The non-receptor protein tyrosine phosphatase (PTP) SHP2, encoded by PTPN11, plays an essential role in RAS-mitogen-activated protein kinase (MAPK) signaling during normal development. It has been ...perplexing as to why both enzymatically activating and inactivating mutations in PTPN11 result in human developmental disorders with overlapping clinical manifestations. Here, we uncover a common liquid-liquid phase separation (LLPS) behavior shared by these disease-associated SHP2 mutants. SHP2 LLPS is mediated by the conserved well-folded PTP domain through multivalent electrostatic interactions and regulated by an intrinsic autoinhibitory mechanism through conformational changes. SHP2 allosteric inhibitors can attenuate LLPS of SHP2 mutants, which boosts SHP2 PTP activity. Moreover, disease-associated SHP2 mutants can recruit and activate wild-type (WT) SHP2 in LLPS to promote MAPK activation. These results not only suggest that LLPS serves as a gain-of-function mechanism involved in the pathogenesis of SHP2-associated human diseases but also provide evidence that PTP may be regulated by LLPS that can be therapeutically targeted.
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•Disease-associated mutations endow SHP2 liquid-liquid phase separation capability•SHP2 LLPS is driven by electrostatic interactions mediated by PTP domain•SHP2 allosteric inhibitors block SHP2 LLPS by locking SHP2 in closed conformation•Mutant SHP2 can recruit and activate WT SHP2 in LLPS to promote MAPK activation
Disease-associated mutants of a critical phosphatase in the RAS-MAPK pathway undergo phase separation through a dominant gain-of-function mechanism, explaining how both enzymatically activating and inactivating mutations dysregulate the pathway and can be therapeutically targeted.
Diseases caused by Rickettsiales bacteria are a global public health problem. To better understand the diversity and origins of Rickettsiales infection in humans and animals, we sampled 134 febrile ...patients, 173 rodents and 43 shrews, as well as 358 ticks, from two cities in Jiangsu and Jiangxi provinces, China. Our data revealed a relatively high prevalence of scrub typhus cases in both localities. In addition, both serological tests and genetic analysis identified three patients infected with Anaplasma bovis, Rickettsia monacensis, and Orientia tsutsugamushi bacteria. Molecular epidemiological investigation revealed the co-circulation of multiple species of Rickettsiales bacteria in small mammals and ticks in both provinces, potentially including novel bacterial species. In sum, these data demonstrate the ongoing importance of Rickettsiales infection in China and highlight the need for the regular surveillance of local arthropods, mammals and humans.
We report the first neutral and water-soluble polymer capable of strong mitochondrial targeting
in vitro
and
in vivo
, zwitterionic poly2-(
N
-oxide-
N
,
N
-diethylamino)ethyl methacrylate (OPDEA). ...OPDEA is quickly internalized
via
macropinocytosis by various cancer cells and transferred into the mitochondria, which slightly lowers the mitochondrial membrane potential as determined by the JC-1 assay.
A neutral water-soluble
N
-oxide polymer can expeditiously enter a cell's mitochondria, and even reach the mitochondria after
i.v.
injection, making it an ideal delivery carrier.
Effective anticancer nanomedicines need to exhibit prolonged circulation in blood, to extravasate and accumulate in tumours, and to be taken up by tumour cells. These contrasting criteria for ...persistent circulation and cell-membrane affinity have often led to complex nanoparticle designs with hampered clinical translatability. Here, we show that conjugates of small-molecule anticancer drugs with the polyzwitterion poly(2-(N-oxide-N,N-diethylamino)ethyl methacrylate) have long blood-circulation half-lives and bind reversibly to cell membranes, owing to the negligible interaction of the polyzwitterion with proteins and its weak interaction with phospholipids. Adsorption of the polyzwitterion-drug conjugates to tumour endothelial cells and then to cancer cells favoured their transcytosis-mediated extravasation into tumour interstitium and infiltration into tumours, and led to the eradication of large tumours and patient-derived tumour xenografts in mice. The simplicity and potency of the polyzwitterion-drug conjugates should facilitate the design of translational anticancer nanomedicines.
Argument remains as to whether birds have lost genes compared with mammals and non-avian vertebrates during speciation. High quality-reference gene sets are necessary for precisely evaluating gene ...gain and loss. It is essential to explore new reference transcripts from large-scale de novo assembled transcriptomes to recover the potential hidden genes in avian genomes.
We explored 196 high quality transcriptomic datasets from five bird species to reconstruct transcripts for the purpose of discovering potential hidden genes in the avian genomes. We constructed a relatively complete and high-quality bird transcript database (1,623,045 transcripts after quality control in five birds) from a large amount of avian transcriptomic data, and found most of the presumed missing genes (83.2%) could be recovered in at least one bird species. Most of these genes have been identified for the first time in birds. Our results demonstrate that 67.94% genes have GC content over 50%, while 2.91% genes are AT-rich (AT% > 60%). In our results, 239 (53.59%) genes had a tissue-specific expression index of more than 0.9 in chicken. The missing genes also have lower Ka/Ks values than average (genome-wide: Ka/Ks = 0.99; missing gene: Ka/Ks = 0.90; t-test = 1.25E-14). Among all presumed missing genes, there were 135 for which we did not find any meaningful orthologues in any of the 5 species studied.
Insufficient reference genome quality is the major reason for wrongly inferring missing genes in birds. Those presumably missing genes often have a very strong tissue-specific expression pattern. We show multi-tissue transcriptomic data from various species are necessary for inferring gene family evolution for species with only draft reference genomes.
Recrystallization induced in situ nanostructure formation was used as a new means to obtain high performance polycrystalline thermoelectric materials, which was realized by a simple hot forging ...process to the coarse-grained Bi0.5Sb1.5Te3 alloys. The pole figure measurement showed that the oriented textures were weakened or eliminated after hot forging of the alloys with a quasi-layered crystal structure, implying the presence of deformation recrystallization. Transmission electron microscopy observation revealed the recrystallization induced in situ nanostructures and high density of defects in the hot forged samples. Transport property measurements indicated that the hot forged samples had both increased electrical power factor and reduced thermal conductivity, compare to the initial alloys without hot forging. The maximum ZT values of 1.3 at room temperature were reproducibly obtained for the hot forged samples, suggesting that the simple new method can be applied for large scale production of high performance polycrystalline thermoelectric materials with in situ nanostructures.
Cryptococcal meningitis (CM) is one of the most common opportunistic infections caused by Cryptococcus neoformans in human immunodeficiency virus (HIV)-infected patients, and is complicated with ...significant morbidity and mortality. This study retrospectively analyzed the clinical features, characteristics, treatment, and outcomes of first-diagnosed HIV-associated CM after 2-years of follow-up.
Data from all patients (n = 101) of HIV-associated CM hospitalized in Shanghai Public Health Clinical Center from September 2013 to December 2016 were collected and analyzed using logistic regression to identify clinical and microbiological factors associated with mortality.
Of the 101 patients, 86/99 (86.9%) of patients had CD4 count <50 cells/mm, 57/101 (56.4%) were diagnosed at ≥14 days from the onset to diagnosis, 42/99 (42.4%) had normal cerebrospinal fluid (CSF) cell counts and biochemical examination, 30/101 (29.7%) had concomitant Pneumocystis (carinii) jiroveci pneumonia (PCP) on admission and 37/92 (40.2%) were complicated with cryptococcal pneumonia, 50/74 (67.6%) had abnormalities shown on intracranial imaging, amongst whom 24/50 (48.0%) had more than one lesion. The median time to negative CSF Indian ink staining was 8.50 months (interquartile range, 3.25-12.00 months). Patients who initiated antiretroviral therapy (ART) before admission had a shorter time to negative CSF Indian ink compared with ART-naïve patients (7 vs. 12 months, χ = 15.53, P < 0.001). All-cause mortality at 2 weeks, 8 weeks, and 2 years was 10.1% (10/99), 18.9% (18/95), and 20.7% (19/92), respectively. Coinfection with PCP on admission (adjusted odds ratio AOR, 3.933; 95% confidence interval CI, 1.166-13.269, P = 0.027) and altered mental status (AOR, 9.574; 95% CI, 2.548-35.974, P = 0.001) were associated with higher mortality at 8 weeks.
This study described the clinical features and outcomes of first diagnosed HIV-associated CM with 2-year follow-up data. Altered mental status and coinfection with PCP predicted mortality in HIV-associated CM.
Numerous studies have focused on lymphoma among patients infected with human immunodeficiency virus (HIV). However, little is known about the treatment options and survival rate of lymphoma in the ...Chinese people living with HIV (PLHIV). Our study aimed to investigate the prognosis and compare outcome of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) with standard cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab(R-CHOP) as front line therapy for PLHIV with diffuse large B-cell lymphoma (DLBCL) receiving modern combined antiretroviral therapy (cART).
A retrospective analysis evaluating PLHIV with DLBCL was performed in Shanghai Public Health Clinical Center from July 2012 to September 2019. The demographic and clinical data were collected, and overall survival (OS) and progression-free survival (PFS) analyses of patients receiving R-CHOP or DA-EPOCH-R therapy were performed by Kaplan-Meier analysis. Additionally, a Cox multiple regression model was constructed to identify related factors for OS.
A total of 54 eligible patients were included in the final analysis with a median follow-up of 14 months (interquartile range IQR: 8-29 months). The proportion of high international prognostic index (IPI) patients was much larger in the DA-EPOCH-R group (n = 29) than that in the R-CHOP group (n = 25). The CD4 cell counts and HIV RNA levels were not significantly different between the two groups. The 2-year OS for all patients was 73%. However, OS was not significantly different between the two groups, with a 2-year OS rate of 78% for the DA-EPOCH-R group and 66% for the R-CHOP group. Only an IPI greater than 3 was associated with a decrease in OS, with a hazard ratio of 5.0. The occurrence of grade 3 and 4 adverse events of chemotherapy was not significantly different between the two groups.
Outcomes of R-CHOP therapy do not differ from those of DA-EPOCH-R therapy. No HIV-related factors were found to be associated with the OS of PLHIV in the modern cART era.
Three types of calli were induced from
Origanum vulgare
(
O. vulgare
) aseptic seedlings, and the friable calli with white appearance and high growth rate were further screened and used to develop ...cell suspension culture to produce polyphenols. Murashige and Skoog (MS) medium with 3.0 mg/L Kinetin (KT) and 0.5 mg/L 2,4-dichlorophenoxy acetic acid (2,4-D) was suitable for both
O. vulgare
cells growth and polyphenols accumulation. To further enhance the polyphenols accumulation,
O. vulgare
cells were treated by phenylalanine (Phe) feeding and salicylic acid (SA) elicitation. Compared with the individual Phe feeding and SA elicitation, SA elicitation combined with Phe feeding showed a much better promotion effect on the polyphenols synthesis in
O. vulgare
cells, especially rosmarinic acid (RosA) accumulation. With the combined treatment of 200 µM SA and 100 µM Phe, total polyphenols content and yield were 41.36 mg/g and 752.93 mg/L, respectively. RosA content and yield reached 31.25 mg/g and 570.37 mg/L, which were 5.44 and 5.47 times that of the control. Furthermore, the total polyphenols extracted from the cultured cells treated by SA elicitation combined with Phe feeding displayed a much higher antioxidant capacity than that of untreated cells, meanwhile its 1,1-diphenyl-2-trinitrophenyl hydrazine (DPPH) and superoxide anion radical-scavenging activity were much stronger than that of vitamin C. What’s more, our results also showed that RosA was the principal contributor to the fine antioxidant capacity of the total polyphenols extracted from the SA and Phe treated cells. Our research indicated that SA elicitation combined with Phe feeding significantly improved the polyphenols yield and antioxidant capacity of the cultured
O. vulgare
cells, and therefore has a promising application prospect in natural polyphenols production.
Disulfiram (DSF) exerts potent anticancer activity via the formation of chelates with copper or zinc ions in tumor tissues, but the low abundance of these ions in the tumor cannot sustain its ...antitumor activity. Herein, we show that a zwitterionic water-soluble N-oxide polymer, poly2-(N-oxide-N,N-dimethylamino)ethyl methacrylate (OPDMA), can complex cupric ions and form nanogels (OPDMA/Cu), which efficiently deliver copper ions to tumor tissue to potentiate DSF significantly for effective antitumor therapy.
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