × 1011 cm·Hz1/2/W at +10 V, respectively. Interestingly, this new type of photodetector is dual-functional, capable of working as either photodiode or photoconductor, when switched by simply adjusting the regimes of bias voltage applied on the devices. By selecting proper bias, the device operation mode would switch between a high-speed photodiode and a high-gain photoconductor. The device exhibits a minimum rise time of ∼210 µs when working as a photodiode and a maximum responsivity of 300 A/W at 6 µW/cm2 when working as a photoconductor. This dual band and multi-functional design would greatly extend the utility of detectors based on nitrides.

The fibrillin-1 RGD motif posttranscriptionally regulates ERK1/2 signaling and fibroblast proliferation via miR-1208.

Fibrillin-1 is an extracellular matrix protein which contains one conserved RGD integrin-binding motif. It constitutes the backbone of microfibrils in many tissues, and mutations in fibrillin-1 cause various connective tissue disorders. Although it is well established that fibrillin-1 interacts with several RGD-dependent integrins, very little is known about the associated intracellular signaling pathways. Recent published evidence identified a subset of miRNAs regulated by fibrillin-1 RGD-cell adhesion, with miR-1208 among the most downregulated. The present study shows that the downregulated miR-1208 controls fibroblast proliferation. Inhibitor experiments revealed that fibrillin-1 RGD suppressed miR-1208 expression via c-Src kinase and the downstream JNK signaling. Bioinformatic prediction and experimental target sequence validation demonstrated four miR-1208 binding sites on the ERK2 mRNA and one on the MEK1 mRNA. ERK2 and MEK1 are critical proliferation-promoting kinases. Decreased miR-1208 levels elevated the total and phosphorylated ERK1/2 and MEK1/2 protein levels and the phosphorylated to total ERK1/2 ratio. Together, the data demonstrate a novel outside-in signaling mechanism explaining how fibrillin-1 RGD-cell binding regulates fibroblast proliferation.

Degree of protection provided by poverty alleviation policies for the middle-aged and older in China: evaluation of effectiveness of medical insurance system tools and vulnerable target recognition.

BACKGROUND: China's medical insurance schemes and poverty alleviation policy at this stage have achieved population-wide coverage and the system's universal function. At the late stage of the elimination of absolute poverty task, how to further exert the poverty alleviation function of the medical insurance schemes has become an important agenda for targeted poverty alleviation. To analyse the risk of catastrophic health expenditure (CHE) occurrence in middle-aged and older adults with vulnerability characteristics from the perspectives of social, regional, disease, health service utilization and medical insurance schemes. METHODS: We used data from the 2018 China Health and Retirement Longitudinal Study (CHARLS) database and came up with 9190 samples. The method for calculating the CHE was adopted from WHO. Logistic regression was used to determine the different characteristics of middle-aged and older adults with a high probability of incurring CHE. RESULTS: The overall regional poverty rate and incidence of CHE were similar in the east, central and west, but with significant differences among provinces. The population insured by the urban and rural integrated medical insurance (URRMI) had the highest incidence of CHE (21.17%) and health expenditure burden (22.77%) among the insured population. Integration of Medicare as a medical insurance scheme with broader benefit coverage did not have a significant effect on the incidence of CHE in middle-aged and older people with vulnerability characteristics. CONCLUSIONS: Based on the perspective of Medicare improvement, we conducted an in-depth exploration of the synergistic effect of medical insurance and the poverty alleviation system in reducing poverty, and we hope that through comprehensive strategic adjustments and multidimensional system cooperation, we can lift the vulnerable middle-aged and older adults out of poverty.

The association between non-symbolic number comparison and mathematical abilities depends on fluency.

Numerous studies have explored the correlation between non-symbolic number comparison and mathematical abilities in children, but the results have been inconsistent. The underlying mental processing featuring fluency may affect the correlation. The current study tested the fluency hypothesis that non-symbolic number comparison is associated with mathematical fluency in the development of mathematical ability. Non-symbolic number comparison, arithmetic computation, mathematical reasoning, non-symbolic number estimation, symbolic number comparison, and a series of basic cognitive processing tasks, including mental rotation, non-verbal matrix reasoning, and choice reaction time, were administered to 1072 first- to fourth-grade children. The results show that non-symbolic number comparison (measured via numerosity comparison) was the only independent predictor of arithmetic computation in higher grades, even after controlled for age, gender, basic cognitive processing, non-symbolic number estimation (measured via numerosity estimation), and symbolic number comparison (measured via digit comparison). However, it did not correlate with mathematical reasoning in any grade. These findings support the fluency hypothesis for developmental correlation between non-symbolic number comparison and mathematical abilities. That is, non-symbolic number comparison correlates with mathematical ability featuring fluency.

Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia.

BACKGROUND: In a single-center phase 1-2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). METHODS: We conducted a phase 2, single-cohort, 25-center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL. The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months. RESULTS: For this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy. The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry. The rates of event-free survival and overall survival were 73% (95% confidence interval [CI], 60 to 82) and 90% (95% CI, 81 to 95), respectively, at 6 months and 50% (95% CI, 35 to 64) and 76% (95% CI, 63 to 86) at 12 months. The median duration of remission was not reached. Persistence of tisagenlecleucel in the blood was observed for as long as 20 months. Grade 3 or 4 adverse events that were suspected to be related to tisagenlecleucel occurred in 73% of patients. The cytokine release syndrome occurred in 77% of patients, 48% of whom received tocilizumab. Neurologic events occurred in 40% of patients and were managed with supportive care, and no cerebral edema was reported. CONCLUSIONS: In this global study of CAR T-cell therapy, a single infusion of tisagenlecleucel provided durable remission with long-term persistence in pediatric and young adult patients with relapsed or refractory B-cell ALL, with transient high-grade toxic effects. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02435849 .).

Sensing of mercury and silver ions using branched Au nanoparticles prepared by hyperbranched polyethylenimine fabricated and capped AuNPs seeds.

Branched AuNPs usually have two or more local surface plasmon resonance (LSPR) absorption bands due to their structural anisotropy, and the LSPR performance is more sensitive to the changes of environmental refractive index than that of spherical AuNPs. The design and preparation of branched AuNPs as colorimetric probes is expected to improve the selectivity and sensitivity of detection of targets. In this paper, branched AuNPs were innovatively synthesized via hyperbranched polyethylenimine (HPEI) fabricated and capped AuNPs as seeds and cetyltrimethylammonium bromide (CTAB) as template agent. The branched AuNPs were characterized by TEM, DLS, zeta potentials and UV-vis spectra. Using the branched AuNPs as a colorimetric probe, the detection system for Hg2+and Ag+showed bright color changes from blue to orange and blue to green based on the morphological evolution of branched AuNPs. The branched AuNPs could selectively detect Hg2+and Ag+at concentrations as low as 77 and 140 nM, respectively. Moreover, this unusual colorimetric method has been successfully used in real water samples and has great potential as a simple, rapid, sensitive and selective method for the detection of Hg2+and Ag+.

Highly sensitive electrochemical BPA sensor based on titanium nitride-reduced graphene oxide composite and core-shell molecular imprinting particles.

A sensitive electrochemical sensor was proposed via combining molecular imprinting technique with the graphene material-doped titanium nitride. The novel graphene with 3-dimensional structure displayed more binding sites and better electrochemical properties. Moreover, this study focused on coating pyrrole with electrical conductivity on the surface of silica as a monomer, and BPA as the template. The interaction made specific detection possible, between monomer and template. With a series of characterizations and electrochemical measurements, CPE (carbon paste electrode)-contained TiN-rGO composite was proved to have conductivity improved. Also, the modified polymer performed well selectivity which reflected in that it was almost impervious to distractions. Under optimized conditions, a linear dependence was observed from 0.5 to 100 nmol L-1 with a detection limit of 0.19 nmol L-1. The sensor explicated outstanding repeatability via repetitive experiment with the RSD of 0.02%, while the results of stability experiment reached the RSD of 1.90%. Eventually, it was used to analyze BPA residues in 3 kinds of daily supplies. The results indicated the potential of the sensor in environmental detection prospectively.

Does the medical insurance system play a real role in reducing catastrophic economic burden in elderly patients with cardiovascular disease in China? Implication for accurately targeting vulnerable characteristics.

BACKGROUND: The vulnerability of cardiovascular disease (CVD) patients' health abilities, combined with the severity of the disease and the overlapping risk factors, leads such people to bear the economic burden of the disease due to the medical services. We estimated the economic burden of CVD and identified the weak link in the design of the medical insurance. METHODS: Data from 5610 middle-aged and elderly with CVD were drawn from the 2015 wave of "China Health and Retirement Longitudinal Study" (CHARLS). The recommended method of the "World Health Organization" (WHO) was adopted to calculate "catastrophic health expenditure" (CHE), "impoverishment by medical expenses" (IME), and applied the treatment-effect model to analyze the determinants of CHE. RESULTS: The incidence of CHE was 19.9% for the elderly families with CVD members, which was 3.6% higher than for uninsured families (16.3%). Families with CVD combined with > 3 other chronic diseases (38.88%) were the riskiest factor for the high CHE in the new rural cooperative medical system (NCMS). Moreover, families with members > 75 years old (33.33%), having two chronic disease (30.74%), and families having disabled members (33.33%), hospitalization members (32.41%) were identified as the high risky determinants for the high CHE in NCMS. CONCLUSIONS: Elderly with physical vulnerabilities were more prone to CHE. The medical insurance only reduced barriers to accessing health resources for elderly with CVD; however it lacked the policy inclination for high-utilization populations, and had poorly accurate identification of the vulnerable characteristics of CVD, which in turn affects the economic protection ability of the medical insurance. The dispersion between the multiple medical security schemes leads to the existence of blind spots in the economic risk protection of individuals and families.

Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 3 Loss Activates Purine Metabolism and Promotes Hepatocellular Carcinoma Progression.

Cancer cells metabolize different energy sources to generate biomass rapidly. The purine biosynthetic pathway was recently identified as an important source of metabolic intermediates for these processes. However, very little was known about the regulatory mechanisms of purine metabolism in hepatocellular carcinoma (HCC). We explored the role of dual-specificity tyrosine (Y) phosphorylation-regulated kinase 3 (Dyrk3) in HCC metabolism. Dyrk3 was significantly down-regulated in HCC compared with normal controls. Its introduction in HCC cells markedly suppressed tumor growth and metastasis in xenograft tumor models. Mass spectrometric analysis of metabolites suggests that the effect of Dyrk3 on HCC occurred at least partially through down-regulating purine metabolism, as evidenced by the fact that inhibiting purine synthesis reverted the HCC progression mediated by the loss of Dyrk3. We further provide evidence that this action of Dyrk3 knockdown requires nuclear receptor coactivator 3 (NCOA3), which has been shown to be a coactivator of activating transcription factor 4 (ATF4) to target purine pathway genes for transcriptional activation. Mechanistically, Dyrk3 directly phosphorylated NCOA3 at Ser-1330, disrupting its binding to ATF4 and thereby causing the inhibition of ATF4 transcriptional activity. However, the phosphorylation-resistant NCOA3-S1330A mutant has the opposite effect. Interestingly, the promoter activity of Dyrk3 was negatively regulated by ATF4, indicating a double-negative feedback loop. Importantly, levels of Dyrk3 and phospho-NCOA3-S1330 inversely correlate with the expression of ATF4 in human HCC specimens. Conclusion: Our findings not only illustrate a function of Dyrk3 in reprograming HCC metabolism by negatively regulating NCOA3/ATF4 transcription factor complex but also identify NCOA3 as a phosphorylation substrate of Dyrk3, suggesting the Dyrk3/NCOA3/ATF4 axis as a potential candidate for HCC therapy.

High operating temperature pBn barrier mid-wavelength infrared photodetectors and focal plane array based on InAs/InAsSb strained layer superlattices.

Improving the operation temperature of the focal plane array (FPA) imagers is critical in meeting the demands to reduce the size, weight, and power (SWaP) for mid-infrared detection systems. In this work, we report the demonstration of a 15 µm-pitch 640×512 middle-format pBn FPA device with a 50% cutoff wavelength of 4.8 µm based on short period of InAs/InAsSb-based "Ga-free" type-II strained-layer superlattices, which achieves a high operating temperature (HOT) reaching 185 K. The pBn FPA exhibits a mean noise equivalent differential temperature (NETD) of 39.5 mK and an operability of 99.6% by using f/2.0 optics for a 300 K background at 150 K. The mean quantum efficiency is 57.6% without antireflection coating and dark current density is 5.39×10-5 A/cm2 at an operation bias of -400 mV, by which the mean specific detectivity(D*) is calculated as high as 4.43×1011 cm.Hz½/W.