Search

With advances in medicine, there have been more and more ways to treat renal calculi in recent years. Percutaneous nephrolithotomy (PCNL) is a safe and effective treatment. The purpose of this paper is to study the efficacy and safety of PCNL combined with negative pressure suction in the treatment of renal calculi by meta-analysis.The PubMed, EMBASE, Cochrane Library, Chinese Journal Full-Text Database, VIP, Wanfang Science and Technology Journal Full-Text Database, and Chinese Biomedical Literature Search databases were searched for articles related to the efficacy and safety of PCNL combined with negative pressure suction in the treatment of renal calculi from the establishment of the databases to October 2021. Endnote X9 software was first used to check and eliminate the articles, and the quality of the included articles were evaluated according to the risk of bias tool of Cochrane Collaboration. Stata 15.1 software was used to record the data. A meta-analysis was performed on the stone clearance rate, operation time, postoperative complications, postoperative fever, septic shock, intrapelvic pressure, and blood loss of PCNL combined with negative pressure suction in the treatment of renal calculi. The reliability of the results was assessed by a sensitivity analysis. Egger's linear test was used to test the publication bias of the articles.A total of 10 articles were included in the meta-analysis, and the total sample size of the study was 820. The meta-analysis showed that when PCNL combined with negative pressure suction was used to treat renal calculi, the stone clearance rate and the occurrence of septic shock of the test group did not differ significantly from that of the control group; the incidence rate of postoperative complications、the operation time, the intraoperative bleeding and the postoperative fever of the test group was significantly better than that of the control group.Compared to the group without negative pressure, PCNL reduces the operation time, postoperative complications, postoperative fever, septic shock, and intraoperative blood loss without increasing the risk of septic shock.

BACKGROUND: Over the past decade, there has been a significant increase in research on the use of mobile health (mHealth) apps as disease management tools. However, very few apps are currently available for prostate cancer (PCa) patient management, and the available apps do not combine the needs of physicians with the requirements of patients. This study aimed to describe the development of a mHealth application for PCa survivors called RyPros, which includes dynamic visualization, intelligent reminders, and instant messaging to support decision-making regarding treatment and follow-up and test the initial accessibility and acceptability application. METHODS: The application was developed through a three-step procedure: logical structure design, application programming, and testing. Dynamic visualization, intelligent reminders, and instant messaging were the core functions of RyPros. Twenty-eight participants who had PCa were enrolled in four weeks of follow-up using the RyPros App. We initially evaluated participants’ acceptance of RyPros based on their use of the app (login data, questionnaire completion) and a satisfaction survey. RESULTS: We successfully designed and tested the application. A total of 32 participants were enrolled, of whom 28 completed the 4-week follow-up, yielding a participation rate of 87.5%. Each participant logged on an average of 2.82 times and achieved an average of 0.89 questionnaires per week over the four weeks. Most participants (64%) liked the app, and most participants (71%) were satisfied, giving the RyPros app a rating of 4 or 5. More than half of the participants (61%) intended to use the RyPros app regularly, and the majority of participants agreed that the three core functionalities of RyPros were helpful (20/28, 71% for instant messaging; 16/28, 57% for visualization; and 18/28, 64% for reminders and assessments). CONCLUSIONS: The mHealth application we developed for PCa survivor management provided dynamic visualization, reminders, assessments, and instant messaging to support decision-making based on multidisciplinary collaboration. PCa survivors showed high acceptance of the RyPros app.

The VG161 represents the first recombinant oncolytic herpes simplex virus type 1 carrying multiple synergistic antitumor immuno-modulating factors. Here, we report its antitumor mechanisms and thus provide firm theoretical foundation for the upcoming clinical application in pancreatic cancer. Generally, the VG161-mediated antitumor outcomes were analyzed by a collaboration of techniques, namely the single-cell sequencing, airflow-assisted desorption electrospray ionization-mass spectrometry imaging (AFADSI-MSI) and nanostring techniques. In vitro, the efficacy of VG161 together with immune checkpoint inhibitors (ICIs) has been successfully shown to grant a long-term antitumor effect by altering tumor immunity and remodeling tumor microenvironment (TME) metabolisms. Cellular functional pathways and cell subtypes detected from patient samples before and after the treatment had undergone distinctive changes including upregulated CD8+ T and natural killer cells. More importantly, significant antitumor signals have emerged since the administration of VG161 injection. In conclusion, VG161 can systematically activate acquired and innate immunity in pancreatic models, as well as improve the tumor immune microenvironment, indicative of strong antitumor potential. The more robusting antitumor outcome for VG161 monotherapy or in combination with other therapies on pancreatic cancer is worth of being explored in further clinical trials.

Mouse embryonic stem cells (mESCs) can self-renew indefinitely and maintain pluripotency. Inhibition of mechanistic target of rapamycin (mTOR) by the kinase inhibitor INK128 is known to induce paused pluripotency in mESCs cultured with traditional serum/LIF medium (SL), but the underlying mechanisms remain unclear. In this study, we demonstrate that mTOR complex 1 (mTORC1) but not complex 2 (mTORC2) mediates mTOR inhibition-induced paused pluripotency in cells grown in both SL and 2iL medium (GSK3 and MEK inhibitors and LIF). We also show that mTORC1 regulates self-renewal in both conditions mainly through eIF4F-mediated translation initiation that targets mRNAs of both cytosolic and mitochondrial ribosome subunits. Moreover, inhibition of mitochondrial translation is sufficient to induce paused pluripotency. Interestingly, eIF4F also regulates maintenance of pluripotency in an mTORC1-independent but MEK/ERK-dependent manner in SL, indicating that translation of pluripotency genes is controlled differently in SL and 2iL. Our study reveals a detailed picture of how mTOR governs self-renewal in mESCs and uncovers a context-dependent function of eIF4F in pluripotency regulation.

Benzo[a]pyrene (B[a]P) is a typical complete carcinogen in tobacco, but its mechanism of inducing the development of chronic pneumonia and consequent lung cancer is unclear. Here we elucidated the role of myeloid-derived suppressor cells (MDSCs) in developing B[a]P-induced chronic lung inflammation and efficacy of immunotherapy in preventing subsequent malignant transformation. Our study showed that as B[a]P could induce the accumulation of MDSCs in lung tissues and enhance the immunosuppressive effect regulated by cytokines and metabolites, thereby promoting the formation of immunosuppressive microenvironment, where effector T cells were exhausted, NK cells were dysfunctional, regulatory T (Treg) cells were expanded, polarized alveolar macrophages were transformed from M1 to M2. Subsequently, we performed the immunotherapy to block TNFɑ only or both TNFɑ and PD-1 at the early- or middle-stage of B[a]P-induced chronic lung inflammation to ameliorate the immunosuppressive microenvironment. We found that TNFɑ antagonist alone or with PD-1 blocker was shown to exert therapeutic effects on malignant transformation at the early stage of B[a]P-induced chronic lung inflammation. Taken together, our findings demonstrated that B[a]P-induced chronic lung inflammation resulted in the accumulation of MDSCs in lung tissues and exercise their immunosuppressive functions, thereby developing an immunosuppressive microenvironment, thus TNFɑ antagonist alone or with PD-1 blocker could prevent or retard the malignant transformation of B[a]P-induced chronic lung inflammation.

Despite advances in optical interconnect, metal interconnect remains the dominant technology, however the type and diversity of metal structures is rapidly changing. Wire-bonding cannot meet required interconnect density and is being replaced with electrodeposition-based flip chip technology. Modern packaging scheme required high diversity of interconnects within the same device: RDL, mircobump, pillar, TSV, tall (mega) pillar, etc. using sequential deposition of different metals such as Cu, Ni, SnAg/Sn, Au. Diverse challenging requirement leads to evolution of chemistries and process control approaches. Many 20th century chemistries were limited to 1 organic additive for Cu process. Today, up to 4 individual additives are used to dial the process. While most of semiconductor front end processing enjoys the luxury of single-use chemistry, it is not yet considered a viable option for electrodeposition. The same electrolyte can be used for processing over 1000 parts in replenishment mode. Maintaining performance under these conditions requires close monitoring of component breakdown and contaminants accumulated in the processes. There is also a real possibility for disproportional trends for individual components of replenishment package. It is no longer enough to monitor just main 3–6 components of the bath. Successful high volume metallization for advanced packaging requires comprehensive metrology/process control. Presentation will provide specific examples of metrology and process control strategy for various metallization solution with emphasize on breakdown products and contaminants. There is no single technology which can cover diversity of metrology needs. CVS is a versatile technology which can be used not only for control of main additives but also to monitor breakdown products of accelerator, suppressor, leveler, Cu(I) contaminants, H2O2 contaminant and even leached photoresist. In case of Ni chemistry, it is useful to monitor breakdown products of sulfamate. UV-Vis spectroscopy shines at monitoring of leached photoresists, Fe(III), breakdown products of sulfamate as well as control of many main components: Cu, Ni, Co, Au, additives. ICP is the best for ultra low level of metal contaminants which can harms deposition process, as well as low level of some target components, like Tl in Au. Novel approach is developed to track additive turnover process based on ICP results. HPLC is valuable to characterize multiple breakdown products of organic additives, while ion chromatography helps to track transformation of ions, such as oxidation of sulfite to sulfate in Au solution. Surface tension aids monitoring of surfactants and their degradation. It is important to differentiate between R&D study and robust “fit-to-purpose” practical process control. While Ion Chromatography approach would be more appropriate for academic study and perhaps process development, simple robust methods like titration, specific gravity are preferable for industrial process control. Similarly, HPLC is a great scientific tool but CVS, spectroscopy and titration are better fit and safer alternative for in-fab operation. Presentation will provide specific examples and comparative analysis of different analytical methods.

BACKGROUND Prostate cancer remains a major cause of mortality in men worldwide, and China's incidence increases significantly. It takes a great deal of effort for clinicians to summarize and analyze data on prostate cancer patients. Only a comprehensive and accurate follow-up of prostate cancer patients can maximize their survival and quality of life. Over the past decade, there has been a significant increase in research and use of apps as disease management tools in mobile health. However, very few apps are currently available for prostate cancer patient management, and these apps do not combine the needs of physicians with the needs of patients. OBJECTIVE To develop a mobile health application called RyPros with dynamic visualization，intelligent reminder, and instant messaging for prostatic cancer patient management, which can provide intelligent suggestions for patients' diagnosis and treatment plan, nursing, follow-up measures, and other decisions, realize individualized treatment, and evaluation, improve communication between doctors and patients, inspire patients to develop "focus on me" awareness and proactively cooperate with the treatment. METHODS The application was developed through a four-step procedure: logical structure design, interface design, application programming, and testing. The application's design was based on guidelines and multi-disciplinary collaboration, with dynamic visualization, intelligent reminder, and instant messaging as the core functions, which could be used for data identification and entry, automatic labeling of patients' status. The application also emphasizes protecting the security and privacy of patients' data. RESULTS We implemented and tested the application successfully. After testing, the application generally ran on both the doctor's and the patient's interfaces. The application interfaces were simple, rapid, and smooth; the data storage and reading were stable and accurate. It analyzed the patient's physiology, prostate-specific antigen, serum testosterone, and other monitoring data and dynamically visualized the data and dynamically labeled the disease stage; reminded the patient for follow-up measures and evaluated the patient's health-related quality of life remotely; communicated between different doctors and doctors-patients through instant messaging modules. CONCLUSIONS A mobile health application that addresses dynamic visualization, intelligent reminder, and instant messaging whose main themes can facilitate disease management for prostate cancer patients.

Ischemia-reperfusion injury (IRI) is an inevitable and serious clinical problem in donations after heart death (DCD) liver transplantation. Excessive sterile inflammation plays a fateful role in liver IRI. Hypothermic oxygenated perfusion (HOPE), as an emerging organ preservation technology, has a better preservation effect than cold storage (CS) for reducing liver IRI, in which regulating inflammation is one of the main mechanisms. HECTD3, a new E3 ubiquitin ligase, and TRAF3 have an essential role in inflammation. However, little is known about HECTD3 and TRAF3 in HOPE-regulated liver IRI. Here, we aimed to investigate the effects of HOPE on liver IRI in a DCD rat model and explore the roles of HECTD3 and TRAF3 in its pathogenesis. We found that HOPE significantly improved liver damage, including hepatocyte and liver sinusoidal endothelial cell injury, and reduced DCD liver inflammation. Mechanistically, both the DOC and HECT domains of HECTD3 directly interacted with TRAF3, and the catalytic Cys (C832) in the HECT domain promoted the K63-linked polyubiquitination of TRAF3 at Lys138. Further, the ubiquitinated TRAF3 at Lys138 increased oxidative stress and activated the NF-κB inflammation pathway to induce liver IRI in BRL-3A cells under hypoxia/reoxygenation conditions. Finally, we confirmed that the expression of HECTD3 and TRAF3 was obviously increased in human DCD liver transplantation specimens. Overall, these findings demonstrated that HOPE can protect against DCD liver transplantation-induced-liver IRI by reducing inflammation via HECTD3-mediated TRAF3 K63-linked polyubiquitination. Therefore, HOPE regulating the HECTD3/TRAF3 pathway is a novel target for improving IRI in DCD liver transplantation.

Tumor necrosis factor receptor-associated factor (TRAF) proteins are a family of signaling molecules that function downstream of multiple receptor signaling pathways, and they play a pivotal role in the regulation of intracellular biological progresses. These TRAF-dependent signaling pathways and physiological functions have been involved in the occurrence and progression of ischemia-reperfusion injury (IRI), which is a common pathophysiological process that occurs in a wide variety of clinical events, including ischemic shock, organ transplantation, and thrombolytic therapy, resulting in a poor prognosis and high mortality. IRI occurs in multiple organs, including liver, kidney, heart, lung, brain, intestine, and retina. In recent years, mounting compelling evidence has confirmed that the genetic alterations of TRAFs can cause subversive phenotype changes during IRI of those organs. In this review, based on current knowledge, we summarized and analyzed the regulatory effect of TRAFs on the IRI of various organs, providing clear direction and a firm theoretical basis for the development of treatment strategies to manipulate TRAF proteins or TRAF-dependent signaling pathways in IRI-related diseases.

Importance Advanced age-related macular degeneration (AMD) is a leading cause of blindness in Western countries. Causal, modifiable risk factors need to be identified to develop preventive measures for advanced AMD. Objective To assess whether smoking, alcohol consumption, blood pressure, body mass index, and glycemic traits are associated with increased risk of advanced AMD. Design, Setting, Participants This study used 2-sample mendelian randomization. Genetic instruments composed of variants associated with risk factors at genome-wide significance (P

Copper electroplating processes are widely used in semiconductor manufacturing, particularly during the packaging stage [1]. Copper deposition is used to build various structures including TSV, RDL, Pillars, and Micro and Mega Bumps. Those processes utilize plating solutions that contain inorganic components and organic additives [2]. During the electroplating process, the additives can partially transform into compounds that are so-called breakdown products. The presence of such breakdown products can interfere with the electrochemical analysis of organic additives. This article presents results of plating tests that show the influence of freshly produced breakdown products on analysis of organic additives. In addition, several options to eliminate this effect are presented.

The ability to identify a specific cancer using minimally invasive biopsy holds great promise for improving the diagnosis, treatment selection, and prediction of prognosis in cancer. Using whole-genome methylation data from The Cancer Genome Atlas (TCGA) and machine learning methods, we evaluated the utility of DNA methylation for differentiating tumor tissue and normal tissue for four common cancers (breast, colon, liver, and lung). We identified cancer markers in a training cohort of 1,619 tumor samples and 173 matched adjacent normal tissue samples. We replicated our findings in a separate TCGA cohort of 791 tumor samples and 93 matched adjacent normal tissue samples, as well as an independent Chinese cohort of 394 tumor samples and 324 matched adjacent normal tissue samples. The DNA methylation analysis could predict cancer versus normal tissue with more than 95% accuracy in these three cohorts, demonstrating accuracy comparable to typical diagnostic methods. This analysis also correctly identified 29 of 30 colorectal cancer metastases to the liver and 32 of 34 colorectal cancer metastases to the lung. We also found that methylation patterns can predict prognosis and survival. We correlated differential methylation of CpG sites predictive of cancer with expression of associated genes known to be important in cancer biology, showing decreased expression with increased methylation, as expected. We verified gene expression profiles in a mouse model of hepatocellular carcinoma. Taken together, these findings demonstrate the utility of methylation biomarkers for the molecular characterization of cancer, with implications for diagnosis and prognosis.

Nickel electroplating is widely used in semiconductor manufacturing, primarily during the packaging stage. It is not used as a final coating, but instead as a barrier layer to prevent formation of copper–tin intermetallic compounds that affect the reliability of solder joints. The nickel is deposited from baths containing nickel salt (in relatively high concentrations), boric acid, and other ions. The quality of the deposited nickel is highly dependent on the composition of the plating bath. Metallic contaminants are acceptable when their concentrations are below approximately 30 ppm. Copper, lead, zinc, and cadmium, even in relatively small quantities (higher than 30 ppm) produce a dull, black, or skip plate condition in the low-current-density areas. These metals may be removed from the plating solution by low-current-density dummy plating, but a sensitive and accurate analytical method must be used to determine when to treat the bath. Copper is considered a main contaminant due to its higher concentrations in the bath and its most detrimental effect on the nickel deposit. To prevent plating defects, the bath contaminants must be monitored.

Aims Ischemia-reperfusion injury (IRI) is harmful to patients following kidney transplantation. Hypothermic machine perfusion (HMP) can be adopted to preserve grafts and reduce consequential injury. We hypothesized that aldehyde dehydrogenase 2 (ALDH2) partly mitigates kidney IRI via regulating excessive autophagy in HMP. Materials and methods The rabbits were assigned to 5 groups: Normal, HMP, HMP + Alda-1, HMP + CYA and cold storage (CS). After the rabbit autologous kidney transplantation, renal pathology and function were evaluated by histological analysis, glomerular related proteins (desmin, nephrin), tubular injury factors (NGAL, Ki67), serum creatinine (Cr) and blood urea nitrogen (BUN). Oxidative stress molecular Malondialdehyde (MDA) and superoxide dismutase (SOD2) expression, as well as inflammatory cytokines (TNF-α, IL-6, IL-10) were assessed by immunohistochemistry. The expression of LC3, p62, ALDH2, p-Akt, mTOR, PTEN, p-PTEN, and 4-HNE were measured by immunohistochemistry, RT-PCR, Western blot analysis or ELISA. Key findings HMP was more effective than CS for kidney preservation, with p- ALDH2 expressed in greater quantities in HMP. The results of kidney pathology and function in HMP + Alda-1 were the best. The MDA & SOD2 and the Vyacheslav score were improved in HMP + CYA. ALDH2 reduced 4-HNE-induced oxidative stress, inflammatory infiltration, the expression of LC3, p62 and inhibited autophagy accompanied by activation of p-Akt and mTOR via p-PTEN/PTEN. Significance Akt-mTOR autophagy pathway is a novel target for ALDH2 to reduce renal IRI partly by inhibition of 4-HNE in HMP, then protecting the donated kidney received after cardiac death (DCD).

Semiconductor packaging migrated from wire bond to flip chip level interconnect to meet size, weight and electrical performance requirements. Lead-free alloys for flip chip attachment has become a common material in electronics. Alloys containing Sn and Ag as well as pure Sn are the most common ones. The mechanical strength, wetting, and fatigue resistance of these alloys and pure Sn is either comparable or surpass lead contained alloys. Electroplating with lead-free alloys is the most desirable technique due to its low cost and usefulness in building fine pitch solder bumps [1]. The new generation of lead free plating systems targeting faster deposition rates, better uniformity with-in die and longer bath life. The co-deposition of elements may be complicated by the large difference in the electrode potentials of tin and alloying metals (e.g. silver, bismuth). To produce uniform and dense deposits, these plating baths include organic additives that are typically separated for two groups with different functions: polarizers that significantly affect the plating rate and control the uniformity of deposit; and grain refiners [2]. For desired properties of deposit, the bath components must be kept within specific concentration ranges. In some cases, the analytical results for bath components should be available more frequently in order to provide feedback to dosing system [3]. To develop most accurate and repeatable analytical methods, the interactions between lead free plating bath components were previously investigated and understood [2]. That allowed to develop efficient analytical techniques for analysis of lead free plating bath components. However, faster analytical methods are required for control of high speed plating baths. The effect of changes in the concentration of organic components on the structure of deposit were studied more recently and will be reported in this work. When the speed of analyses increases, it is critical to keep reproducible state of all electrodes. Therefore, new regeneration method for electrodes was developed. For development of new express analytical methods, we utilized an electrochemical cell with three electrodes connected to a potentiostat/galvanostat. RDE working and counter platinum electrodes were used as well as Ag/AgCl double junction reference electrode. It has been found that multiple factors can reduce the speed of electrochemical analysis. One of the most potent parameters that affect speed of analysis was a scan rate. Fig. 1 shows the electrochemical responses of polarizer at different scan rates. Other parameters and steps of analysis were also evaluated for potential reduction the analysis time. This presentation will provide more information related to the electrochemical behavior of organic additives at specific conditions when the analysis is performed with different speed. Results for other bath components will be also presented. The concentration of inorganic components and silver complexing agent can be determined via non-reagent and virtually real time spectroscopic analytical methods. The presentation will be concluded with a discussion of analytical results for several organic additives at different concentration levels. References: 1. A. Foyet, M. Clauss, W. Zang-Beglinger, J. Woertink, Y. Qin, J. Prange, P. Lopez, , “Electroplating baths of silver and tin alloys”, US Patent, US9512529B2 2. M. Pavlov, D. Lin, E. Shalyt, I. Tsimberg, “Electrochemical Behavior and Analysis of Organic Additives in Modern Lead-Free Wafer Level Packaging Plating Baths, AiMES, ECS and SMEQ Joint International Meeting, September 30 – October 4, 2018, Cancun, Mexico 3. M. Pavlov, D. Lin, E. Shalyt, I. Tsimberg, “Electrochemical Analysis of Semiconductor Plating Baths”, MAM Conference, Milano, Italy, March 18-21, Figure 1

© 2015 Elsevier Inc. Glaucoma, a blinding neurodegenerative disease, whose risk factors include elevated intraocular pressure (IOP), age, and genetics, is characterized by accelerated and progressive retinal ganglion cell (RGC) death. Despite decades of research, the mechanism of RGC death in glaucoma is still unknown. Here, we demonstrate that the genetic effect of the SIX6 risk variant (rs33912345, His141Asn) is enhanced by another major POAG risk gene, p16INK4a (cyclin-dependent kinase inhibitor 2A, isoform INK4a). We further show that the upregulation of homozygous SIX6 risk alleles (CC) leads to an increase in p16INK4a expression, with subsequent cellular senescence, as evidenced in a mouse model of elevated IOP and in human POAG eyes. Our data indicate that SIX6 and/or IOP promotes POAG by directly increasing p16INK4a expression, leading to RGC senescence in adult human retinas. Our study provides important insights linking genetic susceptibility to the underlying mechanism of RGC death and provides a unified theory of glaucoma pathogenesis. Zhang et al. report p16INK4a as a downstream integrator of diverse signals, such as inherited genetic risk, age, and intraocular pressure, in the pathogenesis of glaucoma. They demonstrate that upregulation of SIX6 upon stress directly increases p16INK4a, leading to retinal ganglion cell senescence and death.

PAX6 is a master regulatory gene involved in neuronal cell fate specification. It also plays a critical role in early eye field and subsequent limbal stem cell (LSC) determination during eye development. Defects in Pax6 cause aniridia and LSC deficiency in humans and the Sey (Small eye) phenotype in mice (Massé, K., Bhamra, S., Eason, R., Dale, N., and Jones, E. A. (2007) Nature 449, 1058-1062). However, how PAX6 specifies LSC and corneal fates during eye development is not well understood. Here, we show that PAX6 is expressed in the primitive eye cup and later in corneal tissue progenitors in early embryonic development. In contrast, p63 expression commences after that of PAX6 in ocular adnexal and skin tissue progenitors and later in LSCs. Using an in vitro feeder-free culture system, we show that PAX6 knockdown in LSCs led to up-regulation of skin epidermis-specific keratins concomitant with differentiation to a skin fate. Using gene expression analysis, we identified the involvement of Notch, Wnt, and TGF-β signaling pathways in LSC fate determination. Thus, loss of PAX6 converts LSCs to epidermal stem cells, as demonstrated by a switch in the keratin gene expression profile and by the appearance of congenital dermoid tissue.

Cobalt made an inevitable move into more and more applications as device features shrink. It has largely been replacing tungsten in prior forays: for encapsulating and for high-aspect-ratio fill. Cobalt now has a new target in its sights: copper interconnect [1]. Copper replaced aluminum about 20 years ago and had been successfully utilized in numerous semiconductor manufacturing nodes. However, when the IC industry moved beyond the 10 nm node, copper interconnects became more compact, causing an increase in the resistance-capacitance delay. One way to solve the problem is to utilize a cobalt metallization alternative that provides resistance benefits over conventional technology without compromising reliability and yield [2]. In this electroplating process, a super-filling relies on depletion of protons inside feature, leading to increased current efficiency for Cobalt. Depletion of protons in this case leads to reduction of suppression efficiency and further enhancement of cobalt deposition as compared to field [3, 4]. These publications agree that a successful super-filling requires tight pH control. This presentation reveals results of advanced method that allow to reach 0.005 pH repeatability required for electroplating process. While this cobalt plating process is maturing, tighter process control is required to provide more accurate and precise data as well as faster analysis data generation. Previously developed analytical methods [5, 6] had been refined and improved to address challenges of the modern industrial cobalt plating processes. New, efficient analytical techniques were also developed. These methods can also report additional properties of a plating solution (conductivity and pH) critical for bath performance. Fig 1. shows the electrochemical responses of different proprietary organic additives used in commercial cobalt plating baths. Optimized electroanalytical and hydrodynamic parameters enable the determination of a wide range of concentrations of organic additives without interference from other bath components, as well as from bath pH and temperature. Analysis of organic additives can be performed with relatively simple fluidics that include a single mini electrochemical cell with accurate temperature control. Typical analysis steps include fast electrode conditioning in support electrolyte, several or single injection of plating solution to determine changes in plating rate, and then subsequent calculation of the concentrations. One of the newly developed methods is non-reagent spectroscopic analysis of boric acid. This method can also be combined with non-reagent analysis of cobalt providing very fast analysis of both components. Fig. 2 shows correlation of obtained and expected values for wide range of boric acid concentrations. This presentation will provide more detailed information related to the electrochemical behavior of organic additives and inorganic components. The results of Electrochemical Impedance Spectroscopy investigations and Raman spectroscopy will also be presented. The presentation will be concluded with a discussion of analytical results for all bath components during electroplating process. References: B. Moyer, “The Cobalt Waive Continues”, Electronic Engineering Journal (internet publication), July 16, 2018 Natalia V. Doubina, Matthew A. Rigsby, Jonathan David Reid, “Chemistry additives and process for cobalt film electrodeposition”, US Patent, US 9777386B2 Matthew A. Rigsby, Lee J. Brogan, Natalia V. Doubina, Yihua Liu, Edward C. Opocensky, Tighe A. Spurlin, Jian Zhou and Jonathan D. Reid, “The Critical Role of pH Gradient Formation in Driving Superconformal Cobalt Deposition”, J. Electrochem. Soc. 2019 volume 166, issue 1, D3167-D3174 J. Wu, F. Wafula, S. S. Branagan, H. Suzuki and J. van Eisden, “Mechanism of Cobalt Bottom-Up Filling for Advanced Node Interconnect Metallization”, J. Electrochem. Soc. 2019 volume 166, issue 1, D3136-D3141 M. Pavlov, D. Lin, E. Shalyt, X. Yan, “Electrochemical behavior and Analysis of Organic Additives in Cobalt Damascene Baths”, 230th ECS Meeting PRiME, Honolulu, Hawaii, October 2-7, 2016 M. Pavlov, E. Shalyt, X. Yan, D. Lin, “Process Metrology of Cobalt Damascene Interconnect”, 2016 IEEE IITC and AMC Conference, San Jose CA, May 23-26 Figure 1

An effective blood-based method for the diagnosis and prognosis of hepatocellular carcinoma (HCC) has not yet been developed. Circulating tumour DNA (ctDNA) carrying cancer-specific genetic and epigenetic aberrations may enable a noninvasive 'liquid biopsy' for diagnosis and monitoring of cancer. Here, we identified an HCC-specific methylation marker panel by comparing HCC tissue and normal blood leukocytes and showed that methylation profiles of HCC tumour DNA and matched plasma ctDNA are highly correlated. Using cfDNA samples from a large cohort of 1,098 HCC patients and 835 normal controls, we constructed a diagnostic prediction model that showed high diagnostic specificity and sensitivity (P < 0.001) and was highly correlated with tumour burden, treatment response, and stage. Additionally, we constructed a prognostic prediction model that effectively predicted prognosis and survival (P < 0.001). Together, these findings demonstrate in a large clinical cohort the utility of ctDNA methylation markers in the diagnosis, surveillance, and prognosis of HCC.

The feasibility of measuring cobalt damascene additives with cyclic voltammetric stripping (CVS) method is demonstrated. 2-Mercapto-5-benzimidazolesulfonic acid (MBIS) and thiourea (TU) were selected as model suppressor and accelerator, respectively, according to published information. Inorganic components such as boric acid also affect the electrochemical properties of electrolytes. This article particularly investigates the effects of boric acid on the reduction processes in cobalt baths. The effect of dissolved oxygen on CVS is also studied.

The repair and regeneration of tissues using endogenous stem cells represents an ultimate goal in regenerative medicine. To our knowledge, human lens regeneration has not yet been demonstrated. Currently, the only treatment for cataracts, the leading cause of blindness worldwide, is to extract the cataractous lens and implant an artificial intraocular lens. However, this procedure poses notable risks of complications. Here we isolate lens epithelial stem/progenitor cells (LECs) in mammals and show that Pax6 and Bmi1 are required for LEC renewal. We design a surgical method of cataract removal that preserves endogenous LECs and achieves functional lens regeneration in rabbits and macaques, as well as in human infants with cataracts. Our method differs conceptually from current practice, as it preserves endogenous LECs and their natural environment maximally, and regenerates lenses with visual function. Our approach demonstrates a novel treatment strategy for cataracts and provides a new paradigm for tissue regeneration using endogenous stem cells.

Replacement of tin-lead solder bumps by a suitable lead-free material for flip chip attachment has become an urgent necessity due to the impending ban on the use of lead in electronics. Alloys containing Sn and Ag as well as pure Sn are the most common for the replacement of Sn-Pb. The mechanical strength, wetting, and fatigue resistance of these alloys and pure Sn is comparable or surpass that of Sn-Pb”. Electroplating with lead-free alloys is the most desirable technique due to its low cost and usefulness in building small dimension bumps. However, the co-deposition of elements is complicated by the large difference in the electrode potentials of each element. Besides metal ions, these plating baths include organic additives, chelating agents, and acids. For appropriate plating bath performance, these components must be kept within specific concentration ranges. This is achieved through the use of dedicated chemical analyzers and dosers [1]. Most of these systems use multiple analytical methods that typically include electrochemical techniques. The introduction of new electroplating processes requires the development of new analytical methods. Before a new analytical electrochemical method is developed, the interactions between bath components should be investigated and understood. For this purpose, we utilized an electrochemical cell with three electrodes connected to a potentiostat/galvanostat. We studied the responses of organic components under varying electrochemical and hydrodynamic conditions as well as at different concentrations of bath components. Fig. 1 shows the electrochemical responses of organic additives used in commercial lead-free plating baths [2]. All tests were performed with the working and counter platinum electrodes and a low maintenance Ag/AgCl double junction reference electrode. Optimized electrochemical analysis parameters enable the determination of a wide range of concentrations of organic plating additives without interference from other bath components. Analysis of organic additives can be performed with relatively simple fluidics that include a single electrochemical cell with accurate temperature control. Typical analysis steps include fast electrode conditioning in support electrolyte, several injections of plating solution to determine changes in plating rate, and then subsequent calculation of the concentrations. This presentation will provide more information related to the electrochemical behavior of organic additives and inorganic components. Results of Electrochemical Impedance Spectroscopy investigations will also be presented. Results of electrochemical analyses will be correlated to data obtained with an HPLC analytical technique. The presentation will be concluded with a discussion of analytical results for each organic additive at different concentration levels. References: Pavlov, D. Lin, E. Shalyt, I. Tsimberg, “Electrochemical Analysis of Semiconductor Plating Baths”, MAM Conference, Milano, Italy, March 18-21, 2018 Foyet, M. Clauss, W. Zang-Beglinger, J. Woertink, Y. Qin, J. Prange, P. Lopez, , “Electroplating baths of silver and tin alloys”, US Patent, US9512529B2 Figure 1

PURPOSE Retinitis pigmentosa (RP) is a genetically heterogeneous disease with over 60 causative genes known to date. Nevertheless, approximately 40% of RP cases remain genetically unsolved, suggesting that many novel disease-causing genes are yet to be identified. In this study, we aimed to identify the causative mutation for a large autosomal dominant RP (adRP) family with negative results from known retinal disease gene screening. METHODS Linkage analysis followed by whole-exome sequencing was performed. Stringent variant filtering and prioritization was carried out to identify the causative mutation. RESULTS Linkage analysis identified a minimal disease region of 8 Mb on chromosome 10 with a peak parametric logarithm (base 10) of odds (LOD) score of 3.500. Further whole-exome sequencing identified a heterozygous missense mutation (NM_000188.2:c.2539G>A, p.E847K) in hexokinase 1 (HK1) that segregated with the disease phenotype in the family. Biochemical assays showed that the E847K mutation does not affect hexokinase enzymatic activity or the protein stability, suggesting that the mutation may impact other uncharacterized function or result in a gain of function of HK1. CONCLUSIONS Here, we identified HK1 as a novel causative gene for adRP. This is the first report that associates the glucose metabolic pathway with human retinal degenerative disease, suggesting a potential new disease mechanism.

With miniaturization of semiconductor devices, the size of electroplated features is continuously reduced in the damascene process. Most recently, copper electroplating technology application has been extended in 14 nm, 10 nm, and 7 nm nodes. This advancement has caused significant changes in bath compositions. While new organic additive packages were introduced, the inorganic component concentrations were significantly altered as well. The composition of plating baths used in sub 14 nm nodes was recently described [1, 2]. These publications specified relatively low concentrations of copper between 1 and 10 grams per liter, sulfuric acid between 2 and 15 grams per liter, and 30-150 ppm chloride ions. Such electrolyte also includes organic additives traditionally used in copper electroplating baths (Suppressor, Accelerator, and Leveler). Suppressors are polymeric in nature (e.g. polyethylene glycol, polypropylene glycol, etc.). Accelerators are typically sulfur-containing compounds such as dimercaptopropane sulfonic acid, and bis-(3-sulfopropyl) disulfide (SPS). Levelers are designed to work on protruding features, and typically nitrogen contained compounds, e.g. Janus Green B. Before a new analytical electrochemical method is developed, the interactions between bath components at low copper concentrations should be investigated and understood. For this purpose, we utilized an electrochemical cell with three electrodes connected to a potentiostat/galvanostat. We studied responses of organic components at different electrochemical and hydrodynamic conditions as well as at different concentrations of copper. Fig. 1 shows electrochemical responses of organic additives in solutions with different copper concentrations. All tests were performed with the working platinum electrode set at a constant cathodic current of -10 mA and 10-2500 RPM. As this graph indicates, the copper concentration plays a key role in the electrodeposition process. Reduction in copper concentration causes significant changes of plating potential, which is consistent with observations made in another publication [2]. Injection of Suppressor (PEG) into the solution changes plating overpotential in a similar way to reduction of copper concentration. It is critical to note that addition of Suppressor into solutions with different copper concentration causes almost the same shift in plating potential (Fig. 2). In Fig. 2, the voltages for 1 g/l and 5 g/l copper solutions were adjusted to match the initial potential for a solution with 10 g/l of copper. Unlike the Suppressor effect, Accelerator (SPS) and Leveler (JGB) effects are clearly dependant on the changes in the copper conentrations. Accelerator component transient response shows slower and weaker depolarizatrion at the lowest concentration of copper, while the Leveler polarization effect is stronger at lower copper concentration. Understanding the interactions between bath components at low copper concentrations enables the design of accurate electrochemical methods of analysis for each organic component. This presentation will reveal more information related to the electrochemical behavior of organic additives and inorganic components. Results of EIS investigations will also be represented. The presentation will be concluded with a discussion of analytical results for each organic additive at different concentration levels. References: J. Zhou, J. Reid, “Low copper electroplating solutions for fill and defect control”, US Patent Application, US 13/753,33 J. Zhou, E. Opocensky, J. Reid, “Low Cu electrolyte for advanced damascene plating”, Semiconductor Technology International Conference (CSTIC), 2015 Figure 1

The human lens is comprised largely of crystallin proteins assembled into a highly ordered, interactive macro-structure essential for lens transparency and refractive index. Any disruption of intra- or inter-protein interactions will alter this delicate structure, exposing hydrophobic surfaces, with consequent protein aggregation and cataract formation. Cataracts are the most common cause of blindness worldwide, affecting tens of millions of people1, and currently the only treatment is surgical removal of cataractous lenses. The precise mechanisms by which lens proteins both prevent aggregation and maintain lens transparency are largely unknown. Lanosterol is an amphipathic molecule enriched in the lens. It is synthesized by lanosterol synthase (LSS) in a key cyclization reaction of a cholesterol synthesis pathway. Here we identify two distinct homozygous LSS missense mutations (W581R and G588S) in two families with extensive congenital cataracts. Both of these mutations affect highly conserved amino acid residues and impair key catalytic functions of LSS. Engineered expression of wild-type, but not mutant, LSS prevents intracellular protein aggregation of various cataract-causing mutant crystallins. Treatment by lanosterol, but not cholesterol, significantly decreased preformed protein aggregates both in vitro and in cell-transfection experiments. We further show that lanosterol treatment could reduce cataract severity and increase transparency in dissected rabbit cataractous lenses in vitro and cataract severity in vivo in dogs. Our study identifies lanosterol as a key molecule in the prevention of lens protein aggregation and points to a novel strategy for cataract prevention and treatment.

Renanthera imschootiana Rolfe is an endangered tropical epiphytic orchid that is threatened with extinction due to over-collection and the loss of suitable habitats. In vitro propagation is a useful way to mass produce plants for re-establishment in the wild and for commercial propagation. Seeds collected 150 days after pollination (DAP) were the optimum stage for in vitro culture. Seed germination reached 93.1% on quarter-strength MS (i.e., MS containing a quarter of macro- and micronutrients) medium containing 0.5 mg l(-1) α-naphthaleneacetic acid (NAA), 20% coconut water (CW), 1.0 g l(-1) peptone, 10 g l(-1) sucrose and 1.0 g l(-1) activated charcoal (AC). Quarter-strength MS medium supplemented with 1.0 mg l(-1) BA, 0.5 mg l(-1) NAA, 1.0 g l(-1) peptone, 10 g l(-1) sucrose and 20% CW was suitable for the sub-culture of protocorm-like bodies (PLBs) in which the PLB proliferation ratio was 2.88. Quarter-strength MS medium containing 1.0 mg l(-1) NAA, 1.0 g l(-1) peptone, 100 g l(-1) banana homogenate (BH), and 1.0 g l(-1) AC was suitable for plantlet formation and 95.67% of plantlets developed from PLBs within 60 days of culture. Hyponex N016 medium supplemented with 0.5 mg l(-1) NAA, 1.0 g l(-1) peptone, 20 g l(-1) sucrose, 150 g l(-1) BH, and 1.0 g l(-1) AC was suitable for the in vitro growth of plantlets about 2-cm in height. Plantlets 3-cm in height or taller were transplanted to Chilean sphagnum moss, and 95% of plantlets survived after 60 days in a greenhouse. Three hundred transplanted of seedlings 360-days old were reintroduced into three natural habitats. Highest percentage survival (79.67%) was observed in Yuanjiang Nature Reserve two years after reintroduction, followed by Huolu Mountain forest park (71.33%). This protocol is an efficient means for the large-scale propagation and in vitro and in vivo germplasm conservation of R. imschootiana.

Nature 531, 323–328 (2016); doi:10.1038/nature17181 In this Article, errors in the length of the scale bars were inadvertently introduced into Fig. 3e and Extended Data Fig. 7b. The corrected Fig. 3e is shown as Fig. 1 of this Corrigendum and the corrected Extended Data Fig. 7b is shown in the Supplementary Information to this Corrigendum (both of the corrected scale bars are now shorter).

In this work, two novel crown ether functionalized ionic liquid (FIL)-based solid phase microextraction (SPME) fibers were prepared by sol–gel technology using the synthesized 1-(trimethoxysily)propyl 3-(6′-oxo-benzo-15-crown-5 hexyl) imidazolium bis(trifluoromethanesulphonyl)imide ([TMSP(Benzo15C5)HIM][N(SO 2 CF 3 ) 2 ]) and 1-allyl-3-(6′-oxo-benzo-15-crown-5 hexyl) imidazolium bis(trifluoromethanesulphonyl)imide ([A(Benzo15C5)HIM][N(SO 2 CF 3 ) 2 ]) as selective stationary phases. Owing to the introduction of trimethoxysilypropyl to the imidazole cation, the [TMSP(Benzo15C5)HIM][N(SO 2 CF 3 ) 2 ] could be chemically bonded to the formed sol–gel silica substrate through the hydrolysis and polycondensation reaction. Similarly, the [A(Benzo15C5)HIM][N(SO 2 CF 3 ) 2 ] was able to participate in the formation of the organic–inorganic copolymer coatings through the free radical crosslinking reaction. These two fibers were determined to have “bubble-like” surface characteristics analogous to a previously prepared [A(Benzo15C5)HIM][PF 6 ]-based fiber. Their thermal stabilities were much higher than that of the [A(Benzo15C5)HIM][PF 6 ]-based coating. They were capable of withstanding temperatures as high as 400 °C without evident loss of the crown ether FILs. They also had strong solvent, acid and alkali resistance, good coating preparation reproducibility and high selectivity for medium polar to polar compounds. The high selectivity of these two fibers could be attributed to the strong ion-dipole, hydrogen bonding and π–π interactions provided by the synergetic effect of ILs and benzo-15-crown-5 functionalities. Moreover, the selectivity of these two fibers was rather different although the structures of these two crown ether FILs were very similar. This is maybe because the relative contents of the crown ether FILs chemically bonded to the organic–inorganic copolymer coatings were quite different when prepared by different sol–gel reaction approaches.

The copper dual damascene process has been used in semiconductor manufacturing since it was introduced by IBM in mid-1990. Since then, copper interconnects shrunk dramatically following the principles of Moore’s law. Currently, there are questions regarding the extendibility of the copper dual damascene flow as the IC industry moves beyond the 10 nm node. Copper interconnects are becoming more compact at each node, causing an increase in the resistance-capacitance delay. Furthermore, voids that occur in heavily scaled vias severely impact yield. Leading semiconductor manufacturers are exploring novel metallization methods to solve these issues. One way to solve the problem is to identify metallization alternatives that provide resistance benefits over conventional technology without compromising reliability and yield. Cobalt is considered as a potential replacement candidate for copper.Cobalt plating baths typically contain cobalt salt, boric acid, and organic additives . We have recently developed new analytical techniques for complete analysis of cobalt damascene plating baths. Electrochemical methods are used to study behavior and analyze multiple organic additives present in cobalt plating baths , while other bath components can be effectively analyzed with traditional titration and/or spectroscopic methods. Fig. 1 shows the effects of commercial Suppressor and Accelerator additives used for cobalt plating. The voltammograms indicate decreased plating rate when Suppressor additive is injected into the VMS electrolyte. VMS stands for Virgin make-up solution, which contains only inorganic components. The injection of Accelerator into the electrolyte with Suppressor causes increased plating rate. Fig. 2 shows response curves of Suppressor and Accelerator. All responses are reproducible and allow accurate determination of organic additives in plating baths. This article will also reveal the effects of other bath components on the plating properties of cobalt. We will also present statistical results of electrochemical analysis of both organic additives. Figure 1

With fast development and wide applications of next-generation sequencing (NGS) technologies, genomic sequence information is within reach to aid the achievement of goals to decode life mysteries, make better crops, detect pathogens, and improve life qualities. NGS systems are typically represented by SOLiD/Ion Torrent PGM from Life Sciences, Genome Analyzer/HiSeq 2000/MiSeq from Illumina, and GS FLX Titanium/GS Junior from Roche. Beijing Genomics Institute (BGI), which possesses the world’s biggest sequencing capacity, has multiple NGS systems including 137 HiSeq 2000, 27 SOLiD, one Ion Torrent PGM, one MiSeq, and one 454 sequencer. We have accumulated extensive experience in sample handling, sequencing, and bioinformatics analysis. In this paper, technologies of these systems are reviewed, and first-hand data from extensive experience is summarized and analyzed to discuss the advantages and specifics associated with each sequencing system. At last, applications of NGS are summarized.

Nature 523, 607–611 (2015); doi:10.1038/nature14650 In this Letter, author Yong-Bin Yan was incorrectly associated with affiliation number 5 (Department of Ophthalmology, Xijing Hospital) instead of affiliation number 4 (State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China).