No abstract

Leydig cells (LCs) play crucial roles in producing testosterone, which is critical in the regulation of male reproduction and development. Low levels of testosterone will lead to male hypogonadism. LC transplantation is a promising alternative therapy for male hypogonadism. However, the source of LCs limits this strategy for clinical applications. Thus far, others have reported that LCs can be derived from stem cells by gene transfection, but the safe and effective induction method has not yet been reported. Here, we report that Leydig-like cells can be derived from human induced pluripotent stem cells (iPSCs) using a novel differentiation protocol based on molecular compounds. The iPSCs-derived Leydig-like cells (iPSC-LCs) acquired testosterone synthesis capabilities, had the similar gene expression profiles with LCs, and positively expressed Leydig cell lineage-specific protein markers LHCGR, STAR, SCARB1, SF-1, CYP11A1, HSD3B1, and HSD17B3 as well as negatively expressed iPSC-specific markers NANOG, OCT4, and SOX2. When iPSC-LCs labeled with lipophilic red dye (PKH26) were transplanted into rat testes that were selectively eliminated endogenous LCs using EDS (75 mg/kg), the transplanted iPSC-LCs could survive and function in the interstitium of testes, and accelerate the recovery of serum testosterone levels and testis weights. Collectively, these findings demonstrated that the iPSCs were able to be differentiated into Leydig-like cells by few defined molecular compounds, which may lay the safer groundwork for further clinical application of iPSC-LCs for hypogonadism.

The multi-dimensional multiplexing technology is very promising for further increasing the link capacity of optical interconnects. A 96-channel silicon-based on-chip reconfigurable optical add-drop multiplexer (ROADM) is proposed and demonstrated for the first time to satisfy the demands in hybrid mode/polarization/wavelengthdivision-multiplexing systems. The present ROADM consists of a six-channel mode/polarization de-multiplexer, a 6 × 16 array of microring-resonator (MRR)-based wavelength-selective switches, and a six-channel mode/polarization multiplexer. With such a ROADM, one can add/drop optical signals to/from any channels of the multimode bus waveguide arbitrarily. For the designed and fabricated ROADM chip, there are more than 1000 elements integrated monolithically, including 96 MRRs, 576 waveguide crossings, 192 grating couplers, 96 micro-heaters, 112 pads, six polarization-splitter-rotators (PSRs), four asymmetric adiabatic couplers and four asymmetric directional couplers. For any channel added/dropped with the fabricated ROADM, the on-chip excess loss is about 5–20 dB, the inter-mode crosstalk is <−12 dB, and the inter-wavelength crosstalk is <−24 dB. The system experiments are demonstrated by using 10-GBaud quadrature phase shift keying (QPSK) signals, showing that the observed optical signal noise ratio (OSNR) power penalties induced by the ROADM are less than 2 dB at a BER of 3.8 × 10−3.

The upstream role of sensory innervation during bone homeostasis is widely underestimated in bone repairing strategies. Herein, a neuromodulation approach is proposed to orchestrate bone defect healing by constructing engineered sensory nerves (eSN) in situ to leverage the adaptation feature of SN during tissue formation. NGF liberated from ECM‐constructed eSN effectively promotes sensory neuron differentiation and enhances CGRP secretion, which lead to improved RAOECs mobility and osteogenic differentiation of BMSC. In turn, such eSN effectively drives ossification in vivo via NGF‐TrkA signaling pathway, which substantially accelerates critical size bone defect healing. More importantly, eSN also adaptively suppresses excessive bone formation and promotes bone remodeling by activating osteoclasts via CGRP‐dependent mechanism when combined with BMP‐2 delivery, which ingeniously alleviates side effects of BMP‐2. In sum, this eSN approach offers a valuable avenue to harness the adaptive role of neural system to optimize bone homeostasis under various clinical scenario.

Abstract:Objective: Axenfeld-Rieger syndrome (ARS) is phenotypically and genetically heterogeneous. In this study, we identified the underlying genetic defect in a Chinese family with ARS. Methods: A detailed family history and clinical data were recorded. The ocular phenotype was documented using slit-lamp photography and systemic anomalies were also documented where available. The genomic DNA was extracted from peripheral blood leukocytes. All coding exons and intron-exon junctions of paired-like homeodomain transcription factor 2 (PITX2) gene and the forkhead box C1 (FOXC1) gene were amplified by polymerase chain reaction (PCR) and screened for mutation by direct DNA sequencing. Variations detected in exon 5 of PITX2 were further evaluated with cloning sequencing. The exon 5 of PITX2 was also sequenced in 100 healthy controls, unrelated to the family, for comparison. Structural models of the wild type and mutant homeodomain of PITX2 were investigated by SWISS-MODEL. Results: Affected individuals exhibited variable ocular phenotypes, whereas the systemic anomalies were similar. After direct sequencing and cloning sequencing, a heterozygous deletion/insertion mutation c.198_201delinsTTTCT (p.M66Ifs*133) was revealed in exon 5 of PITX2. This mutation co-segregated with all affected individuals in the family and was not found either in unaffected family members or in 100 unrelated controls. Conclusions: We detected a novel frameshift mutation p.M66Ifs*133 in PITX2 in a Chinese family with ARS. Although PITX2 mutations and polymorphisms have been reported from various ethnic groups, we report for the first time the identification of a novel deletion/insertion mutation that causes frameshift mutation in the homeodomain of PITX2 protein.

Leydig cells (LCs) are the primary source of testosterone in the testis, and testosterone deficiency caused by LC functional degeneration can lead to male reproductive dysfunction. LC replacement transplantation is a very promising approach for this disease therapy. Here, we report that human adipose derived stem cells (ADSCs) can be differentiated into Leydig‐like cells using a novel differentiation method based on molecular compounds. The isolated human ADSCs expressed positive CD29, CD44, CD59 and CD105, negative CD34, CD45 and HLA‐DR using flow cytometry, and had the capacity of adipogenic and osteogenic differentiation. ADSCs derived Leydig‐like cells (ADSC‐LCs) acquired testosterone synthesis capabilities, and positively expressed LC lineage‐specific markers LHCGR, STAR, SCARB1, SF‐1, CYP11A1, CYP17A1, HSD3B1 and HSD17B3 as well as negatively expressed ADSC specific markers CD29, CD44, CD59 and CD105. When ADSC‐LCs labelled with lipophilic red dye (PKH26) were injected into rat testes which were selectively eliminated endogenous LCs using ethylene dimethanesulfonate (EDS, 75 mg/kg), the transplanted ADSC‐LCs could survive and function in the interstitium of testes, and accelerate the recovery of blood testosterone levels and testis weights. These results demonstrated that ADSCs could be differentiated into Leydig‐like cells by few defined molecular compounds, which might lay the foundation for further clinical application of ADSC‐LC transplantation therapy.

We propose a large scanning range silicon optical phased array (OPA), which is polarization multiplexed and bidirectional with only one waveguide grating antenna array. Mach-Zehnder interferometers (MZIs) and polarization splitterrotator (PSR) are utilized to select the polarization states and propagation directions of the input light to the waveguide grating emitter array. By optimizing the parameters of the waveguide grating, the longitudinal far-field steering range is increased by four times compared to that of the conventional ones among the same wavelength range. The simulation results show that the 54.5° longitudinal scanning range could be realized with the tuning wavelength ranging from 1500 nm to 1600 nm. The high wavelength tuning efficiency is up to 0.545 °/nm. The beam steering range in the lateral direction is 77.8° via phase tuning.

Objective This study aimed to investigate the feasibility and reliability of pulse oximetry combined with cardiac auscultation in screening neonatal congenital heart disease (CHD). Methods This was a retrospective, observational, screening study. All newborns included in the study were at the Second Affiliated Hospital of Wenzhou Medical University from July 2019 to January 2020. Primary screening of CHD was conducted by pulse oximetry combined with cardiac auscultation assays. Indices, including sensitivity, specificity, the positive/negative predictive value, the positive/negative likelihood ratio, and the diagnostic odds ratio, were calculated. The area under the relative operating characteristic curve of the subjects was measured. Results A total of 3327 neonates were enrolled, among whom 139 were diagnosed with CHD and the incidence of CHD was 4.2%. The sensitivity, specificity, diagnostic odds ratio, and area under the relative operating characteristic curve of pulse oximetry combined with cardiac auscultation were 89.9%, 94.7%, 169.0, and 0.923, respectively. Conclusions Pulse oximetry combined with cardiac auscultation is a novel screening method with acceptable accuracy and feasibility for neonatal CHD. This combination method is worth promoting widely.