RESUMO
A high level of PD-L1 in cancer cells promotes tumor immune escape and inhibits tumor immunotherapy. Although PD-L1 gene expression is upregulated by multiple pathways, its gene transcriptional repression is still unclear. Here we found that loss of PPARα, one of the peroxisome-proliferator-activated receptors (PPARs) family members, promoted colorectal tumor immune escape. Mechanistically, PPARα directly bound to the PD-L1 promoter resulting in its gene transcriptional repression, which in turn increased T cell activity, and PPARα agonist enhanced this event. However, ERK induced PPARα-S12 phosphorylation leading to blockade of PPARα-mediated PD-L1 transcriptional repression, and the combination of ERK inhibitor with PPARα agonist significantly inhibited tumor immune escape. These findings suggest that the ERK-PPARα pathway inhibited PD-L1 gene transcriptional repression and promoted colorectal tumor immune escape.
Assuntos
Antígeno B7-H1 , Neoplasias Colorretais , PPAR alfa , Evasão Tumoral , PPAR alfa/metabolismo , PPAR alfa/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Humanos , Fosforilação , Animais , Camundongos , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Sistema de Sinalização das MAP QuinasesRESUMO
In this work, we design a van der Waals heterojunction composed of semiconducting penta-PdPSe and semi-metallic graphene (G) monolayers based on state-of-the-art theoretical calculations. Our results show that both monolayers well preserve their intrinsic features and possess an n-type near Ohmic Schottky contact with a low Schottky barrier height of 0.085 eV for the electrons at the vertical interface. The electronic band alignment suggests a negative band bending of -1.47 eV at the lateral interface, implying electrons as the major transport carriers. Moreover, the transmission gap closely mirrors the heterojunction's band gap, indicating a subtle yet profound interaction between graphene and penta-PdPSe monolayers, which leads to enhanced optical absorption coefficient reaching 106 cm-1 and strong conductivity spanning the visible to ultraviolet region. In addition, our study demonstrates the ability to modify the penta-PdPSe/G heterojunction interface, switching between p-type as well as Ohmic contacts by applying external electric fields. These properties render the penta-PdPSe/G heterojunction promising for optoelectronic applications.
RESUMO
Covalent organic frameworks can be used for next-generation rechargeable metal-ion batteries due to their controllable spatial and chemical architectures and plentiful elemental reserves. In this study, the arsenic-based covalent organic framework (As-COF) is designed by employing the geometrical symmetry of a semiconducting phosphazene-based covalent organic framework that uses p-phenylenediamine as a linker and hexachorocyclotriphosphazene as an As-containing monomer in a C3-like spatial configuration. The As-COF with engineered nanochannels demonstrates exceptional anodic behavior for potassium (K) and calcium (Ca) ion batteries. It exhibits a high storage capacity of about 914(2039) mA h g-1, low diffusion barriers of 0.12(0.26) eV, low open circuit voltage of 0.23(0.18) V, and a minimal volume expansion of 2.41(2.32)% for K (Ca) ions. These attributes collectively suggest that As-COF could significantly advance high-capacity rechargeable batteries.
RESUMO
Phycosphere niches host rich microbial consortia that harbor dynamic algae-bacteria interactions with fundamental significance in varied natural ecosystems. Hence, culturing the uncultured microbial majority of the phycosphere microbiota is vital for deep understanding of the intricate mechanisms governing the dynamic interactions, and also to provide novel and rich microbial resources, and to discover new natural bioactive metabolites. Synechococcus elongatus PCC 7942 is a robust model cyanobacterium widely used in environment, synthesis biology, and biotechnology research. To expand the number of novel phycosphere species that were brought into culture and to discover the natural bioactivities, we presented a new yellow-pigmented bacterium named ABI-127-1, which was recovered from the phycosphere of PCC 7942, using an optimized bacterial isolation procedure. Combined polyphasic taxonomic and phylogenomic characterization was performed to confidently identify the new isolate as a potential novel species belonging to the genus Qipengyuania. The observed bioactivity of strain ABI-127-1 with promoting potential towards the growth and CO2 fixation efficiency of the host microalgae was measured. Additionally, the bacterial production of active bioflocculant exopolysaccharides was evaluated after culture optimization. Thus, these findings revealed the potential environmental and biotechnological implications of this new microalgae growth-promoting bacterium isolated from the phycosphere microenvironment.
Assuntos
Microalgas , Microbiota , Synechococcus , Filogenia , Synechococcus/genética , BiotecnologiaRESUMO
A significant issue in developing metal-catalyzed plastic polymer materials is obtaining distinctive catalytic characteristics to compete with current plastics in industrial commodities. We performed first-principle DFT calculations on the key insertion steps for industrially important monomers, vinyl fluoride (VF) and 3,3,3-trifluoropropene (TFP), to explain how the ligand substitution patterns affect the complex's polymerization behaviors. Our results indicate that the favorable 2,1-insertion of TFP is caused by less deformation in the catalyst moiety of the complexes in contrast to the 1,2-insertion mode. In contrast to the VF monomer, the additional interaction between the fluorine atoms of 3,3,3-trifluoropropene and the carbons of the catalyst ligands also contributed to favor the 2,1-insertion. It was found that the regioselectivity of the monomer was predominated by the progressive alteration of the catalytic geometry caused by small dihedral angles that were developed after the ligand-monomer interaction. Based on the distribution of the 1,2- and 2,1-insertion products, the activity and selectivity were influenced by the steric environment surrounding the palladium center; thus, an increased steric bulk visibly improved the selectivity of the bulkier polar monomer (TFP) during the copolymerization mechanism. In contrast, better activity was maintained through a sterically less hindered Pd metal center; the calculated moderate energy barriers showed that a catalyst with less steric hindrance might provide an opportunity for a wide range of prospective industrial applications.
RESUMO
Rigorous coupled-wave analysis (RCWA) has become one of the most efficient electromagnetic solvers to cope with the diffractions of large-scale periodic nanostructures. Conventional RCWAs focus on planar diffractions and their iterative stabilities. Conical diffractions, as more general incidence cases, are paid little attention in developing their universal and stable implementations for multilayered gratings. Here, we reformulate RCWA algorithms step by step for conical diffractions in a global Cartesian coordinate system. By applying some mathematics tricks, it is found that boundary conditions in conical diffractions can be reduced to the same forms as that of planar diffractions. Conventional stable algorithms including enhanced transmittance matrices and scattering matrices can be directly implemented to attain robust diffraction efficiencies as well as electromagnetic fields for multilayered gratings. An exemplary application in diffractive-waveguide-based augmented reality verified our algorithms.
RESUMO
A dual-polarized double-layer microstrip antenna with a metasurface structure is proposed for 5G and 5G Wi-Fi. A total of 4 modified patches are used for the middle layer structure, and 24 square patches are used for the top layer structure. The double-layer design has achieved -10 dB bandwidths of 64.1% (3.13 GHz~6.08 GHz) and 61.1% (3.18 GHz~5.98 GHz). The dual aperture coupling method is adopted, and the measured port isolation is more than 31 dB. A low profile of 0.096λ0 is obtained (λ0 is the wavelength of 4.58 GHz in the air) for a compact design. Broadside radiation patterns have been realized, and the measured peak gains are 11.1 dBi and 11.3 dBi for two polarizations. The antenna structure and E-field distributions are discussed to clarify its working principle. This dual-polarized double-layer antenna can accommodate 5G and 5G Wi-Fi simultaneously, which can be a competitive candidate for 5G communication systems.
RESUMO
Metalenses of adjustable power and ultrathin flat zoom lens system have emerged as a promising and key photonic device for integrated optics and advanced reconfigurable optical systems. Nevertheless, realizing an active metasurface retaining lensing functionality in the visible frequency regime has not been fully explored to design reconfigurable optical devices. Here, we present a focal tunable metalens and intensity tunable metalens in the visible frequency regime through the control of the hydrophilic and hydrophobic behavior of freestanding thermoresponsive hydrogel. The metasurface is comprised of plasmonic resonators embedded on the top of hydrogel which serves as dynamically reconfigurable metalens. It is shown that the focal length can be continuously tuned by adjusting the phase transition of hydrogel, the results reveal that the device is diffraction limited in different states of hydrogel. In addition, the versatility of hydrogel-based metasurfaces is further explored to design intensity tunable metalens, that can dynamically tailor the transmission intensity and confined it into the same focal spot under different states, i.e., swollen and collapsed. It is anticipated that the non-toxicity and biocompatibility make the hydrogel-based active metasurfaces suitable for active plasmonic devices with ubiquitous roles in biomedical imaging, sensing, and encryption systems.
RESUMO
Objective: The aim of this study was to elaborate the link of thyroid hormones (THs) and metabolic syndrome (MetS) in a Chinese euthyroid employee population with MetS component(s). Methods: An annual health checkup was performed on employees in 2019. Anthropometric parameters, metabolic parameters, and thyroid function were measured. A questionnaire was used in conjunction with Zhenhai Lianhua Hospital database to receive employees' medication records and thyroid surgical history records. Results: A total of 5486 eligible employees were included; the prevalence of MetS was generally higher in males than in females (38.9 vs. 30.4%, P < 0.001). Among employees with central obesity, hypertriglyceridemia, hyperglycemia, hypertension, and low high-density lipoprotein cholesterol (HDL-C), the prevalence of MetS was 68.8, 63.6, 68.2, 48.8, and 60.0% in males and 72.6, 63.3, 61.3, 42.3, and 42.3% in females, respectively. Logistic regression analysis showed that thyroid-stimulating hormone and free thyroxine (FT4) quartiles had no significant impact on MetS. Free triiodothyronine/free thyroxine (FT3/FT4) and free triiodothyronine (FT3)) quartiles were positively associated with the increased odds ratio (OR) for MetS and dyslipidemia (hypertriglyceridemia and low HDL-C), regardless of gender. In males, FT3 and FT3/FT4 quartiles were positively associated with the OR for central obesity, whereas FT4 quartiles were negatively associated; both FT3 and FT4 quartiles were positively associated with increased OR of hyperglycemia, while similar results were not observed in females. Interaction analysis indicated no significant effect of gender and TH interactions on risk of MetS. Conclusion: High FT3 and FT3/FT4 were strongly linked with MetS and dyslipidemia in our study, even in the euthyroid individuals. Tighter control of thyroid function was necessary for those with preexisting MetS component(s).
RESUMO
Marine toxins (MTs) are a group of structurally complex natural products with unique toxicological and pharmacological activities. In the present study, two common shellfish toxins, okadaic acid (OA) (1) and OA methyl ester (2), were isolated from the cultured microalgae strain Prorocentrum lima PL11. OA can significantly activate the latent HIV but has severe toxicity. To obtain more tolerable and potent latency reversing agents (LRAs), we conducted the structural modification of OA by esterification, yielding one known compound (3) and four new derivatives (4-7). Flow cytometry-based HIV latency reversal activity screening showed that compound 7 possessed a stronger activity (EC50 = 46 ± 13.5 nM) but was less cytotoxic than OA. The preliminary structure-activity relationships (SARs) indicated that the carboxyl group in OA was essential for activity, while the esterification of carboxyl or free hydroxyls were beneficial for reducing cytotoxicity. A mechanistic study revealed that compound 7 promotes the dissociation of P-TEFb from the 7SK snRNP complex to reactivate latent HIV-1. Our study provides significant clues for OA-based HIV LRA discovery.
Assuntos
Dinoflagellida , Infecções por HIV , HIV-1 , Humanos , Ácido Okadáico/toxicidade , Latência Viral , Toxinas Marinhas/química , Dinoflagellida/químicaRESUMO
The advancement of metal-catalyzed copolymers is a formidable challenge for achieving distinct catalytic properties to compete with existing plastic polymers in industrial commodities. Herein, we reveal the roles of electronic and steric environments in the thermodynamic preference of microstructures in ethylene/divinyl formal (DVF) co-polymerization using a Pd catalyst under mild conditions to accommodate the respective industrial applicabilities. The insertion products of DVF result in the alteration of the steric crowding, ultimately favoring the efficient formation of cyclic units having potential applications in the manufacture of high-strength fibers. More specifically, to achieve an improved yield of the end copolymer, we tuned the catalytic activity and regioselectivity through a variety of catalysts during ethylene-DVF co-polymerization. The naphthalene-bridged (P^O)PdMe catalyst was found to be promising in terms of the least hindered (buried volume of 47.8%) environment with the thermodynamic preference of 2,1-insertion with an energy of 5.1 kcal mol-1 among all the Pd-metal based catalysts. The highest activity with moderate energy barriers of the proposed catalyst will open new avenues for achieving a variety of potential applications, which is typically not possible using existing polymerization techniques.
RESUMO
Purpose: This study aimed to identify independent risk factors for carotid atherosclerosis (CAS) and construct and validate a CAS risk prediction model based on the Chinese population. Methods: This retrospective study included 4,570 Chinese adults who underwent health checkups (including carotid ultrasound) at the Zhenhai Lianhua Hospital, Ningbo, China, in 2020. All the participants were randomly assigned to the training and validation sets at a ratio of 7:3. Independent risk factors associated with CAS were identified using multivariate logistic regression analysis. The least absolute shrinkage and selection operator combined with 10-fold cross-validation were screened for characteristic variables, and nomograms were plotted to demonstrate the risk prediction model. C-index and receiver operating characteristic curves, calibration plots, and decision curve analysis (DCA) were used to evaluate the risk model's discrimination, calibration, and clinical applicability. Results: Age, body mass index, diastolic blood pressure, white blood cell count, mean platelet volume, alanine transaminase, aspartate transaminase, and gamma-glutamyl transferase were identified as independent risk factors for CAS. In the training, internal validation, and external validation sets, the risk model showed good discriminatory power with C-indices of 0.961 (0.953-0.969), 0.953 (0.939-0.967), and 0.930 (0.920-0.940), respectively, and excellent calibration. The results of DCA showed that the prediction model could be beneficial when the risk threshold probabilities were 1-100% in all sets. Finally, a network computer (dynamic nomogram) was developed to facilitate the physicians' clinical operations. The website is https://nbuhgq.shinyapps.io/DynNomapp/. Conclusion: The development of risk models contributes to the early identification and prevention of CAS, which is important for preventing and reducing adverse cardiovascular and cerebrovascular events.
RESUMO
BACKGROUND: Interleukin (IL)-38, a novel anti-inflammatory cytokine in the IL-1 family, has an important role in various autoimmune/inflammatory diseases. However, the level of serum IL-38 in hyperuricemia (HUA) and its clinical applications are still unknown. METHODS: Forty-four HUA patients and 43 healthy controls were enrolled in this study. The levels of serum IL-38 in the participants were detected by enzyme-linked immunosorbent assay. Multivariable logistic regression analysis was used to identify independent risk factors associated with HUA. The least absolute shrinkage and selection operator combined with 10-fold cross-validation was used to screen the characteristic variables for modeling and the logistic regression model was visualized by nomogram. The discrimination, degree of concordance, and clinical applicability of the models were evaluated by receiver operator characteristic curve, calibration plot, and decision curve analysis, respectively. RESULTS: Compared with that in healthy controls, the level of serum IL-38 was reduced in HUA patients (275.09 ± 294.89 vs 505.99 ± 312.94, P < 0.01). The area under the curve of serum IL-38 was 0.768 (cutoff value: 246.91 pg/ml). IL-38, platelet count, mean platelet volume, and total protein were identified as independent risk factors for HUA. The risk model showed an excellent clinical differentiation value (area under the curve: 0.961) and degree of fit. Decision curve analysis indicated that the prediction model could be beneficial for patients when the threshold probability was 1%-95%. CONCLUSIONS: Low level of serum IL-38 shows some potential in the clinical diagnosis and risk prediction of HUA. In addition, as a novel biomarker of HUA, serum IL-38 would contribute to the in-depth study of its pathogenesis in the future.
Assuntos
Hiperuricemia , Biomarcadores , Humanos , Hiperuricemia/diagnóstico , Hiperuricemia/etiologia , Interleucinas , Contagem de Plaquetas , Fatores de RiscoRESUMO
Chromatographic fractionation of the EtOH extracts of the marine-derived fungus Aspergillus versicolor A18 has led to the isolation of 11 homo/hetero-dimers of aromatic bisabolane sesquiterpenoids including eight diphenyl ether-coupled aromatic bisabolanes (1a/1b and 5−10) and three homodimers (2−4), together with their monomers including three aromatic bisabolanes (11−13) and two diphenyl ethers (14 and 15). Their structures and absolute configurations were elucidated by extensive spectroscopic analysis including HRESIMS, 1D/2D NMR, calculated ECD, and the optical rotatory data. Among the four new compounds, (+/−)-asperbisabol A (1a/1b), asperbisabol B (2), and asperbisabol C (3), the enantiomers 1a and 1b represent an unprecedented skeleton of diphenyl ether-coupled aromatic bisabolane sesquiterpenoids with a spiroketal core moiety. The neuroprotective effects of selected compounds against sodium nitroprusside (SNP)-induced injury were evaluated in PC12 cells by the MTT assay. Five compounds (1a, 6, and 8−10) showed remarkable neuroprotective activities at 10 µM, being more active than the positive control edaravone.
Assuntos
Aspergillus , Sesquiterpenos , Aspergillus/química , China , Estrutura Molecular , Sesquiterpenos Monocíclicos , Sesquiterpenos/químicaRESUMO
Wearable lower limb hydraulic exoskeletons can be used to augment the human performance in heavy load transportation. Nonlinear and walking phase-dependent dynamics make the lower limb hydraulic exoskeleton become difficult to be modeled. This paper presents a generalized multiphase dynamic modeling method in which the dynamic model of each walking phase can all be solved based on a general higher dimensional dynamic model and different holonomic constraints. Compared to traditional lower limb exoskeleton modeling methods where the modeling of each walking phase is done independently, the proposed method is simple and applicable to arbitrary walking phases, especially for double leg support phase (closed-chain dynamics). Based on the established dynamic models, MIMO adaptive robust cascade force controllers (ARCFC) are designed both for double leg support phase and single leg support phase to effectively address high-order nonlinearities and various modeling uncertainties in hydraulic exoskeletons. An additional torque allocation method is proposed to deal with the overactuated characteristic in double leg support. Comparative simulations are conducted to verify the excellent human-machine interaction force control performance of the proposed scheme.
RESUMO
We consider the state estimation of a maneuvering target in 3D using bearing and elevation measurements from a passive infrared search and track (IRST) sensor. Since the range is not observable, the sensor must perform a maneuver to observe the state of the target. The target moves with a nearly constant turn (NCT) in the XY-plane and nearly constant velocity (NCV) along the Z-axis. The natural choice for the NCT motion is to allow perturbations in speed and angular rate in the stochastic differential equation, as has been pointed out previously for a 2D scenario using range and bearing measurements. The NCT motion in the XY-plane cannot be discretized exactly, whereas the NCV motion along the Z-axis is discretized exactly. We discretize the continuous-time NCT model using the first and second-order Taylor approximations to obtain discrete-time NCT models, and we consider the polar velocity and Cartesian velocity-based states for the NCT model. The dynamic and measurement models are nonlinear in the target state. We use the cubature Kalman filter to estimate the target state. Accuracies of the first and second-order Taylor approximations are compared using the polar velocity-based and Cartesian velocity-based models using Monte Carlo simulations. Numerical results for realistic scenarios considered show that the second-order Taylor approximation provides the best accuracy using the polar velocity or Cartesian velocity-based models.
Assuntos
Algoritmos , Método de Monte Carlo , Movimento (Física)RESUMO
Diabetes mellitus is a metabolic disease caused by a combination of genetic and environmental factors. The importance of the inflammatory response occurring in the pancreas and adipose tissue in the occurrence and progression of diabetes has been gradually accepted. Excess blood glucose and free fatty acids produce large amounts of inflammatory cytokines and chemokines through oxidative stress and endoplasmic reticulum stress. There is sufficient evidence that proinflammatory mediators, such as interleukin (IL)-1ß, IL-6, macrophage chemotactic protein-1, and tumor necrosis factor-α, are engaged in insulin resistance in peripheral adipose tissue and the apoptosis of pancreatic ß-cells. IL-36, IL-37, and IL-38, as new members of the IL-1 family, play an indispensable role in the regulation of immune system homeostasis and are involved in the pathogenesis of inflammatory and autoimmune diseases. Recently, the abnormal expression of IL-36, IL-37, and IL-38 in diabetes has been reported. In this review, we discuss the emerging functions, potential mechanisms, and future research directions on the role of IL-36, IL-37, and IL-38 in diabetes mellitus and its complications.
Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Interleucinas , Glicemia/metabolismo , Citocinas , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Células Secretoras de Insulina/metabolismo , Interleucina-1 , Interleucinas/metabolismoRESUMO
The study aimed to evaluate the safety of copper ion sterilization based on copper ion residues in zebrafish (Brachydanio rerio), as well as bacterial community structure and diversity in recirculating aquaculture systems (RASs). The copper ion content was determined using national food safety standard GB 5009.13-2017. Bacterial community structures and alpha and beta diversity indexes were examined using the 16S rRNA gene sequences produced by Illumina HiSeq sequencing. The results revealed no significant copper ion enrichment in B. rerio when the copper ion concentration was 0.15 mg/L. The relative abundances of Erythrobacter, nitrite bacteria, and Flavanobacteria were clearly higher in the treatment group than in the control and differences in bacterial species richness and diversity were obvious. In addition, there was no sharp decrease in the microflora at the outflow of the copper ion generator. In conjunction with the changes in ammonia nitrogen, nitrate, and nitrite concentrations during the experiment, the results indicated that there were no significant effects on the purification efficacy of the biological filter, but the abundances of beneficial bacteria increased significantly. This is of great relevance in order to understand the response of bacterial communities affected by changing environmental conditions, such as copper ion sterilization.
Assuntos
Cobre , Peixe-Zebra , Animais , Aquicultura , Bactérias/genética , Cobre/farmacologia , Água Doce , RNA Ribossômico 16S/genética , EsterilizaçãoRESUMO
In the silicone material extrusion (MEX) process, product profile error and performance defects are common problems due to changes in strand shape. A process optimization method considering strand morphology, denoted as SMO, which allows adjustment of the strand shape by adjusting process parameters during the printing process is presented. The relation between process parameters (extrusion speed, moving speed, nozzle height, and nozzle radius) and the geometric parameters (strand width and strand height) of the cross-section, as well as the relationship between strand spacing, layer height, and process parameters in no void constraint is discussed and verified. SMO was utilized to produce specimens with tunable strand width and strand height. Tensile tests and profile scans were performed to compare SMO with other methods to verify its feasibility. Specimens fabricated using the SMO method have up to a 7% increase in tensile strength, up to a 10% reduction in processing time, and about a 60% reduction in strand height error over unused ones. The results show that the SMO method with adjustable strand width can effectively balance efficiency and mechanical properties compared to uniform infill, and the SMO method with adjustable strand height can provide higher accuracy compared to uniform strand height. The proposed method is validated and improves the efficiency and accuracy of silicone MEX.
RESUMO
Germ plasm is a special cytoplasmic component containing special RNAs and proteins, and is located in specific regions of oocytes and embryos. Only the blastomeres inheriting the germ plasm can develop into primordial germ cells (PGCs). By using Vasa mRNA as a germline marker, we previously demonstrated that germline specification followed the preformation mode in the prawn Macrobrachium nipponense. In this study, we raised the Vasa antibody to identify germ plasm in the oocyte and trace the origin and migration of PGCs. In previtellogenic oocytes, Vasa protein was detected in the perinuclear region, in which electron-dense granules associated with numerous mitochondria were mostly visualized under a transmission electron microscope. In mature oocytes, immunosignal was localized to a large granule under the plasma membrane. During early embryogenesis, the granule was inherited by a single blastomere from 1-cell to 16-cell stages, and thereafter was segregated into two daughter blastomeres at the 32-cell stage. In gastrula, the Vasa-positive cells were large with typical PGC characteristics, containing a big round nucleus and a prominent nucleolus. The immunosignal was localized to the perinuclear region again. In the zoea stage, the Vasa-positive cells migrated toward the genital ridge and clustered in the dorsomedial region close to the yolk portion. Accordingly, we concluded that the prawn PGCs could be specified from the 16-cell stage by inheriting the germplasm. To our knowledge, this is the first report on the identification of the prawn germ plasm and PGCs. The continuous expression of Vasa protein throughout oogenesis and embryogenesis suggests that Vasa protein could be an important factor in germ plasm that functions in early germ cell specification.