SALM5, a synaptic adhesion molecule implicated in autism, induces presynaptic differentiation through binding to the LAR family receptor protein tyrosine phosphatases (LAR-RPTPs) that have been ...highlighted as presynaptic hubs for synapse formation. The mechanisms underlying SALM5/LAR-RPTP interaction remain unsolved. Here we report crystal structures of human SALM5 LRR-Ig alone and in complex with human PTPδ Ig1-3 (MeA
). Distinct from other LAR-RPTP ligands, SALM5 mainly exists as a dimer with LRR domains from two protomers packed in an antiparallel fashion. In the 2:2 heterotetrameric SALM5/PTPδ complex, a SALM5 dimer bridges two separate PTPδ molecules. Structure-guided mutations and heterologous synapse formation assays demonstrate that dimerization of SALM5 is prerequisite for its functionality in inducing synaptic differentiation. This study presents a structural template for the SALM family and reveals a mechanism for how a synaptic adhesion molecule directly induces cis-dimerization of LAR-RPTPs into higher-order signaling assembly.
The tumor suppressor gene
is frequently mutated in a variety of tumors including gliomas and liver cancers, which are highly unresponsive to current therapies. Here, we performed a genome-wide ...synthetic lethal screen, using CRISPR-Cas9 genome editing, to identify potential therapeutic targets specific for
-mutated cancers. In isogenic hepatocellular carcinoma (HCC) cell lines engineered for ATRX loss, we identified 58 genes, including the checkpoint kinase
, uniquely required for the cell growth of ATRX null cells. Treatment with the WEE1 inhibitor AZD1775 robustly inhibited the growth of several ATRX-deficient HCC cell lines
, as well as xenografts
. The increased sensitivity to the WEE1 inhibitor was caused by accumulated DNA damage-induced apoptosis. AZD1775 also selectively inhibited the proliferation of patient-derived primary cell lines from gliomas with naturally occurring
mutations, indicating that the synthetic lethal relationship between
and
could be exploited in a broader spectrum of human tumors. As WEE1 inhibitors have been investigated in several phase II clinical trials, our discovery provides the basis for an easily clinically testable therapeutic strategy specific for cancers deficient in
. SIGNIFICANCE:
-mutant cancer cells depend on WEE1, which provides a basis for therapeutically targeting WEE1 in
-deficient cancers.
.
Here we report a study on the role of chemical diffusion and reaction on the morphology evolution of silver particles. Electrochemical reaction is employed to synthesize silver particles. The ...reaction rate is regulated by current density while the diffusion rate of silver ions is regulated by the viscosity of solution. Silver dendritic particles are largely synthesized at various diffusion and reaction conditions. At a high reaction rate, silver dendrites are formed at the medium diffusion rates of silver ions while the dendritic structures are only formed at an extremely low diffusion rate of silver ions when the reaction proceeds slowly. Therefore, the interplay of diffusion and reaction plays a key role on the structure development of dendrites because the interplay determines the chemical distribution on the growth front of crystals. Once a chemical concentration gradient is established at the growth front, the dendritic structures is triggered.
The construction of railway and highway embankments has a significant influence on the behavior of existing pile foundations, especially in the situation of high embankments and extensively soft ...soils, which are commonly encountered in coastal areas. A high embankment might produce large lateral movement and bending moment to the existing adjacent piles, which would cause the failure of the pile if the surcharge loading is not properly considered. A field test was designed and performed to investigate the effect of lateral surcharge loading on the existing adjacent pile in extensively soft soils. A 4 m high embankment was constructed in five lifts and was close to the existing adjacent steel pipe pile with a length of 35 m. The deformation of the pile and the soft soils, the excess pore water pressure, and lateral earth pressures were measured during the surcharge loading test. The test results showed that the lateral displacement of the steel pipe pile at the ground surface exceeded 229.9 mm and could not maintain constant due to the surcharge loading. The lateral displacement decreased along with the pile depth and was relatively small when the pile depth exceeded 10 m. Large lateral displacements were observed in the soft soils at different locations. The surcharge loading zone showed obvious downward displacements, while the soft soils close to the loading zone showed upward displacements. The excess pore water pressure changed regularly with the construction of the embankment, and its maximum value reached 53.6 kPa. The lateral earth pressures that acted on the pile continuously increased with the increase in the embankment height, which caused large deformation of the pile.
Human periostin plays a multifaceted role in remodeling the extracellular matrix milieu by interacting with other proteins and itself in both a heterophilic and homophilic manner. However, the ...structural mechanism for its extensive interactions has remained elusive. Here, we report the crystal structures of human periostin (EMI‐Fas1I–IV) and its Cys60Ala mutant. In combination with multi‐angle light‐scattering analysis and biochemical assays, the crystal structures reveal that periostin mainly exists as a dimer in solution and its homophilic interaction is mainly mediated by the EMI domain. Furthermore, Cys60 undergoes cysteinylation as confirmed by mass spectroscopy, and this site hardly affects the homophilic interaction. Also, the structures yield insights into how periostin forms heterophilic interactions with other proteins under physiological or pathological conditions.
Weiss-Kruszka syndrome (WSKA) is a rare disease most often caused by mutations in the
gene. To screen for hereditary diseases, exons from the patient's genome were sequenced. Genomic PCR experiments ...followed by Sanger sequencing were used to confirm the mutated genomic regions in the patient and his parents. We report a new mutation site, a heterozygous mutation (NM_021224.6:c.6311dup) in
in a male patient of 8 years old. The mutation in the
gene caused WSKA. This patient is the first case with WSKA characterized by attention-deficit hyperactivity disorder and complete growth hormone deficiency without pituitary lesions. Our results suggest that the heterozygous mutation in
is the direct cause of WSKA in this patient. Mutations in other genes interacting with
result in similar symptoms of WSKA. Furthermore,
and its interacting proteins ASXL2 and VPS13B may form a protein complex that is important for normal development but awaits more studies to reveal its detailed functions.
Here we report a study on controllable synthesis of hierarchical silver structures via regulating reaction kinetics. Silver particles with various morphologies are synthesized by a solution-based ...reduction approach at the addition of amino acids. The amino acid is used to coordinate with silver ions to slow down the reduction of silver ions. With the increase of glycine concentration, the morphologies of silver particles switch from dendrites, to flowers and to compacted spheres, which is attributed to the decrease of reaction rate as a result of the coordination. Three more amino acids are examined and confirms the role of reaction kinetic in shaping silver particles. Furthermore, by increasing the concentration of the reductant, the silver morphologies change from compact spheres to loose flowers as a result of the increase of reaction rate. Therefore the silver hierarchical structure can be reversibly switched by reaction kinetics. The silver particles synthesized are tested for surface enhanced Raman scattering (SERS) property and the dendritic particles present a remarkable SERS activity. This study shows that reaction kinetics is a powerful tool to tune hierarchical structures of silver particles, which is expected to be transferable to other material systems.
Rapid urbanization on a global scale leads to a number of issues such as arable land occupation and ecological degradation. In this context, analyzing the driving mechanism of urban land expansion in ...complex urban systems facilitates sustainable urban development. Most relevant studies focused on the role of each driving factor and less considered the interaction between different factors spatially and temporally. In order to provide a deep insight into the complex driving mechanism of urban expansion, this study began with an analysis of the spatio-temporal characteristics of urban expansion in the Pearl River Delta (PRD) urban agglomeration in different periods. Then, the driving mechanism of urban expansion intensity (UEI) and urban expansion landscape pattern were analyzed, based on the interaction of different driving factors over space and time. The result showed as follows. (1) During the period of 2000–2008, the overall UEI in the PRD was higher than that of the period of 2008–2015. From 2000 to 2015, the most important source of urban land expansion was farmland, followed by forest land. Meanwhile, the decline in the proportion of outlying expansion type indicated that the urban land has gradually become more compact. (2) From 2000 to 2015, the socio-economic factors had a greater effect on UEI than natural factors. And the interaction between the pairs of factors on UEI during 2000–2008 was significantly stronger than that during 2008–2015. (3) The driving factors of the urban landscape expansion index during the period from 2008 to 2015 were far more powerful than 2000–2008. And the interaction between the pairs of factors on urban landscape expansion index during 2000–2008 was significantly stronger than that during 2008–2015.
Soil nutrients are essential factors that reflect farmland quality. Nitrogen, phosphorus, and potassium are essential elements for plants, while silicon is considered a “quasi-essential” element. ...This study investigated the spatial distribution of plant nutrients in soil in a hilly region of the Pearl River Delta in China. A total of 201 soil samples were collected from farmland topsoil (0–20 cm) for the analysis of total nitrogen (TN), available phosphorus (AP), available potassium (AK), and available silicon (ASi). The coefficients of variation ranged from 47.88% to 76.91%. The NSRs of TN, AP, AK, and ASi were 0.15, 0. 07, 0.12, and 0.13, respectively. The NSRs varied from 0.02 to 0.20. All variables exhibited weak spatial dependence (R2 < 0.5), except for TN (R2 = 0.701). After comparing the prediction accuracy of the different methods, we used the inverse distance weighting method to analyze the spatial distribution of plant nutrients in soil. The uniform spatial distribution of AK, TN overall showed a trend of increasing from northeast to southwest, and the overall spatial distribution of AP and ASi showed that the northeast was higher than the southwest. This study provides support for the delimitation of basic farmland protection areas, the formulation of land use spatial planning, and the formulation of accurate farmland protection policies.
In this paper, we consider the optimization of the quantum circuit for discrete logarithm of binary elliptic curves under a constrained connectivity, focusing on the resource expenditure and the ...optimal design for quantum operations such as the addition, binary shift, multiplication, squaring, inversion, and division included in the point addition on binary elliptic curves. Based on the space-efficient quantum Karatsuba multiplication, the number of CNOTs in the circuits of inversion and division has been reduced with the help of the Steiner tree problem reduction. The optimized size of the CNOTs is related to the minimum degree of the connected graph.
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