Class A plexins (PlxnAs) act as semaphorin receptors and control diverse aspects of nervous system development and plasticity, ranging from axon guidance and neuron migration to synaptic ...organization. PlxnA signaling requires cytoplasmic domain dimerization, but extracellular regulation and activation mechanisms remain unclear. Here we present crystal structures of PlxnA (PlxnA1, PlxnA2, and PlxnA4) full ectodomains. Domains 1–9 form a ring-like conformation from which the C-terminal domain 10 points away. All our PlxnA ectodomain structures show autoinhibitory, intermolecular “head-to-stalk” (domain 1 to domain 4-5) interactions, which are confirmed by biophysical assays, live cell fluorescence microscopy, and cell-based and neuronal growth cone collapse assays. This work reveals a 2-fold role of the PlxnA ectodomains: imposing a pre-signaling autoinhibitory separation for the cytoplasmic domains via intermolecular head-to-stalk interactions and supporting dimerization-based PlxnA activation upon ligand binding. More generally, our data identify a novel molecular mechanism for preventing premature activation of axon guidance receptors.
•Structural studies reveal a major ring-like conformation for PlxnA ectodomains•PlxnA ectodomains make head-to-stalk cis-interactions in vitro and on cell surface•Disruption of PlxnA cis-interactions induces cell and growth cone collapse•PlxnA ectodomain structure and interaction enable autoinhibition and activation
PlxnA signaling, important in nervous system development and plasticity, requires multi-leveled regulation. Kong et al. reveal a novel mechanism for PlxnAs, in which autoinhibition pre- and activation post-ligand binding are achieved through distinct conformations and cis-interactions of the receptor ectodomains.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Genetic factors increase the individual risk of colorectal cancer (CRC); however, the extent to which a healthy lifestyle can offset increased genetic risk is unknown. This study investigated whether ...a healthy lifestyle is associated with lower CRC risk, regardless of genetic risk.
We recruited 390,365 participants without cancer at baseline (2006-2010) from the UK Biobank. The primary outcome was CRC incidence. A healthy lifestyle score constructed using 16 factors of six dimensions (smoking, drinking, body mass index, diet, exercise, and sleep) was categorized into three risk categories: favorable, intermediate, and unfavorable. To calculate the polygenic risk scores (PRSs) of UK Biobank participants, we extracted 454,678 single nucleotide polymorphisms (SNPs) from the UK Biobank and FinnGen Biobank after quality control. Cox proportional hazards regression was performed to evaluate the associations and was expressed as hazard ratios (HRs) with 95% confidence intervals (CIs).
During a median follow-up of 10.90 years, 4,090 new CRC cases were reported in the UK Biobank. The "best-fit" PRSs were constructed using 59 SNPs based on the UK Biobank cohort and FinnGen genome-wide association study summary data (R
= 0.23%) and were divided into low (lowest quintile), intermediate (including second-fourth quintile), and high (highest quintile) genetic risk categories. The multivariate-adjusted Cox model revealed that participants with favorable lifestyles had HRs of 0.66 (95% CI = 0.60-0.72) for developing CRC
. those with unfavorable lifestyles; low genetic risk was associated with a decreased risk of CRC (HR = 0.67, 95% CI =0.61-0.74) compared with those with high genetic risk. The HRs for low genetic risk participants with favorable lifestyles were 0.44 (95% CI =0.36-0.55)
. participants with high genetic risk and unfavorable lifestyles. Among the participants with low, intermediate, or high genetic risk, the HRs of favorable
. unfavorable lifestyles were 0.74, 0.64, and 0.72 (all
< 0.05).
Low genetic risk and a favorable lifestyle were significantly associated with a decreased risk of CRC. A favorable lifestyle was associated with a lower CRC risk, regardless of genetic risk.
Methane-oxidizing bacteria play a central role in greenhouse gas mitigation and have potential applications in biomanufacturing. Their primary metabolic enzyme, particulate methane monooxygenase ...(pMMO), is housed in copper-induced intracytoplasmic membranes (ICMs), of which the function and biogenesis are not known. We show by serial cryo-focused ion beam (cryoFIB) milling/scanning electron microscope (SEM) volume imaging and lamellae-based cellular cryo-electron tomography (cryoET) that these ICMs are derived from the inner cell membrane. The pMMO trimer, resolved by cryoET and subtomogram averaging to 4.8 Å in the ICM, forms higher-order hexagonal arrays in intact cells. Array formation correlates with increased enzymatic activity, highlighting the importance of studying the enzyme in its native environment. These findings also demonstrate the power of cryoET to structurally characterize native membrane enzymes in the cellular context.
Carboxysomes are a paradigm of self-assembling proteinaceous organelles found in nature, offering compartmentalisation of enzymes and pathways to enhance carbon fixation. In α-carboxysomes, the ...disordered linker protein CsoS2 plays an essential role in carboxysome assembly and Rubisco encapsulation. Its mechanism of action, however, is not fully understood. Here we synthetically engineer α-carboxysome shells using minimal shell components and determine cryoEM structures of these to decipher the principle of shell assembly and encapsulation. The structures reveal that the intrinsically disordered CsoS2 C-terminus is well-structured and acts as a universal "molecular thread" stitching through multiple shell protein interfaces. We further uncover in CsoS2 a highly conserved repetitive key interaction motif, IVTG, which is critical to the shell assembly and architecture. Our study provides a general mechanism for the CsoS2-governed carboxysome shell assembly and cargo encapsulation and further advances synthetic engineering of carboxysomes for diverse biotechnological applications.
Background. In recent decades, the GII.4 norovirus genotype has predominated in epidemics worldwide and been associated with an increased rate of evolutionary change. In 2014, a novel GII.17 variant ...emerged and persisted, causing large outbreaks of gastroenteritis in China and sporadic infections globally. The origin, evolution, and transmission history of this new variant are largely unknown. Methods. We generated 103 full capsid and 8 whole-genome sequences of GII.17 strains collected between August 2013 and November 2015 in Guangdong, China. Phylogenetic analyses were performed by integrating our data with those for all publically available GII.17 sequences. Results. The novel emergent lineage GII.17_Kawasaki_2014 most likely originated from Africa around 2001 and evolved at a rate of 5.6 × 10⁻³ substitutions/site/year. Within this lineage, a new variant containing several important amino acid changes emerged around August 2013 and caused extensive epidemics in 2014-2015. The phylodynamic and epidemic history of the GII.17_Kawasaki lineage shows similarities with the pattern observed for GII.4 norovirus evolution. Virus movements from Hong Kong to neighboring coastal cities were frequently observed. Conclusions. Our results provide new insights into GII.17 norovirus evolution and transmission and highlight the potential for a rare norovirus genotype to rapidly replace existing strains and cause local epidemics.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The thermal history of the Dabie-Sulu orogenic belt provides important constraints on the collision process between the South China and North China blocks during the Mesozoic, and possible ...lithospheric thinning event(s) in the eastern North China Block. This study reports on the thermal evolution of the Sulu ultrahigh-pressure metamorphic (UHP) terrane using zircon U‐Pb geochronology and multiple thermochronology methods such as mica and hornblende 40Ar/39Ar, zircon and apatite fission track, and zircon and apatite (U‐Th)/He dating. 40Ar/39Ar and zircon (U‐Th)/He data show that the UHP terrane experienced accelerated cooling during 180–160Ma. This cooling event could be interpreted to have resulted from extensional unroofing of an earlier southward thrusting nappe, or, more likely, an episode of northward thrusting of the UHP rocks as a hanging wall. A subsequent episode of exhumation took place between ca. 125Ma and 90Ma as recorded by zircon (U‐Th)/He data. This event was more pronounced in the northwest section of the UHP terrane, whereas in the southeast section, the zircon (U‐Th)/He system retained Jurassic cooling ages of ca. 180–160Ma. The mid-Cretaceous episode of exhumation is interpreted to have resulted from crustal extension due to the removal of thickened, enriched mantle. A younger episode of exhumation was recorded by apatite fission track and apatite (U‐Th)/He ages at ca. 65–40Ma. Both latter events were linked to episodic thinning of lithosphere along the Sulu UHP terrane in an extensional environment, likely caused by the roll-back of the Western Pacific subduction system.
•The Sulu UHP terrane experienced three episodes of exhumation since 210Ma.•210–160Ma exhumation is consistent with the crustal detachment model.•125–90Ma and 65–40Ma cooling indicates episodic lithospheric thinning.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Modification of target molecules by ubiquitin or ubiquitin-like (Ubl) proteins is generally reversible. Little is known, however, about the physiological function of the reverse reaction, ...deconjugation. Atg8 is a unique Ubl protein whose conjugation target is the lipid phosphatidylethanolamine (PE). Atg8 functions in the formation of double-membrane autophagosomes, a central step in the well-conserved intracellular degradation pathway of macroautophagy (hereafter autophagy). Here we show that the deconjugation of Atg8−PE by the cysteine protease Atg4 plays dual roles in the formation of autophagosomes. During the early stage of autophagosome formation, deconjugation releases Atg8 from non-autophagosomal membranes to maintain a proper supply of Atg8. At a later stage, the release of Atg8 from intermediate autophagosomal membranes facilitates the maturation of these structures into fusion-capable autophagosomes. These results provide new insights into the functions of Atg8−PE and its deconjugation.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
A new single-fed wide dual-band circularly polarized (CP) dielectric resonator antenna (DRA) is presented in this letter. The DRA is excited by a microstrip line through the narrow underneath ...rectangular aperture, and its HE 111 and HE 11δ (2 <; δ <; 3 ) modes are utilized for the dual-band design. To achieve CP fields, two notches are truncated from the cylindrical DRA at φ = 45 ° and 225 ° . A pair of equal arc-shaped slots are used to improve the axial-ratio (AR) and impedance bandwidths. The antenna features impedance bandwidths (|S 11 | <; -10 dB ) of 26.25% and 11.17%, and 3-dB AR bandwidths of 15.8% and 5.02% in the lower and upper bands, respectively. To verify the simulation, the antenna is designed and measured. Reasonable agreement between measured and simulated results is obtained.
•An integrated indicator system for the special assessment of oases (the Oasis Integrated Model) is established.•The Oases Integrated Model was used in the Tarim River Basin (TRB) during ...1990–2020.•The salinity and meteorological indicators play an imperative role in the spatial distribution of artificial and natural oases.•Na ion could better explain the distribution of artificial oases, and Mg ion could better illustrate the distribution of natural oases.
Understanding the distribution of natural and artificial oases is essential for effective management of desert oases and water resources in arid regions. In order to explore characterization of Oases, we developed an ensemble method for the identification of factors influencing the distribution of oases in the upper reaches of the Tarim River Basin (TRB), China. To determine the affected elements of artificial and natural oases in arid lands through multi-function choices from 1990 to 2020, the Oases Integrated Analysis Model (OIAM) was used. The following input data was included in the OIAM: meteorological conditions, salinity, depth of groundwater, time sequence of Landsat images, and environmental chemicals such as calcium, bicarbonate, potassium, sodium, sulfate, and fluoride ions. Several functional methods were used to assess the efficiency of the OIAM. The results indicated that the OIAM consistently outperformed stable Wi (spatial contribution rate to Oases’ indicators). Moreover, the results from OIAM indicated that salinity and meteorological indicators influenced the spatial distribution of artificial and natural oases. For environmental chemical, Na and Mg ions were strongly associated with the distribution of artificial and natural oases, respectively. This indicates that the OIAM model effectively identifies factors influencing the distribution of artificial and natural oases in arid regions, and thus can be applied to other similar regions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This paper analyses the characteristics of geothermal gradient and terrestrial heat flow in the Tianshan‐Altun region on the basis of available published data, such as geothermal gradient, measured ...temperature during oil test producing, rock thermophysics, and heat flow. Based on the steady‐state heat conduction equation, this paper has set up a 3D model by adopting basin modelling method to carry out deep temperature field simulation, with the aim to determine deep thermal structural parameters, the lithospheric thermal thickness, and the crustal contribution rate to the terrestrial heat flow. The geological section of Golmud‐Ejin Banner and the geological section of West Kunlun‐Tarim‐Tianshan were selected to represent the regional temperature and its thermal structure. The results show that the Tianshan‐Altun region has a low temperature geothermal field (averaging temperature gradient 2.2 °C/100 m, heat flow 56.3 mW/m2). The Qaidam Basin has the highest value (averaging 3.2 °C/100 m, 57.4 mW/m2). The lithospheric thermal thickness of the Tianshan‐Altun region is between 110 and 210 km. There are great differences of lithospheric thermal thickness on both sides of the Altun‐Tagh Fault. The west has thicker thermal lithospheric thickness (160–210 km) than the east (110–180 km). The contribution rate of the crust to the terrestrial heat flow decreases in the following order: the Qaidam Basin, the Jiudong Basin, the Jungger Basin, the Tarim Basin, and the Tuha Basin. Sedimentary basins have higher temperature and thinner thermal lithosphere than tectonic orogens when at the same depth. It can be observed that great thermal differences exist on both sides of the Altun‐Tagh Fault. There are relative similarities of low temperature, deeper thermal structure, and thicker lithospheric thermal thickness among the Tarim Basin, the Junggar Basin, and the Yining Basin in a wide geological area because of their shared deep geological basement. The Qaidam Basin and the Hexi Corridor Basin, which are located to the east of Altun‐Tagh Fault, have higher thermal background.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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