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Endoplasmic reticulum (ER) and lysosomes coordinate a network of key cellular processes including unfolded protein response (UPR) and autophagy in response to stress. How ER stress is signaled to lysosomes remains elusive. Here we find that ER disturbance activates chaperone-mediated autophagy (CMA). ER stressors lead to a PERK-dependent activation and recruitment of MKK4 to lysosomes, activating p38 MAPK at lysosomes. Lysosomal p38 MAPK directly phosphorylates the CMA receptor LAMP2A at T211 and T213, which causes its membrane accumulation and active conformational change, activating CMA. Loss of ER stress-induced CMA activation sensitizes cells to ER stress-induced death. Neurotoxins associated with Parkinson’s disease fully engages ER-p38 MAPK–CMA pathway in the mouse brain and uncoupling it results in a greater loss of SNc dopaminergic neurons. This work identifies the coupling of ER and CMA as a critical regulatory axis fundamental for physiological and pathological stress response. The endoplasmic reticulum (ER) and lysosome are central to cellular stress responses, but it is unclear how ER stress is signaled to lysosomes. Here the authors show that ER stress activates chaperone-mediated autophagy (CMA) via direct phosphorylation of the CMA receptor LAMP2A by the lysosomal p38 MAPK.

Background Targeting mitochondrial oncoproteins presents a new concept in the development of effective cancer therapeutics. ATAD3A is a nuclear-encoded mitochondrial enzyme contributing to mitochondrial dynamics, cholesterol metabolism, and signal transduction. However, its impact and underlying regulatory mechanisms in cancers remain ill-defined. Methods We used head and neck squamous cell carcinoma (HNSCC) as a research platform and achieved gene depletion by lentiviral shRNA and CRISPR/Cas9. Molecular alterations were examined by RNA-sequencing, phospho-kinase profiling, Western blotting, RT-qPCR, immunohistochemistry, and immunoprecipitation. Cancer cell growth was assessed by MTT, colony formation, soft agar, and 3D cultures. The therapeutic efficacy in tumor development was evaluated in orthotopic tongue tumor NSG mice. Results ATAD3A is highly expressed in HNSCC tissues and cell lines. Loss of ATAD3A expression suppresses HNSCC cell growth and elicits tumor regression in orthotopic tumor-bearing mice, whereas gain of ATAD3A expression produces the opposite effects. From a mechanistic perspective, the tumor suppression induced by the overexpression of the Walker A dead mutant of ATAD3A (K358) produces a potent dominant-negative effect due to defective ATP-binding. Moreover, ATAD3A binds to ERK1/2 in the mitochondria of HNSCC cells in the presence of VDAC1, and this interaction is essential for the activation of mitochondrial ERK1/2 signaling. Most importantly, the ATAD3A-ERK1/2 signaling axis drives HNSCC development in a RAS-independent fashion and, thus, tumor suppression is more effectively achieved when ATAD3A knockout is combined with RAS inhibitor treatment. Conclusions These findings highlight the novel function of ATAD3A in regulating mitochondrial ERK1/2 activation that favors HNSCC development. Combined targeting of ATAD3A and RAS signaling may potentiate anticancer activity for HNSCC therapeutics.

The dominant mode of interannual variability in the Antarctic sea ice is presented by a significant seesaw structure with an out-of-phase relationship between the sea ice anomaly in the Ross-Amundsen Sea and the Weddell Sea around the Antarctic continent, which is commonly called the “Antarctic dipole” (ADP). The present work shows that the relationship of El Niño-Southern Oscillation (ENSO) during its mature phase and the ADP in the subsequent austral cold season (June to November) underwent a significant decadal shift around the early 2000s with the correlation coefficients between them being reduced from 0.72 in 1979–2001 to 0.21 in 2002–2020. Further study suggests that this decadal shift is mainly due to the different responses of sea surface temperature (SST) in the Tasman Sea to ENSO. Before the early 2000s, the SST around the Tasman Sea was highly responsive to ENSO variability. Such SST anomalies persisted to the subsequent austral cold season and stimulated a downstream wave train similar to the Pacific South American pattern (PSA). Subsequently, a dipole pattern was induced with water vapor convergence (divergence) over the Ross-Amundsen Sea (the Weddell Sea), causing more (less) downward longwave radiation over there. Consequently, decreased (increased) SIC anomaly occurred in the Ross-Amundsen Sea (the Weddell Sea), favoring the formation of the ADP. After the early 2000s, the SST anomalies in the Tasman Sea in response to ENSO reduced notably, and therefore there was no significant ENSO signal transmitting to the ADP region to influence the sea ice change over there, resulting in the weakening of the ENSO-ADP relationship.

The climate response to the Tibetan Plateau (TP) snow cover (TPSC) has been receiving extensive concern. However, relatively few studies have been devoted to revealing the potential factors that can contribute to the TPSC interannual variability, especially during boreal summer. This study finds that the May Southern Hemisphere (SH) annular mode (SAM), the dominating mode of atmospheric circulation variability in the SH extratropics, exhibits a significant positive relationship with the interannual variations in western TPSC during boreal summer. Observational analysis and numerical experiments manifest that the signal of the May SAM can be “prolonged” by a meridional Indian Ocean tripole (IOT) sea surface temperature anomaly (SSTA) via atmosphere–ocean interaction. The IOT SSTA pattern persists into the following summer and excites anomalous local-scale zonal–vertical circulation. Subsequently, a tropical dipole rainfall (TDR) mode is induced with precipitation anomalies between the tropical western Indian Ocean and the eastern Indian Ocean–Maritime Continent. Rossby wave ray tracing diagnosis reveals that the wave energies, generated by the latent heat release of the TDR mode, can propagate northward into the western TP. As a response, abnormal cyclone (or anticyclone) and upward (or downward) movement are triggered over the western TP, providing favorable dynamical conditions for more (or less) TPSC. Moreover, the strong May SAM is usually followed by a cold air temperature anomaly over the western TP in summer, which is unfavorable for snow-cover melting, and vice versa. In brief, the IOT SSTA plays an “ocean bridge” role and the TDR mode plays an “atmosphere bridge” role in the process of the May SAM impacting the following summer TPSC variability. The results may provide new insight into the cross-equatorial propagation of the SAM influence.

An eight-week experiment was conducted to evaluate the effects of eight light intensities (0, 0.83, 1.61, 8.17, 15.89, 31.38, 63.69, and 124.31 μmol m -2 s -1 ) on the survival, growth, antioxidant, molting-related and apoptosis-related gene expression of juvenile swimming crab Portunus trituberculatus . The results showed that the survival rate of crabs was the highest under the light intensities of 8.17 and 15.89 μmol m -2 s -1 . Under this light intensity, the crabs had the lowest hemolymph glucose (GLU) but the highest triglyceride (TG) content. The crabs in these treatments also had the highest total antioxidant capacity (T-AOC), superoxide dismutase (SOD), catalase (CAT) activities, and the lowest malondialdehyde (MDA) content. The growth performance (including weight gain and specific growth rate) and molting frequency of crabs increased with increasing light intensity. The improved growth performance and molting of 8.17 and 15.89 μmol m -2 s -1 groups were also accompanied by up-regulated of the retinoid-X receptor ( rxr ), ecdysone receptor ( ecr ), nuclear receptor E75 ( e75 ) gene expression, and down-regulated molt-inhibiting hormone ( mih ) gene expression. In addition, suboptimal light intensity (0, 0.83, 63.69, and 124.31 μmol m -2 s -1 ) significantly up-regulated the expression of apoptosis-related genes including c-Jun N-terminal kinase ( jnk ), tumor suppressor p53 ( p53 ), and B-cell lymphoma-2 ( bcl-2 ). Taken together, the suitable light intensity for the juvenile P. trituberculatus was estimated to be 9.96 μmol m -2 s -1 .

A 19-day experiment was conducted to investigate the optimal light intensity and photoperiod combination for larval swimming crabs Portunus trituberculatus in terms of survival, development, and apoptosis-related gene expression. Two photoperiods, i.e., 12 and 18 h photophases, and three light intensities, i.e., 126.08, 173.17, and 191.53 μmol m−2 s−1, were used in the study. The results showed that the cumulative survival rate (CSR) of larvae decreased with the increasing light intensity, and the adverse effect of high light intensity was only observed in long photophase groups. On the contrary, a long photophase and low light intensity elevated the CSR from zoea III to juvenile crabs. A long photophase also accelerated the development of zoea III larvae and upregulated the molting-related (ecr and rxr) and apoptosis-related (jnk, p53, and bcl-2) gene expressions. Taken together, the present study suggested that the light intensity and the photoperiod had a combined effect on P. trituberculatus larvae. The optimal light intensity and photoperiod for P. trituberculatus larvae were 126.08 μmol m−2 s−1 and an 18 h photophase, respectively.

The relationship between the seasonal Antarctic sea ice concentration (SIC) variability and the extratropical southern Indian Ocean (SIO) sea surface temperature (SST) is explored in this study. It is found that the Antarctic SIC in a wide band of the SIO, Ross Sea, and Weddell Sea is significantly related to an SIO dipole (SIOD) SST anomaly on the interannual time scale during austral spring. This relationship is linearly independent of the effects of El Niño–Southern Oscillation, the Indian Ocean dipole, and the Southern Hemisphere annular mode. The positive phase of the SIOD, with warm SST anomalies off of western Australia and cold SST anomalies centered around 60°E in high latitudes, stimulates a downstream wave train that induces large-scale cyclonic circulations over the SIO and the Ross and Weddell Seas. Subsequently, anomalous horizontal moisture advection causes water vapor divergence, changes the surface energy budget, and cools the underlying ocean, which leads to the increased SIC over the region in the SIO, Ross Sea, and Weddell Sea. This SIOD SST anomaly reached a record low during the austral spring of 2016 and promoted the prominent wave pattern at high latitudes, contributing to the dramatic decline of sea ice in the 2016 spring. In addition, the proportion of the SIC trend that is linearly congruent with the SIOD SST trend during austral spring is quantified. The results indicate that the trend in the SIOD SST may account for a significant component of the 1979–2014 SIC trend in the Ross Sea with the congruency peaking at 60%.

Pathogenic germline mutations occurring in the BRCA1 (MIM:113705) and BRCA2 (MIM: 600185), which always result in truncated protein or nonsense-mediated mRNA decay, have been identified to increase the risk of hereditary breast, ovarian, pancreatic, prostate, and melanoma cancers. Recent studies show that BRCA1/2 germline mutations also contribute to half of all hereditary breast and ovarian cancer (HBOC). In this case series, we reported a novel frameshift mutation of the BRCA1 gene. This novel frameshift mutation occurs in exon10 of BRCA1 and may result in a lack of the serine cluster domain and BRCA1 C-terminus domain, which mediates the function of BRCA1 in DNA repair and are responsible for activation function of BRCA1. The mutation was present in a Chinese hereditary male/female breast and ovarian cancer family characterized by a high incidence of breast cancer and/or ovarian cancer among the relatives and by a high incidence of triple negative breast cancer (TNBC). Our findings speculate that BRCA1 E1148Rfs*7 mutation may be related to the occurrence of HBOC and even TNBC. Interestingly, three cases of TNBC with this novel BRCA1 mutation in this case series showed a good disease-free survival, one of them has a disease-free survival up to 7 years. Therefore, further study is required to confirm that whether this mutation is associated with good prognosis of HBOC.

Density functional theory (DFT) methods including LC-ωPBE, CAM-B3LYP, B3LYP, and B3LYP-D3, combined with double Zeta all-electron DZVP basis set, have been employed to conduct computational investigations on nickel-mediated reaction of o-carboranylzirconacycle, n-hexene, and 2-bromophenyltrimethylsilylacetylene in toluene solution. A multistep mechanism leading to the C,C,B-substituted carborane-fused tricyclics, including (1) sequential insertion of alkene and alkyne into Ni–C bonds; (2) double 1,2-migration of the TMS group; (3) B–H activation assisted by Cs2CO3 additive; and (4) reduction cage B–C (sp2) coupling, was proposed. Among these steps, the B–H activation of o-carborane was located as rate-determining step (RDS). With assistance of Cs2CO3 additive (replaced by K2CO3 in simulation), the RDS free-energy barrier at PCM-LC-ωPBE/DZVP level was calculated to be 23.1–23.9 kcal·mol−1, transferring to a half-life of 3.9–15.1 h at 298 K. The predicted half-life coincides well with 80% experimental yields of C,C,B-substituted carborane-fused tricyclics after 12 h. Kinetic data obtained by employing LC-ωPBE method also reproduced the experimental diastereoselective ratio well. Various B–H activation pathways with and without Cs2CO3 additive were taken into consideration, which illustrates Cs2CO3 as an essential guarantee for smooth occurrence of this reaction at room temperature.

In this study, the oxygen-tolerant mutant strain Clostridium sp. Aeroto-AUH-JLC108 was found to produce indole when grown aerobically. The tnaA gene coding for tryptophanase responsible for the production of indole was cloned. The tnaA gene from Aeroto-AUH-JLC108 is 1677 bp and has one point mutation (C36G) compared to the original anaerobic strain AUH-JLC108. Phylogenetic analyses based on the amino acid sequence showed significant homology to that of TnaA from Flavonifractor. Furthermore, we found that the tnaA gene also exhibited cysteine desulfhydrase activity. The production of hydrogen sulfide (H2S) was accompanied by decrease in the amount of the dissolved oxygen in the culture medium. Similarly, the amount of indole produced by strain Aeroto-AUH-JLC108 obviously decreased the oxidation–reduction potential (ORP) in BHI liquid medium. The results demonstrated that production of indole and H2S helped to form a hypoxic microenvironment for strain Aeroto-AUH-JLC108 when grown aerobically.