Notch and the pre-TCR coordinate thymocyte proliferation by induction of the SCF subunits Fbxl1 and Fbxl12.

Proliferation is tightly regulated during T cell development, and is limited to immature CD4-CD8- thymocytes. The major proliferative event is initiated at the 'ß-selection' stage following successful rearrangement of Tcrß, and is triggered by and dependent on concurrent signaling by Notch and the pre-T cell receptor (TCR); however, it is unclear how these signals cooperate to promote cell proliferation. Here, we found that ß-selection-associated proliferation required the combined activity of two Skp-cullin-F-box (SCF) ubiquitin ligase complexes that included as substrate recognition subunits the F-box proteins Fbxl1 or Fbxl12. Both SCF complexes targeted the cyclin-dependent kinase inhibitor Cdkn1b for polyubiquitination and proteasomal degradation. We found that Notch signals induced the transcription of Fbxl1, whereas pre-TCR signals induced the transcription of Fbxl12. Thus, concurrent Notch and pre-TCR signaling induced the expression of two genes, Fbxl1 and Fbxl12, whose products functioned identically but additively to promote degradation of Cdkn1b, cell cycle progression, and proliferation of ß-selected thymocytes.

Highly Sensitive, Degradable, and Rapid Self-Healing Hydrogel Sensor with Semi-Interpenetrating Network for Recognition of Micro-Expressions.

Flexible conductive hydrogels have revolutionized the lives and are widely applied in health monitoring and wearable electronics as a new generation of sensing materials. However, the inherent low mechanical strength, sensitivity, and lack of rapid self-healing capacity results in their short life, poor detection accuracy, and environmental pollution. Inspired by the molecular structure of bone and its chemical characteristics, a novel fully physically cross-linked conductive hydrogel is fabricated by the introduction of nanohydroxyapatite (HAp) as the dynamic junction points. In detail, the dynamically cross-linked network, including multiple physical interactions, provides it with rapid self-healing ability and excellent mechanical properties (elongation at break (>1200%), tensile strength (174kPa), and resilience (92.61%)). Besides, the ions (Cl-, Li+, Ca2+) that move freely within the system impart outstanding electrical conductivity (2.46 ± 0.15 S m-1), high sensitivity (gauge factor, GF>8), good antifreeze (-40.2 °C), and humidity properties. The assembled sensor can be employed to sensitively detect various large human motions and subtle changes in behavior (facial expressions, speech recognition). Meanwhile, the hydrogel sensor can also degrade in phosphate-buffered saline solution without causing any environmental pollution. Therefore, the designed hydrogels may become a promising candidate material in the future potential applications for smart wearable sensors and electronic skin.

Nuclear adaptor Ldb1 regulates a transcriptional program essential for the maintenance of hematopoietic stem cells.

The nuclear adaptor Ldb1 functions as a core component of multiprotein transcription complexes that regulate differentiation in diverse cell types. In the hematopoietic lineage, Ldb1 forms a complex with the non-DNA-binding adaptor Lmo2 and the transcription factors E2A, Scl and GATA-1 (or GATA-2). Here we demonstrate a critical and continuous requirement for Ldb1 in the maintenance of both fetal and adult mouse hematopoietic stem cells (HSCs). Deletion of Ldb1 in hematopoietic progenitors resulted in the downregulation of many transcripts required for HSC maintenance. Genome-wide profiling by chromatin immunoprecipitation followed by sequencing (ChIP-Seq) identified Ldb1 complex-binding sites at highly conserved regions in the promoters of genes involved in HSC maintenance. Our results identify a central role for Ldb1 in regulating the transcriptional program responsible for the maintenance of HSCs.

One-step assembly of a MacMillan catalyst-based phenolic-type polymer.

We report herein a "bottom-up" approach for the one-step assembly of a MacMillan catalyst-based phenolic-type polymer (Mac-CP). The resulting self-supported polymeric organocatalyst possesses homogeneously distributed and highly concentrated catalytic sites. Furthermore, Mac-CP is soluble in CH3CN but insoluble in hexane. This unique property can be used to employ the polymer as an efficient catalyst in homogeneous organocatalysis and heterogeneous recycling. As a result, Mac-CP possesses comparable catalytic activity and enantioselectivity to its homogeneous counterpart in the asymmetric Diels-Alder reaction (95% yield, 93% enantiomeric excess (ee) for endo and 92% ee for exo).

Ldb1 is required for Lmo2 oncogene-induced thymocyte self-renewal and T-cell acute lymphoblastic leukemia.

Prolonged or enhanced expression of the proto-oncogene Lmo2 is associated with a severe form of T-cell acute lymphoblastic leukemia (T-ALL), designated early T-cell precursor ALL, which is characterized by the aberrant self-renewal and subsequent oncogenic transformation of immature thymocytes. It has been suggested that Lmo2 exerts these effects by functioning as component of a multi-subunit transcription complex that includes the ubiquitous adapter Ldb1 along with b-HLH and/or GATA family transcription factors; however, direct experimental evidence for this mechanism is lacking. In this study, we investigated the importance of Ldb1 for Lmo2-induced T-ALL by conditional deletion of Ldb1 in thymocytes in an Lmo2 transgenic mouse model of T-ALL. Our results identify a critical requirement for Ldb1 in Lmo2-induced thymocyte self-renewal and thymocyte radiation resistance and for the transition of preleukemic thymocytes to overt T-ALL. Moreover, Ldb1 was also required for acquisition of the aberrant preleukemic ETP gene expression signature in immature Lmo2 transgenic thymocytes. Co-binding of Ldb1 and Lmo2 was detected at the promoters of key upregulated T-ALL driver genes (Hhex, Lyl1, and Nfe2) in preleukemic Lmo2 transgenic thymocytes, and binding of both Ldb1 and Lmo2 at these sites was reduced following Cre-mediated deletion of Ldb1. Together, these results identify a key role for Ldb1, a nonproto-oncogene, in T-ALL and support a model in which Lmo2-induced T-ALL results from failure to downregulate Ldb1/Lmo2-nucleated transcription complexes which normally function to enforce self-renewal in bone marrow hematopoietic progenitors.

Themis, a T cell-specific protein important for late thymocyte development.

During positive selection, thymocytes transition through a stage during which T cell antigen receptor (TCR) signaling controls CD4-versus-CD8 lineage 'choice' and subsequent maturation. Here we describe a previously unknown T cell-specific protein, Themis, that serves a distinct function during this stage. In Themis(-/-) mice, thymocyte selection was impaired and the number of transitional CD4(+)CD8(int) thymocytes as well as CD4(+) or CD8(+) single-positive thymocytes was lower. Notably, although we detected no overt TCR-proximal signaling deficiencies, Themis(-/-) CD4(+)CD8(int) thymocytes showed developmental defects consistent with attenuated signaling that were reversible by TCR stimulation. Our results identify Themis as a critical component of the T cell developmental program and suggest that Themis functions to sustain and/or integrate signals required for proper lineage commitment and maturation.

The Effectiveness of Preoperative Correction Techniques in Improving Nasal Deformity in Children With Unilateral Complete Cleft Lip and Palate.

OBJECTIVE: Unilateral complete cleft lip and palate (UCCLP) is associated with apparent nasal deformities before the cheilorrhaphy. The aim of this study was to determine whether preoperative correction techniques are effective in the treatment of nasal deformities in infant with unilateral UCCLP used by the systematic review and meta-analysis. METHODS: We searched Medline, Cochrane Library, EMBASE, PubMed, and Chinese BioMedical Literature Database (CBM) until January 31, 2019, to identify studies that compared the effectiveness of preoperative correction techniques in the treatment of nasal deformities in infant with UCCLP. Two authors individually extracted the data and performed the quality assessments. The height of nasal columella, the width of the affected side nasal ala and the inclination of the nasal columella were evaluated. RESULTS: Seven articles were incorporated into the systematic review, and 5 (274 participants) in the meta-analysis according to the inclusion criteria. The preoperative correction could increase the height of nasal columella in children with UCCLP [SMD: 2.64 mm; 95% confidence intervals (CI); (1.35 mm, 3.94 mm); P < 0.0001]. Moreover, the preoperative correction resulted in reduced width of the affected side nasal ala [SMD: -5.14 mm; 95% CI; (-8.96 mm, -1.31 mm); P = 0.008]; However, the evidence was insufficient to determine a significant effect on the inclination of the nasal columella [SMD: -3.48 degrees; 95% CI; (-7.56 degrees, 0.59 degrees); P = 0.09]. CONCLUSIONS: Preoperative correction for children with UCCLP can increase the height of nasal columella, reduce the width of the affected side nasal ala, improve the nasal symmetry, and reduce nasal deformity, however, no significant effect could be observed for the inclination of the nasal columella.

Visible-light-enabled aerobic oxidative Csp3-H functionalization of glycine derivatives using an organic photocatalyst: access to substituted quinoline-2-carboxylates.

A practical visible-light-induced aerobic oxidative dehydrogenative coupling reaction of glycine derivatives with olefins has been developed to efficiently synthesize quinoline-2-carboxylates. This metal-free process proceeds smoothly under mild conditions and exhibits good tolerance of functional groups. Given the low cost of the catalyst and feedstock materials, the mild reaction conditions and the absence of hazardous byproducts, this protocol should find broad applications in the synthesis of quinoline-2-carboxylate derivatives.

The stage-dependent roles of Ldb1 and functional redundancy with Ldb2 in mammalian retinogenesis.

The Lim domain-binding proteins are key co-factor proteins that assemble with LIM domains of the LMO/LIM-HD family to form functional complexes that regulate cell proliferation and differentiation. Using conditional mutagenesis and comparative phenotypic analysis, we analyze the function of Ldb1 and Ldb2 in mouse retinal development, and demonstrate overlapping and specific functions of both proteins. Ldb1 interacts with Lhx2 in the embryonic retina and both Ldb1 and Ldb2 play a key role in maintaining the pool of retinal progenitor cells. This is accomplished by controlling the expression of the Vsx2 and Rax, and components of the Notch and Hedgehog signaling pathways. Furthermore, the Ldb1/Ldb2-mediated complex is essential for generation of early-born photoreceptors through the regulation of Rax and Crx. Finally, we demonstrate functional redundancy between Ldb1 and Ldb2. Ldb1 can fully compensate the loss of Ldb2 during all phases of retinal development, whereas Ldb2 alone is sufficient to sustain activity of Lhx2 in both early- and late-stage RPCs and in Müller glia. By contrast, loss of Ldb1 disrupts activity of the LIM domain factors in neuronal precursors. An intricate regulatory network exists that is mediated by Ldb1 and Ldb2, and promotes RPC proliferation and multipotency; it also controls specification of mammalian retina cells.