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A novel ionic silicone polymer is introduced in perovskites to achieve stable inverted perovskite solar cells with high efficiency by deep defect passivation and shallow vacancy repair simultaneously.

We developed a nickel-catalyzed remote arylalkylation of unactivated alkenes via kinetically and thermodynamically disfavored 6- and 7-membered nickelacycles.

We report herein an intermolecular syn-arylalkylation and alkenylalkylation of alkenyl amines with two different organohalides (iodides and bromides) using Ni(II) catalyst. The cleavable bidentate quinolinamide is utilized after extensive directing group screening to enable olefin difunctionalization with high levels of regio-, chemo-, and diastereocontrol. This general and practical protocol is compatible with α- or β-substituted terminal alkenes and internal alkenes, providing rapid access to branched aliphatic amines bearing two skipped and vicinal stereocenters with high diastereoselectivities that would otherwise be difficult to synthesize.

Sb2S3 is a promising candidate for the flexible solar cells or the top subcells in tandem solar cells due to its wide-bandgap, less toxic, acceptable cost and progressive power conversion efficiency (PCE). However, the poor quality and high trap states of Sb2S3 films limit the device performance further enhancement. Herein, we adopt a multidentate ionic liquid, tetramethylammonium hexafluorophosphate ([TMA][PF6]) as a novel additive to address this issue. The octahedral [PF6]− contains six different oriented fluorine atoms with the lone pair electrons, which could coordinate with Sb atoms due to the multidentate anchoring. Thus, the high-quality Sb2S3 film with low trap states has been achieved. Moreover, the Fermi level of the Sb2S3 film has been upshifted, thereby showing an effective charge transfer. As a result, all photovoltaic parameters of the optimized Sb2S3 devices are obviously enhanced, boosting the final PCE from 4.43 (control device) to 6.83 %. Our study about the multidentate anchoring is manifested to be an effective method to enhance the Sb2S3 device performance.

Background Rhesus macaque (Macaca mulatta) is commonly used in biomedical research because of its high similarity with human beings, and understand the genetic diversity of wild macaques is necessary. Although there have been many genetic diversity reports on this species, there is still a deficiency of comprehensive understanding of genetic background due to limited sample range, especially, involving Qinghai-Tibet Plateau samples. Here, extensive sampling is conducted in macaque populations across almost all distribution areas, including China, India, Vietnam, Bangladesh, Nepal and Myanmar. It also focuses on genetic differentiation, migration diffusion and population dynamics in western China. Results 57 unique haplotypes were obtained from 452 samples in 34 geographical areas and 60 mtDNA haplotypes were downloaded, resulting in a total of 117 haplotypes covering almost all macaque distribution areas. The phylogenetic analysis exhibited three major haplogroups (Clade Ⅰ~Ⅲ) with obvious geographical distribution patterns. Clade Ⅰ is mainly composed of macaques from western China, Clade Ⅱ is from central and eastern China, Vietnam, India and Nepal, and Clade Ⅲ is from Bangladesh and Myanmar. The divergence age among three Clade is 1.67 ~ 2.81 Ma. Further, Clade Ⅰ from western China is divided into five obviously divergent subclades (Sub A-E). We found macaques in western Sichuan contain two morphology subspecies: M. m. lasiotus and M. m. vestita, different from the previous one subspecies (M. m. lasiotus) report. Notably, comprehensive analysis suggested that the populations in southeastern Sichuan, eastern Yunnan and Guizhou (Sub B) may be an independent new subspecies. We also found Bangladesh may be a re-radiation central of the whole rhesus macaques, and three possible radiation routes of rhesus macaques entering China were speculated: from Yunnan to western China, from Guangxi to central and eastern China, and along the coastline to Hainan. In addition, demographic history analysis revealed the macaque population is stable and has not experienced significant population expansion. Conclusions In conclusion, this study investigated the distribution patterns of different subspecies of macaques, and proposed possible radiation routes. To our knowledge, it’s the first comprehending analysis based on almost all distribution areas of rhesus macaques.

Although DNA damage repair plays a critical role in cancer chemotherapy, the function of lncRNAs in this process remains largely unclear. In this study, in silico screening identified H19 as an lncRNA that potentially plays a role in DNA damage response and sensitivity to PARP inhibitors. Increased expression of H19 is correlated with disease progression and with a poor prognosis in breast cancer. In breast cancer cells, forced expression of H19 promotes DNA damage repair and resistance to PARP inhibition, whereas H19 depletion diminishes DNA damage repair and increases sensitivity to PARP inhibitors. H19 exerted its functional roles via direct interaction with ILF2 in the cell nucleus. H19 and ILF2 increased BRCA1 stability via the ubiquitin-proteasome proteolytic pathway via the H19- and ILF2-regulated BRCA1 ubiquitin ligases HUWE1 and UBE2T. In summary, this study has identified a novel mechanism to promote BRCA1-deficiency in breast cancer cells. Therefore, targeting the H19/ILF2/BRCA1 axis might modulate therapeutic approaches in breast cancer.

Metal halide perovskites have attracted great attention and are rapidly developing mainly due to their excellent optoelectronic properties. Currently, the efficiency of inverted (p–i–n) PSCs is around 23%, which is catching up with that of the regular structured devices. Short-term and low-efficiency operational stability are the main obstacles to the commercialization of PSCs. Although many modified materials have been proven to effectively enhance device performance, they do not satisfy operational stability at high efficiency. Here, we propose a multidentate-cross-linking strategy, which uses multi-branched and adequate chemical anchor sites in three-dimensional star-polymer to directly chelate perovskite materials in multiple directions, thereby regulating the morphology of perovskite, passivating defects at surface/GBs, inhibiting the non-radiative recombination, and improving the stability of the device. As a result, the modified PSC achieves a 22.74% efficiency, which is one of the highest values reported for the inverted PSCs. Meanwhile, the encapsulated modified device exhibits significant advancement of operational stability with 93% of the initial efficiency (∼22.00%) under maximum power point tracking at 45 °C for 1000 h, and an estimated T80 (time to retain 80% of the initial efficiency) lasted nearly 4000 h. The three-dimensional star-polymer multidentate-cross-linking strategy has proved to be a new direction for realizing commercial applications of PSCs with excellent operational stability for high-efficiency devices.

The performance enhancement of inverted perovskite solar cells applying nickel oxide (NiO

The competition between charge recombination and extraction principally affects the fill factor (FF) and power conversion efficiency (PCE) of planar thin-film solar cells. In Sb2S3 thin-film solar cells, the electrocharge recombination and extraction n transport layer (ETL) plays a significant role in electron extraction and determination of Sb2S3 film absorber quality. Herein, a TiO2 ETL is strategically modified using an inorganic salt zinc halide (i.e., ZnCl2, ZnBr2, ZnI2), which simultaneously improves the electronic properties of TiO2 and promotes the growth of Sb2S3 films with larger grain size and higher crystallinity. The experimental results and theoretical calculations further reveal that the zinc halide can interact with TiO2 and simultaneously bond strongly with the upper Sb2S3 film, which creates a unique pathway for electron transfer, passivates the trap states, and alleviates the recombination losses effectively. As a result, an average PCE of 6.87 ± 0.11% and the highest PCE of 7.08% have been attained with an improved FF from 51.22 to 61.61% after ZnCl2 introduction. Additionally, introduction of ZnCl2 helps the unencapsulated devices to maintain 93% of their original performance after 2400 h of storage in a nitrogen-filled glovebox. This work develops an effective route for the optimization of ETLs and defect healing using simple and low-cost inorganic salts.

A star-shaped polymer enables inverted perovskite solar cells with efficiency over 22% and a very high fill factor of 0.862., Stabilizing high-efficiency perovskite solar cells (PSCs) at operating conditions remains an unresolved issue hampering its large-scale commercial deployment. Here, we report a star-shaped polymer to improve charge transport and inhibit ion migration at the perovskite interface. The incorporation of multiple chemical anchor sites in the star-shaped polymer branches strongly controls the crystallization of perovskite film with lower trap density and higher carrier mobility and thus inhibits the nonradiative recombination and reduces the charge-transport loss. Consequently, the modified inverted PSCs show an optimal power conversion efficiency of 22.1% and a very high fill factor (FF) of 0.862, corresponding to 95.4% of the Shockley-Queisser limited FF (0.904) of PSCs with a 1.59-eV bandgap. The modified devices exhibit excellent long-term operational and thermal stability at the maximum power point for 1000 hours at 45°C under continuous one-sun illumination without any significant loss of efficiency.

The competition between charge recombination and extraction principally affects the fill factor (FF) and power conversion efficiency (PCE) of planar thin-film solar cells. In Sb

Summary Catalytic difunctionalization of alkenes has been a prominent research theme in recent years. Here, we develop a removable bidentate picolinamide-assisted regioselective dicarbofunctionalization of homoallylic amines with organohalides and arylboronic acids. The catalytic system, using cost-effective and air-stable Ni(II) precatalyst, which could be activated by arylboronic acids, provides access to the regioselective diarylation and arylalkylation of unactivated alkenes. This reaction is compatible with α- or β-substituted terminal alkenes and internal alkenes and exhibits excellent functional group and heterocycle tolerance. Preliminary mechanistic studies suggest that the reaction proceeds via a NiI/NiIII catalytic cycle rather than a Ni0/NiII cycle. Notably, the general and practical protocol developed herein represents, to the best of our knowledge, the first example of Ni-catalyzed 3-component 2,1-diarylation and arylalkylation of alkenes with arylboronic acids and organohalides.

Tamoxifen-resistant (TAMR) estrogen receptor-positive (ER+) breast cancer is characterized by elevated Erb-B2 receptor tyrosine kinase 2 (ERBB2) expression. However, the underlying mechanisms responsible for the increased ERBB2 expression in the TAMR cells remain poorly understood. Herein, we reported that the ERBB2 expression is regulated at the post-transcriptional level by miR26a/b and the RNA-binding protein human antigen R (HuR), both of which associate with the 3′-UTR of the ERBB2 transcripts. We demonstrated that miR26a/b inhibits the translation of ERBB2 mRNA, whereas HuR enhances the stability of the ERBB2 mRNA. In TAMR ER+ breast cancer cells with elevated ERBB2 expression, we observed a decrease in the level of miR26a/b and an increase in the level of HuR. The forced expression of miR26a/b or the depletion of HuR decreased ERBB2 expression in the TAMR cells, resulting in the reversal of tamoxifen resistance. In contrast, the inactivation of miR26a/b or forced expression of HuR decreased tamoxifen responsiveness of the parental ER+ breast cancer cells. We further showed that the increase in HuR expression in the TAMR ER+ breast cancer cells is attributable to an increase in the HuR mRNA isoform with shortened 3′-UTR, which exhibits increased translational activity. This shortening of the HuR mRNA 3′-UTR via alternative polyadenylation (APA) was observed to be dependent on cleavage stimulation factor subunit 2 (CSTF2/CstF-64), which is up-regulated in the TAMR breast cancer cells. Taken together, we have characterized a model in which the interplay between miR26a/b and HuR post-transcriptionally up-regulates ERBB2 expression in TAMR ER+ breast cancer cells.

What happens in the early and still undetectable human malignancy is unknown because direct observations are impractical. Here we present a “Big Bang” model, whereby a tumor grows predominantly as a single expansion producing numerous intermixed sub-clones, which are not subject to stringent clonal selection. In this model, both public and most detectable private mutations arise during the earliest phase of tumor growth. Multi-scale genomic profiling of 349 individual glands sampled from 15 colorectal tumors revealed the absence of selective sweeps, uniformly high intra-tumor heterogeneity, and sub-clone mixing in distant tumor regions, as postulated by the Big Bang. By integrating the data in a spatial model of tumor growth and statistical inference framework we also verified the most striking prediction of our model, namely that most detectable intra-tumor heterogeneity originates from private alterations acquired early during growth, and not from the later expansion of selected sub-clones. Hence, early sub-clones define the genomic profile of colorectal carcinomas and advanced adenomas, whereas potentially dangerous late-arising sub-clones will go undetected. Moreover, our results suggest that sub-clone mixing may be a biomarker of malignant potential. This new model provides a quantitative framework that explains the origins of intra-tumor heterogeneity and tumor growth dynamics with significant clinical implications. Citation Format: Andrea Sottoriva, Haeyoun Kang, Zhicheng Ma, Trevor A. Graham, Matthew Salomon, Junsong Zhao, Paul Marjoram, Kim Siegmund, Michael F. Press, Darryl Shibata, Christina Curtis. A Big Bang model of human colorectal tumor growth. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B2-23.

Intratumoural mutational heterogeneity (ITH) or the presence of different private mutations in different parts of the same tumour is commonly observed in human tumours. The mechanisms generating such ITH are uncertain. Here we find that ITH can be remarkably well structured by measuring point mutations, chromosome copy numbers, and DNA passenger methylation from opposite sides and individual glands of a 6cm human colorectal adenoma. ITH was present between tumour sides and individual glands, but the private mutations were side-specific and subdivided the adenoma into two major subclones. Furthermore, ITH disappeared within individual glands because the glands were clonal populations composed of cells with identical mutant genotypes. Despite mutation clonality, the glands were relatively old, diverse populations when their individual cells were compared for passenger methylation and by FISH. These observations can be organized into an expanding star-like ancestral tree with co-clonal expansion, where many private mutations and multiple related clones arise during the first few divisions. As a consequence, most detectable mutational ITH in the final tumour originates from the first few divisions. Much of the early history of a tumour, especially the first few divisions, may be embedded within the detectable ITH of tumour genomes. Copyright (c) 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Alternative polyadenylation (APA) is an important post-transcriptional regulatory mechanism and involved in many diseases, including cancer. CFIm25, a subunit of the cleavage factor I encoded by NUDT21, is required for 3'RNA cleavage and polyadenylation. Although it has been recently reported to be involved in glioblastoma tumor suppression, its roles and the underlying functional mechanism remain unclear in other types of cancer. In this study, we characterized NUDT21 in hepatocellular carcinoma (HCC). Reduced expression of NUDT21 was observed in HCC tissue compared to adjacent non-tumorous compartment. HCC patients with lower NUDT21 expression have shorter overall and disease-free survival times than those with higher NUDT21 expression after surgery. Knockdown of NUDT21 promotes HCC cell proliferation, metastasis, and tumorigenesis, whereas forced expression of NUDT21 exhibits the opposite effects. We then performed global APA site profiling analysis in HCC cells and identified considerable number of genes with shortened 3'UTRs upon the modulation of NUDT21 expression. In particular, we further characterized the NUDT21-regulated genes PSMB2 and CXXC5. We found NUDT21 knockdown increases usage of the proximal polyadenylation site in the PSMB2 and CXXC5 3' UTRs, resulting in marked increase in the expression of PSMB2 and CXXC5. Moreover, knockdown of PSMB2 or CXXC5 suppresses HCC cell proliferation and invasion. Taken together, our study demonstrated that NUDT21 inhibits HCC proliferation, metastasis and tumorigenesis, at least in part, by suppressing PSMB2 and CXXC5, and thereby provided a new insight into understanding the connection of HCC suppression and APA machinery.

Previous studies have demonstrated that Artemin (ARTN) functions as a cancer stem cell (CSC) and metastatic factor in mammary carcinoma. Herein, we report that ARTN mediates acquired resistance to trastuzumab in HER2-positive mammary carcinoma cells. Ligands that increase HER2 activity increased ARTN expression in HER2-positive mammary carcinoma cells, whereas trastuzumab inhibited ARTN expression. Forced expression of ARTN decreased the sensitivity of HER2-positive mammary carcinoma cells to trastuzumab both in vitro and in vivo. Conversely, siRNA-mediated depletion of ARTN enhanced trastuzumab efficacy. Cells with acquired resistance to trastuzumab exhibited increased ARTN expression, the depletion of which restored trastuzumab sensitivity. Trastuzumab resistance produced an increased CSC population concomitant with enhanced mammospheric growth. ARTN mediated the enhancement of the CSC population by increased BCL-2 expression, and the CSC population in trastuzumab-resistant cells was abrogated upon inhibition of BCL-2. Hence, we conclude that ARTN is one mediator of acquired resistance to trastuzumab in HER2-positive mammary carcinoma cells.

Intratumoural mutational heterogeneity (ITH) or the presence of different private mutations in different parts of the same tumour is commonly observed in human tumours. The mechanisms generating such ITH are uncertain. Here we find that ITH can be remarkably well structured by measuring point mutations, chromosome copy numbers, and DNA passenger methylation from opposite sides and individual glands of a 6 cm human colorectal adenoma. ITH was present between tumour sides and individual glands, but the private mutations were side-specific and subdivided the adenoma into two major subclones. Furthermore, ITH disappeared within individual glands because the glands were clonal populations composed of cells with identical mutant genotypes. Despite mutation clonality, the glands were relatively old, diverse populations when their individual cells were compared for passenger methylation and by FISH. These observations can be organized into an expanding star-like ancestral tree with co-clonal expansion, where many private mutations and multiple related clones arise during the first few divisions. As a consequence, most detectable mutational ITH in the final tumour originates from the first few divisions. Much of the early history of a tumour, especially the first few divisions, may be embedded within the detectable ITH of tumour genomes.

What happens in the early, still undetectable human malignancy is unknown because direct observations are impractical. Here we present and validate a “Big Bang” model, whereby tumors grow predominantly as a single expansion producing numerous intermixed sub-clones that are not subject to stringent selection, and where both public (clonal) and most detectable private (subclonal) alterations arise early during growth. Genomic profiling of 349 individual glands from 15 colorectal tumors revealed the absence of selective sweeps, uniformly high intra-tumor heterogeneity (ITH), and sub-clone mixing in distant regions, as postulated by our model. We also verified the prediction that most detectable ITH originates from early private alterations, and not from later clonal expansions, thus exposing the profile of the primordial tumor. Moreover, some tumors appear born-to-be-bad, with sub-clone mixing indicative of early malignant potential. This new model provides a quantitative framework to interpret tumor growth dynamics and the origins of ITH with significant clinical implications.

A tumor is thought to start from a single cell and genome. Yet genomes in the final tumor are typically heterogeneous. The mystery of this intratumoral heterogeneity (ITH) has not yet been uncovered, but much of this ITH may be secondary to replication errors. Methylation of cytosine bases often exhibits ITH and therefore may encode the ancestry of the tumor. In this study, we measure the passenger methylation patterns of a specific CpG region in 9 colorectal tumors by bisulfite sequencing and apply a tumor development model. Based on our model, we are able to retrieve information regarding the ancestry of each tumor using approximate Bayesian computation. With a large simulation study we explore the conditions under which we can estimate the model parameters, and the initial state of the first transformed cell. Finally we apply our analysis to clinical data to gain insight into the dynamics of tumor formation.

Background Humans and rodents with impaired phytanic acid (PA) metabolism can accumulate toxic stores of PA that have deleterious effects on multiple organ systems. Ruminants and certain fish obtain PA from the microbial degradation of dietary chlorophyll and/or through chlorophyll-derived precursors. In contrast, humans cannot derive PA from chlorophyll and instead normally obtain it only from meat, dairy, and fish products. Results Captive apes and Old world monkeys had significantly higher red blood cell (RBC) PA levels relative to humans when all subjects were fed PA-deficient diets. Given the adverse health effects resulting from PA over accumulation, we investigated the molecular evolution of thirteen PA metabolism genes in apes, Old world monkeys, and New world monkeys. All non-human primate (NHP) orthologs are predicted to encode full-length proteins with the marmoset Phyh gene containing a rare, but functional, GA splice donor dinucleotide. Acox2, Scp2, and Pecr sequences had amino acid positions with accelerated substitution rates while Amacr had significant variation in evolutionary rates in apes relative to other primates. Conclusions Unlike humans, diverse captive NHPs with PA-deficient diets rich in plant products have substantial RBC PA levels. The favored hypothesis is that NHPs can derive significant amounts of PA from the degradation of ingested chlorophyll through gut fermentation. If correct, this raises the possibility that RBC PA levels could serve as a biomarker for evaluating the digestive health of captive NHPs. Furthermore, the evolutionary rates of the several genes relevant to PA metabolism provide candidate genetic adaptations to NHP diets.