Trends and differences of the temperature effect on mismatch in different CMOS technology nodes

Statistical drain-current differences between pairs of supposedly identical transistors, usually known as matching, represent a crucial aspect of analog and mixed-signal circuits. Although matching has been a subject of study for more than two decades, how the temperature affects it is still scarcely discussed in the open literature [1,2]. In previous work, we discussed temperature effects on matching properties for a low-power CMOS 65-nm platform [1]. Measurements have been performed over a temperature range of 0 ◦C to 125 ◦C under several operating conditions. We discussed the temperature impact on relative current mismatch in the deep subthreshold region and the behavior of relative ION mismatch for individual pairs over temperature. Both subjects are important in modern circuit designs since the subthreshold region is often employed in ultra low-power circuits, while a drift in the individual pair mismatch can create problems in trimmed circuits. In this paper we expand the original study by considering a wide span of technology nodes (140 nm to 45 nm). A broader range of device architectures and gate lengths is crucial for a better understanding of the physics behind the mismatch-temperature relation and propose consistent compact model solutions. The relative drain current mismatch is analyzed using fluctuation sweeps. In figures 1 and 2 an example of this comparison is shown. The device architecture has a big impact on the matching already at room temperature, for example in the case of NMOS for C45 (Fig. 1) the presence of the halos worsens the matching [3]. It is therefore interesting to see how such changes affect the temperature dependence. In this respect, trends of the threshold voltage mismatch and the relative current factor mismatch will be also shown. In conclusion, this paper provides reliable information for circuit designers and system architects on the issue of the influence of temperature on mismatch based on a large set of measurements spanning different technology nodes

Improvement of regeneration in pepper: a recalcitrant species

[EN] Organogenesis is influenced by factors like genotype, type of explant, culture medium components, and incubation conditions. The influence of ethylene, which can be produced in the culture process, can also be a limiting factor in recalcitrant species like pepper. In this work, bud induction was achieved from cotyledons and hypocotyls-from eight pepper cultivars-on Murashige and Skoog (MS) medium supplemented with 22.2 mu M 6-benzyladenine (6BA) and 5.71 mu M indole-3-acetic acid (IAA), in media with or without silver nitrate (SN) (58.86 mu M), a suppressor of ethylene action. In the SN-supplemented medium, the frequencies of explants with buds and with callus formation were lower in both kinds of explant, but higher numbers of developed shoots were isolated from explants cultured on SN. Bud elongation was better in medium with gibberellic acid (GA(3)) (2.88 mu M) than in medium free of growth regulators or supplemented with 1-aminocyclopropane-1-carboxylic acid (ACC) at 34.5 mu M. However, isolation of shoots was difficult and few plants were recovered. The effect of adding SN following bud induction (at 7 d) and that of dark incubation (the first 7 d of culture) was also assessed in order to improve the previous results. When SN was added after bud induction, similar percentages of bud induction were found for cotyledons (average frequency 89.37% without SN and 94.37% with SN) whereas they doubled in hypocotyls (50% without SN and 87.7% with SN). In addition, in both kinds of explant, the number of developed plants able to be transferred to soil (developed and rooted) was greatly increased by SN. Dark incubation does not seem to improve organogenesis in pepper, and hypocotyl explants clearly represent a better explant choice-with respect to cotyledonary explants-for the pepper cultivars assayed.We thank the COMAV germplasm bank at Universitat Politecnica de Valencia and the Arid Lands Institute for pepper seeds and the Tunisian Ministry of Higher Education and Scientific Research who fund N. Gammoudi's stay.Gammoudi, N.; San Pedro-Galan, T.; Ferchichi, A.; Gisbert Domenech, MC. (2018). Improvement of regeneration in pepper: a recalcitrant species. In Vitro Cellular & Developmental Biology - Plant. 54(2):145-153. https://doi.org/10.1007/s11627-017-9838-1S145153542Ashrafuzzaman M, Hossain MM, Razi Ismail M, Shahidul Haque M, Shahidullah SM, Uz Zaman S (2009) Regeneration potential of seedling explants of chilli (Capsicum annuum). Afr J Biotechnol 8:591–596Bortesi L, Fischer R (2015) The CRISPR/Cas9 system for plant genome editing and beyond. 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Physiol Plant 53:319–326Hyde CL, Phillips GC (1996) Silver nitrate promotes shoot development and plant regeneration of chile pepper (Capsicum annuum L.) via organogenesis. In Vitro-Plant 32:72–80Kothari SL, Joshi A, Kachhwaha S, Ochoa-Alejo N (2010) Chilli peppers—a review on tissue culture and transgenesis. Biotechnol Adv 28:35–48Kumar AO, Rupavathi T, Tata SS (2012) Adventitious shoot bud induction in chili pepper (Capsicum annuum L. cv. X-235). In J Sci Nat 3:192–196Kumar PP, Lakshmanan P, Thorpe TA (1998) Regulation of morphogenesis in plant tissue culture by ethylene. In Vitro Cell Dev Biol Plant 34:94–103Liu W, Parrott WA, Hildebrand DF, Collins GB, Williams EG (1990) Agrobacterium induced gall formation in bell pepper (Capsicum annuum L.) and formation of shoot-like structures expressing introduced genes. 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In: George EF, Hall MA, Klerk G-JD (eds) Plant propagation by tissue culture, vol 1, 3rdedn. Springer, Dordrecht, The Netherlands, pp 239–248Murashige T, Skoog F (1962) A revised medium for rapid growth and bioassays with tobacco tissue cultures. Physiol Plant 15:473–497Nogueira RC, Paiva R, de Oliveira LM, Soares GA, Soares FP, Castro AHF, Paiva PDO (2007) Calli induction from leaf explants of murici-pequeno (Byrsonima intermedia A. Juss.) Ciênc Agrotec 31:366–370Ochoa-Alejo N, Ramirez-Malagon R (2001) In vitro chili pepper biotechnology. In Vitro Cell Devl Biol Plant 37:701–729Orlińska M, Nowaczy P (2015) In vitro plant regeneration of 4 Capsicum spp. genotypes using different explant types. Turk J Biol 39:60–68Reid MS (1995) Ethylene in plant growth, development and senescence. In: Davies PJ (ed) Plant hormones: physiology, biochemistry and molecular biology, 2nd edn. 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Modulating signaling networks by CRISPR/Cas9-mediated transposable element insertion

In a recent past, transposable elements (TEs) were referred to as selfish genetic components only capable of copying themselves with the aim of increasing the odds of being inherited. Nonetheless, TEs have been initially proposed as positive control elements acting in synergy with the host. Nowadays, it is well known that TE movement into host genome comprises an important evolutionary mechanism capable of increasing the adaptive fitness. As insights into TE functioning are increasing day to day, the manipulation of transposition has raised an interesting possibility of setting the host functions, although the lack of appropriate genome engineering tools has unpaved it. Fortunately, the emergence of genome editing technologies based on programmable nucleases, and especially the arrival of a multipurpose RNA-guided Cas9 endonuclease system, has made it possible to reconsider this challenge. For such purpose, a particular type of transposons referred to as miniature inverted-repeat transposable elements (MITEs) has shown a series of interesting characteristics for designing functional drivers. Here, recent insights into MITE elements and versatile RNA-guided CRISPR/Cas9 genome engineering system are given to understand how to deploy the potential of TEs for control of the host transcriptional activity.Fil: Vaschetto, Luis Maria Benjamin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Diversidad y Ecología Animal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto de Diversidad y Ecología Animal; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Cátedra de Diversidad Animal I; Argentin

Phase II study of eribulin in combination with gemcitabine for the treatment of patients with locally advanced or metastatic triple negative breast cancer (ERIGE Trial). Clinical and pharmacogenetic results on behalf of the Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC)

Background: There are no well-established chemotherapy regimens for metastatic triple negative breast cancer. The combination of a microtubule inhibitor (eribulin) with a nucleoside analog (gemcitabine) may synergistically induce tumor cell death, especially in tumors like triple negative breast cancers (TNBC) characterized by high cell proliferation, aggressive tumor behavior, and chemo-resistance. Materials and Methods:This is an open-label, national multicenter phase II study evaluating the combination of eribulin (0.88 mg/m2) plus gemcitabine (1000 mg/m2) on day 1 and 8, q21 as either first- or second-line treatment of locally advanced or metastatic TNBC.The primary endpoint was the objective response rate (ORR) for evaluable patients (pts). The study was designed according to the Simon's two stage optimal design. We chose the lower activity (p0) of 0.20 and target activity level (p1) of 0.35. A prospective, molecular correlative study has been being carried out on germinal DNA of study population to assess the role of BRCA mutations and single nucleotide polymorphisms (SNPs) in predicting efficacy and toxicity of the combination regimen. Results: From July 2013 to September 2016, 83 evaluable pts (37 in the first stage, 46 in the second one) were enrolled. They received a median number of 6 cycles of treatment (range 1-24). The ORR (CR+PR) was 37.35% (90% CI: 28.47-46.93) and the clinical benefit rate (CR+PR+SD 65 24wks) was 48.78% (90% CI: 39.24%-58.39%). The most common grade 3-4 adverse events (> 10% of patients) were neutropenia and liver toxicity. With a median follow-up of 28.8 months, the median progression-free survival (PFS) and overall survival (OS) were 5.1 months (95% CI: 4.2-7.0) and 14.7 months (95% CI: 10.2-20.0), respectively. BRCA1/2 deleterious mutations were observed in 15 (22%) out of 68 genotyped pts. Women with BRCA1/2 mutations were associated with worse ORR, PFS and OS than those with BRCA1/2 wild-type. A panel of SNPs in genes of study drug metabolism pathways was evaluated. Among these, CYP3A4 392A >G and FGD4 2044236G>A SNPs were associated with greater liver toxicity by logistic regression analysis. Furthermore, CDA*2 79A>C, RRM1 2455 A>G, and CYP2C8 416G>A SNPs were associated with poorer overall survival by Cox proportional hazards model. Conclusions:The combination of eribulin and gemcitabine shows promising activity and a moderate toxicity profile in metastatic TNBC. BRCA status and pharmacogenetics tests may help identify pts with high probability of response with negligible toxicity

Synchronous Presence of EGFR, ALK Driver Mutations Along With PD L1 Overexpression in a Resected Early Stage Non-Small Cell Lung Cancer: A Case Report and Review of Literature.

Treatment of lung cancer has been revolutionized with development of drugs that target key driver mutations and immune checkpoints. Until recently, it was believed that these driver mutations are mutually exclusive. However, few reports have emerged citing the presence of both mutations either synchronously or metachronously. We describe a case report of lung adenocarcinoma harboring two driver mutations in the same tumor cells as well as exhibiting high PDL1 expression. We further discuss the possible association of these driver mutations with PDL1 expression

Biopsy confirmation of metastatic sites in breast cancer patients:clinical impact and future perspectives

Determination of hormone receptor (estrogen receptor and progesterone receptor) and human epidermal growth factor receptor 2 status in the primary tumor is clinically relevant to define breast cancer subtypes, clinical outcome,and the choice of therapy. Retrospective and prospective studies suggest that there is substantial discordance in receptor status between primary and recurrent breast cancer. Despite this evidence and current recommendations,the acquisition of tissue from metastatic deposits is not routine practice. As a consequence, therapeutic decisions for treatment in the metastatic setting are based on the features of the primary tumor. Reasons for this attitude include the invasiveness of the procedure and the unreliable outcome of biopsy, in particular for biopsies of lesions at complex visceral sites. Improvements in interventional radiology techniques mean that most metastatic sites are now accessible by minimally invasive methods, including surgery. In our opinion, since biopsies are diagnostic and changes in biological features between the primary and secondary tumors can occur, the routine biopsy of metastatic disease needs to be performed. In this review, we discuss the rationale for biopsy of suspected breast cancer metastases, review issues and caveats surrounding discordance of biomarker status between primary and metastatic tumors, and provide insights for deciding when to perform biopsy of suspected metastases and which one (s) to biopsy. We also speculate on the future translational implications for biopsy of suspected metastatic lesions in the context of clinical trials and the establishment of bio-banks of biopsy material taken from metastatic sites. We believe that such bio-banks will be important for exploring mechanisms of metastasis. In the future,advances in targeted therapy will depend on the availability of metastatic tissue

High-throughput methodology to identify CRISPR-generated Danio rerio mutants using fragment analysis with unmodified PCR products

Targeted mutagenesis in zebrafish, fruit flies, and C. elegans has been significantly improved over the years through CRISPR technology. CRISPR enables researchers to efficiently examine cellular pathways by inducing small, targeted mutations in vivo. Though these mutations are commonly random insertions or deletions (indels), they often result in functionally disrupted alleles of a target gene if the CRISPR components are appropriately designed. However, current protocols used to identify the presence of CRISPR-generated indels are often labor intensive, time-consuming, or expensive. Here, we describe a straightforward, high-throughput method for identifying the presence of mutations by using a fragment analyzer platform which allows for DNA fragment sizing through high-resolution capillary gel-electrophoresis. Following this protocol, small indels-down to 2 base pairs-can be quickly and reliably identified, thus allowing for large-scale genotyping of newly-generated or stable mutant lines

Making complex things simpler: modern tools to edit the plant genome

There are several technologies for plant genome editing, of which the most simple and universal is CRISPR/Cas. Currently, this technology is widely used for gene knockout, deleting genome fragments and inserting exogenous sequences in the plant genome. For each of these applications, many different types of genetic tools have been developed that are used by various research groups to solve specific problems. The CRISPR/Cas technology for plant genome editing is at an early stage of optimization, which is reflected by the ongoing search for the most effective, simple and flexible techniques. As a result, experimental work has to be preceded by a rather long and laborious process of selecting a genetic tool that will be optimal for a specific experimental task. In our review we describe the main variants of the CRISPR/Cas technology used to edit a plant genome. We classify them in terms of experimental tasks solved, major components and technology performance. In the first half of the review a detailed description of two major components of CRISPR/Cas technology – nuclease and guide RNA – is given, the effect of structural features of these elements on editing efficiency is analyzed. Experimental data on the relationship between editing efficiency and nucleotide sequence of guide RNA are generalized. We also give the characteristic for different variants of nucleases used for plant genome editing and discuss their benefits for different experimental purposes. In the second half of the review various strategies for expression of CRISPR/Cas elements in plant cells, in particular, advantages and disadvantages of stable transformation and transient expression, are discussed. The effect of various regulatory elements of genes encoding nuclease and guide RNA on editing efficiency is described. Special emphasis is placed on the techniques of increasing targeted gene replacement efficiency

Нейроэндокринный рак молочной железы. Клиническое наблюдение. Индивидуальный подход

Introduction. Neuroendocrine breast tumors represent a rare subtype of breast cancer, accounting for less than 1 % of all neuroendocrine neoplasms. Starting from their pathology definition, and going through their prevalence, prognosis and treatment, our knowledge is still really uncertain.Materials and methods. The article presents a rare clinical observation of a neuroendocrine breast tumor. A breast fibroadenoma was diagnosed at the initial diagnosis stage in a private clinic; after a surgical treatment and further morphological study, it was estimated: a diagnosis of Cancer in situ of the left breast T1N0M0, stage I. Next, 3D-conformal remote radiation therapy was performed on the area of the left breast.Results and discussion. After conducting positron emission tomography, multiple metastases were detected in the lymph nodes, bones, and liver. Additionally, micropreparations were consulted at the Federal Reference Center in St. Petersburg and at an independent third-party molecular biological laboratory in Germany (Munich). Given all the instrumental, molecular biological, histological and immunohistochemical studies of the patient, an individual regimen of drug therapy was selected.Conclusion. After 18 months of personalized drug therapy, we observed a positive trend and a significant decrease in metabolic activity according to positron emission tomography.Введение. Нейроэндокринные опухоли молочной железы представляют собой редкий подтип рака молочной железы, составляя менее 1 % всех нейроэндокринных новообразований. Исходя из определения патологии, распространенности, прогноза и лечения, наши знания все еще остаются неоформленными.Материалы и методы. В статье представлено редкое клиническое наблюдение нейроэндокринной опухоли молочной железы. Фиброаденома молочной железы диагностирована на начальном этапе в частной клинике. После хирургического лечения и дальнейшего морфологического исследования было оценено: диагноз «Рак in situ» левой груди T1N0M0, I стадия. Затем была проведена 3D-конформная дистанционная лучевая терапия в области левой груди.Результаты и обсуждение. После проведения позитронно-эмиссионной томографии обнаружены множественные метастазы в лимфатических узлах, костях и печени. Кроме того, по микропрепаратам консультировались в Федеральном справочном центре в Санкт-Петербурге и в независимой сторонней молекулярно-биологической лаборатории в Германии (Мюнхен). Учитывая все инструментальные, молекулярно-биологические, гистологические и иммуногистохимические исследования пациента, была подобрана индивидуальная схема медикаментозной терапии.Заключение. После 18 месяцев индивидуальной лекарственной терапии мы наблюдали положительную динамику и значительное снижение метаболической активности по данным позитронно-эмиссионной томографии