Novel compound heterozygous variants in ARL13B lead to Joubert syndrome.

Joubert syndrome (JBTS) is a systematic developmental disorder mainly characterized by a pathognomonic mid-hindbrain malformation. All known JBTS-associated genes encode proteins involved in the function of antenna-like cellular organelle, primary cilium, which plays essential roles in cellular signal transduction and development. Here, we identified four unreported variants in ARL13B in two patients with the classical features of JBTS. ARL13B is a member of the Ras GTPase family and functions in ciliogenesis and cilia-related signaling. The two missense variants in ARL13B harbored the substitutions of amino acids at evolutionarily conserved positions. Using model cell lines, we found that the accumulations of the missense variants in cilia were impaired and the variants showed attenuated functions in ciliogenesis or the trafficking of INPP5E. Overall, these findings expanded the ARL13B pathogenetic variant spectrum of JBTS.

An actin filament branching surveillance system regulates cell cycle progression, cytokinesis and primary ciliogenesis.

Dysfunction of cell cycle control and defects of primary ciliogenesis are two features of many cancers. Whether these events are interconnected and the driving mechanism coordinating them remains elusive. Here, we identify an actin filament branching surveillance system that alerts cells of actin branching insufficiency and regulates cell cycle progression, cytokinesis and primary ciliogenesis. We find that Oral-Facial-Digital syndrome 1 functions as a class II Nucleation promoting factor to promote Arp2/3 complex-mediated actin branching. Perturbation of actin branching promotes OFD1 degradation and inactivation via liquid-to-gel transition. Elimination of OFD1 or disruption of OFD1-Arp2/3 interaction drives proliferating, non-transformed cells into quiescence with ciliogenesis by an RB-dependent mechanism, while it leads oncogene-transformed/cancer cells to incomplete cytokinesis and irreversible mitotic catastrophe via actomyosin ring malformation. Inhibition of OFD1 leads to suppression of multiple cancer cell growth in mouse xenograft models. Thus, targeting OFD1-mediated actin filament branching surveillance system provides a direction for cancer therapy.

Ciliary transition zone proteins coordinate ciliary protein composition and ectosome shedding.

The transition zone (TZ) of the cilium/flagellum serves as a diffusion barrier that controls the entry/exit of ciliary proteins. Mutations of the TZ proteins disrupt barrier function and lead to multiple human diseases. However, the systematic regulation of ciliary composition and signaling-related processes by different TZ proteins is not completely understood. Here, we reveal that loss of TCTN1 in Chlamydomonas reinhardtii disrupts the assembly of wedge-shaped structures in the TZ. Proteomic analysis of cilia from WT and three TZ mutants, tctn1, cep290, and nphp4, shows a unique role of each TZ subunit in the regulation of ciliary composition, explaining the phenotypic diversity of different TZ mutants. Interestingly, we find that defects in the TZ impair the formation and biological activity of ciliary ectosomes. Collectively, our findings provide systematic insights into the regulation of ciliary composition by TZ proteins and reveal a link between the TZ and ciliary ectosomes.

Cell cycle arrest induced by trichoplein depletion is independent of cilia assembly.

Cilia assembly and centriole duplication are closely coordinated with cell cycle progression, and inhibition of cilia disassembly impedes cell cycle progression. The centrosomal protein trichoplein (TCHP) has been shown to promote cell cycle progression in the G1 -S phase by disassembling cilia. In this study, we showed that deletion of TCHP not only prevented the progression to the S phase but also resulted in cell cycle exit and entrance into G0 phase. Surprisingly, we found that loss of TCHP-induced G0 arrest could not be reversed by blocking the assembly of cilia. In cells without IFT20 or CEP164, two genes encoding key factors for ciliogenesis, depletion of TCHP still led to G0 arrest. Mechanistically, we also found that TCHP depletion-induced cell cycle arrest was not mediated through a centrosome surveillance mechanism, but inhibition of Rb or concomitant inhibition of both Rb and p53 signaling pathways was required to reverse the cell cycle phenotype. In conclusion, our study provides new insights into the function of TCHP in cell cycle progression.

Implementation of a twin-beam state-based clock synchronization system with dispersion-free HOM feedback.

In the field of clock synchronization, the application of frequency-entangled source is a promising direction to improve accuracy and security. In this paper, we analyze the performance of the twin-beam state and the difference-beam state using a practical second-order interference-based scheme. The advantages of the twin-beam state are pointed out especially for the dispersion-free property of HOM interference in a long-distance clock transfer. With the introduction of dispersion-compensated material, our experimental system based on a twin-beam state achieves a clock accuracy at 4 ps with a time offset precision of 1.8 ps over 10 s acquisition time while the time deviation is 0.15 ps over an averaging time of 5500 s in a 22 km-long transmission. These properties exhibit a leading position compared with the current clock synchronization system using the same theoretical scheme and also competitive among the implementations using other second-order interference-based schemes.

Disrupted intraflagellar transport due to IFT74 variants causes Joubert syndrome.

PURPOSE: Ciliopathies are a group of disorders caused by defects of the cilia. Joubert syndrome (JBTS) is a recessive and pleiotropic ciliopathy that causes cerebellar vermis hypoplasia and psychomotor delay. Although the intraflagellar transport (IFT) complex serves as a key module to maintain the ciliary structure and regulate ciliary signaling, the function of IFT in JBTS remains largely unknown. We aimed to explore the impact of IFT dysfunction in JBTS. METHODS: Exome sequencing was performed to screen for pathogenic variants in IFT genes in a JBTS cohort. Animal model and patient-derived fibroblasts were used to evaluate the pathogenic effects of the variants. RESULTS: We identified IFT74 as a JBTS-associated gene in three unrelated families. All the affected individuals carried truncated variants and shared one missense variant (p.Q179E) found only in East Asians. The expression of the human p.Q179E-IFT74 variant displayed compromised rescue effects in zebrafish ift74 morphants. Attenuated ciliogenesis; altered distribution of IFT proteins and ciliary membrane proteins, including ARL13B, INPP5E, and GPR161; and disrupted hedgehog signaling were observed in patient fibroblasts with IFT74 variants. CONCLUSION: IFT74 is identified as a JBTS-related gene. Cellular and biochemical mechanisms are also provided.

Entanglement protection of Ince-Gauss modes in atmospheric turbulence using adaptive optics.

In this paper, we describe the study of the faithful propagation of entangled orbital angular momentum states of light under atmospheric turbulence. The spatial mode is encoded in the Ince-Gauss modes that constitute a complete family of exact and orthogonal solutions of the paraxial wave equation in an elliptic coordinate system. Adaptive optics is employed to protect the entanglement from degradation, in which the threshold of turbulence strength could be enhanced for a reliable entanglement distribution. We find that the evolution of entanglements relies on ellipticity and shows the opposite trend when adopting adaptive optics. The turbulence strengths, at which the concurrences of various entangled states become zero, are different without adaptive optics but almost the same with adaptive optics. The trace of the density matrix is independent of the different ellipticity with or without adaptive optics. We believe that this investigation is useful for long-distance quantum communications and quantum networks using orbital angular momentum as information carriers.

Novel Compound Heterozygous Variants in MKS1 Leading to Joubert Syndrome.

Joubert syndrome (JBTS) and Meckel-Gruber syndrome (MKS) are rare recessive disorders caused by defects of cilia, and they share overlapping clinical features and allelic loci. Mutations of MKS1 contribute approximately 7% to all MKS cases and are found in some JBTS patients. Here, we describe a JBTS patient with two novel mutations of MKS1. Whole exome sequencing (WES) revealed c.191-1G > A and c.1058delG compound heterozygous variants. The patient presented with typical cerebellar vermis hypoplasia, hypotonia, and developmental delay, but without other renal/hepatic involvement or polydactyly. Functional studies showed that the c.1058delG mutation disrupts the B9 domain of MKS1, attenuates the interactions with B9D2, and impairs its ciliary localization at the transition zone (TZ), indicating that the B9 domain of MKS1 is essential for the integrity of the B9 protein complex and localization of MKS1 at the TZ. This work expands the mutation spectrum of MKS1 and elucidates the clinical heterogeneity of MKS1-related ciliopathies.

Whole exome sequencing reveals novel CEP104 mutations in a Chinese patient with Joubert syndrome.

BACKGROUND: Joubert syndrome (JS, OMIM: 213300) is a recessive developmental disorder characterized by cerebellar vermis hypoplasia and a distinctive mid-hindbrain malformation called the "molar tooth sign" on axial magnetic resonance imaging. To date, more than 35 ciliary genes have been identified as the causative genes of JS. METHODS: Whole exome sequencing was performed to detect the causative gene mutations in a Chinese patient with JS followed by Sanger sequencing. RT-PCR and Sanger sequencing were used to confirm the abnormal transcript of centrosomal protein 104 (CEP104, OMIM: 616690). RESULTS: We identified two novel heterozygous mutations of CEP104 in the proband, which were c.2364+1G>A and c.414delC (p.Asn138Lysfs*11) (GenBank: NM_014704.3) and consistent with the autosomal recessive inheritance mode. CONCLUSION: Our study reported the fourth case of JS patients with CEP104 mutations, which expands the mutation spectrum of CEP104 and elucidates the clinical heterogeneity of JS.

Implementation and security analysis of practical quantum secure direct communication.

Rapid development of supercomputers and the prospect of quantum computers are posing increasingly serious threats to the security of communication. Using the principles of quantum mechanics, quantum communication offers provable security of communication and is a promising solution to counter such threats. Quantum secure direct communication (QSDC) is one important branch of quantum communication. In contrast to other branches of quantum communication, it transmits secret information directly. Recently, remarkable progress has been made in proof-of-principle experimental demonstrations of QSDC. However, it remains a technical feat to bring QSDC into a practical application. Here, we report the implementation of a practical quantum secure communication system. The security is analyzed in the Wyner wiretap channel theory. The system uses a coding scheme of concatenation of low-density parity-check (LDPC) codes and works in a regime with a realistic environment of high noise and high loss. The present system operates with a repetition rate of 1 MHz at a distance of 1.5 kilometers. The secure communication rate is 50 bps, sufficient to effectively send text messages and reasonably sized files of images and sounds.

Measurement-device-independent quantum communication without encryption.

Security in communication is vital in modern life. At present, security is realized by an encryption process in cryptography. It is unbelievable if a secure communication is achievable without encryption. In quantum cryptography, there is a unique form of quantum communication, quantum secure direct communication, where secret information is transmitted directly over a quantum channel. Quantum secure direct communication is drastically distinct from our conventional concept of secure communication, because it does not require key distribution, key storage and ciphertext transmission, and eliminates the encryption procedure completely. Hence it avoids in principle all the security loopholes associated with key and ciphertext in traditional secure communications. For practical implementation, defects always exist in real devices and it may downgrade the security. Among the various device imperfections, those with the measurement devices are the most prominent and serious ones. Here we report a measurement-device-independent quantum secure direct communication protocol using Einstein-Podolsky-Rosen pairs. This protocol eradicates the security vulnerabilities associated with the measurement device, and greatly enhances the practical security of quantum secure direct communication. In addition to the security advantage, this protocol has an extended communication distance, and a high communication capacity.

Magneto-optical double resonance driven by fictitious fields.

Light-shift caused by the interaction between atoms and detuned light can be equivalent to the phenomena that atoms are coupled to an external magnetic or electric field. A fictitious magnetic or electric field is used to describe the effect of light-shift. Whether fictitious magnetic or electric field should be used depends on the polarization state of the detuned light. The fictitious fields can shift Zeeman sublevels and excite transitions between different sublevels. We study the magneto-optical double resonance of optically polarized 4He atoms driven by the detuned light with either circular or linear polarization states, model the light-shift with effective Hamiltonian, and the polarized 4He metastable state with density matrix calculations. Our proposed theoretical explanations based on the fictitious fields show good agreement with experimental results, especially for amplitude and frequency shifts of the signals at Larmor frequency and double Larmor frequency driven by the fictitious electric field.

Laser pumped 4He magnetometer with light shift suppression.

We report a laser-pumped 4He atomic magnetometer with light shift suppression through the atomic sensor itself. A linearly polarized light is used to optically align the 4He metastable atoms and we monitor the magneto-optical double resonance (MODR) signals produced by the left- and right-circularly orthogonal components. It is shown that light shift leads to the atomic alignment to orientation conversion effect, and thus, the difference between the two MODR signals. One of these two MODR signals is locked at the Larmor frequency and is used to measure the ambient magnetic field, while the differential signal is, simultaneously, fed back to suppress the light shift. The scheme could be of the advantage to the design of compact magnetometers by reducing the systematic errors due to light shift.

Differences in the levels of gastric cancer risk factors between Nanjing and Minqing counties, China.

OBJECTIVES: In Fujian Province, China, gastric cancer is one of the leading causes of mortality among all malignant tumors. Nanjing county and Minqing county are located in inland Fujian and have similar general demographics. However, the adjusted mortality rate of gastric cancer in Minqing was found to be much higher than that in Nanjing. We sought to explore factors associated with this increased risk of gastric cancer between the two counties. METHODS: We recruited 231 and 224 residents from Nanjing and Minqing, respectively, and analyzed differences between their dietary habits, Helicobacter pylori infection rates, and concentrations of serum pepsinogen I, pepsinogen II, gastrin-17, and ratio of pepsinogen I:II. RESULTS: Subjects in Minqing had more first-degree relatives who had been diagnosed with upper gastrointestinal tumor, more unhealthy dietary habits, a higher Helicobacter pylori positive rate, and greater proportion of abnormal serum gastrin-17 than those in Nanjing did. CONCLUSIONS: The factors that differed between these two counties might indicate that residents in Minqing have a higher risk for developing gastric cancer than those in Nanjing do.

Observation and optimization of 4He atomic polarization spectroscopy.

Polarization spectroscopy in (4)He around 1083 nm is observed and optimized with a distributed feedback fiber laser and is applied for frequency stabilization. In order to improve the accuracy and long-term stability of the frequency-locking performance, a power stabilization module is added, and the dependences of the peak-to-peak amplitude and frequency difference (width) of the polarization spectroscopy signal on various pump and probe powers are investigated.