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Orientadores: Mônica Alonso Cotta, Peter Alexander Bleinroth Schulz Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Física Gleb Wataghin Resumo: Neste trabalho caracterizamos as propriedades elétricas de nanoestruturas semicondutoras de InAs/InP, principalmente quantum dots e quantum wires, obtidas pelo modo de crescimento Stranski-Krastanov com epitaxia por feixe químico (CBE). Medidas de topografia, de condutância elétrica e corrente-voltagem com resolução espacial foram realizadas nas estruturas crescidas utilizando microscopia de força atômica em modo condutivo (C-AFM) com ponta metalizada. Estruturas tipo mesa foram processadas nas amostras usadas em C-AFM e medidas elétricas a temperaturas mais baixas que 273 K foram adquiridas. Transporte por emissão termiônica tridimensional (não-homogêneo) foi observado entre a ponta condutora e as nanoestruturas de InAs. Isso sugere que as vizinhanças da nanoestrutura, formada pela wetting layer (WL), alteram a configuração da altura da barreira, tornando-a dependente da voltagem aplicada na junção metal-semicondutor. Por outro lado, a voltagem de limiar, definida como a voltagem necessária para obter a menor corrente elétrica detetável, varia com o tamanho e forma da nanoestrutura; ela está relacionada com o estado eletrônico da nanoestrutura e também com o gap eletrônico do semicondutor, que é menor nas nanoestruturas maiores. Condução elétrica por hopping e ruído telegráfico aleatório (RTN) foram observados a baixas temperaturas nos dispositivos fabricados via e-beam com dezenas ou centenas de nanoestruturas de InAs/InP. O transporte tipo hopping de Éfros-Shklovskii ocorre a temperaturas mais altas (> 70 K) e polarizações baixas onde a densidade de portadores no dispositivo é baixa e a interação coulombiana forte. Com o aumento da polarização o hopping muda para intervalo variável de Mott em sistemas 2D, e correlacionado com a dimensionalidade da WL ¿o canal de condução. O RTN aparece em temperaturas mais baixas (< 40 K) mas somente nos dispositivos contendo nanoestruturas que permitem o aprisionamento de portadores. Simulações numéricas usando um modelo heurístico mostraram que poucas nanoestruturas podem alterar o transporte elétrico num ensemble com centenas delas Abstract: In this work we characterized the electrical properties of InAs/InP semiconductor nanostructures, mainly quantum dots e quantum wires, obtained by Stranski-Krastanov growth mode using chemical beam epitaxy (CBE). Topography, electrical conductance, and current-voltage measurements with spatial resolution were performed on the grown structures using atomic force microscopy in conductive mode (C-AFM) with metalized tip. Mesa-like structures were processed on the samples used in C-AFM; electrical measurements at temperatures lower than 273 K were then acquired. Three-dimensional thermionic emission (non-homogeneous) transport was observed between the conductive tip and the InAs nanostructures. This suggests that the nanostructure neighborhood, formed by the wetting layer (WL), changes the barrier height configuration and makes it dependent on the voltage applied to the metal-semiconductor junction. On the other hand, the threshold voltage, defined as the voltage necessary to detect the lowest current level, varies with nanostructure size and shape; it is related to the nanostructure electronic state and also to the semiconductor electronic gap that is smaller for the larger nanostructures. Electrical conductance via hopping and random telegraphic noise (RTN) were observed at low temperatures on the devices fabricated via e-beam with dozens or hundreds of InAs/InP nanostructures. The Éfros-Shklovskii hopping transport occurs at higher temperatures (> 70 K) and low polarizations where the device carrier density is low and the coulombian interaction is strong. Increasing the polarization the hopping changes to the Mott variable range on 2D system, which correlates to the WL dimensionality ¿the conduction channel. The RTN appears in low temperatures (< 40 K) but only in those devices with nanostructures that allow carrier trapping. Numerical simulations using a heuristic model showed that few nanostructures can change the electrical transport in an ensemble with hundreds of them Doutorado Física Doutor em Ciências FAPESP 01/13463-1

Orientador: Mônica Alonso Cotta Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Fisica Gleb Wataghin Resumo: Este trabalho teve como objetivo implementar novas técnicas de microscopia por varredura com ponta de prova no equipamento existente no LPD/DFA/UNICAMP e aplicá-las ao estudo de propriedades elétricas de nanoestruturas semicondutoras. Em particular, foi necessário projetar, construir e implementar no microscópio, um circuito eletrônico de medição de corrente com alta sensibilidade para realizar medidas de condutividade local com microscopia por força atômica, utilizando uma ponta condutora. Com a adição de uma placa de aquisição de dados, foi possível obter também medidas de corrente-voltagem com resolução espacial (espectroscopia I'V). As técnicas implementadas foram primeiramente aplicadas em diferentes materiais no sentido de testar seu funcionamento, resolução e limites de utilização. Posteriormente aplicamos as técnicas de caracterização elétrica a filmes semicondutores crescidos por epitaxia de feixe químico, com particular interesse em filmes tensionados que originam nanoestruturas. O modo de força eletrostática foi utilizado para medidas do potencial de superfície (diferença entre as funções trabalho de dois materiais), com a finalidade de determinar a posição do nível de Fermi das diferentes amostras estudadas. Neste caso, a placa de aquisição de dados foi utilizada para fornecer diretamente o potencial de superfície, semelhante à técnica Kelvin-Probe. Embora a técnica não tenha mostrado resolução espacial para identificação das nanoestruturas na superfície da amostra, puderam ser observadas diferenças entre as várias amostras analisadas, interpretadas como resultado da presença do filme tensionado. Medidas de corrente e espectroscopia I'V, em amostras de InAs/InP, mostraram que a característica elétrica do contato entre a ponta metalizada e um dot é do tipo Schottky, devido à oxidação causada pela exposição ao ar. Variações de corrente sobre diferentes regiões de um mesmo dot são atribuídas a efeitos de convolução ponta-amostra. Utilizando o microscópio de força atômica como ferramenta para nanolitografia, foram desenvolvidos os processos iniciais para produção de dispositivos com as nanoestruturas crescidas. Isso permitirá que sejam realizadas medidas de transporte elétrico entre as nanoestruturas, com temperaturas mais baixas que a ambiente Abstract: In this work new scanning probe techniques were implemented to the existing atomic force microscope at LPD/DFA/UNICAMP and used to study the electrical properties of semiconductor nanostructures. To achieve this goal, it was necessary to design, build and set up an eletronic circuit able to measure currents with high sensitivity, for local conductance measurements with the atomic force microscope using conducting tips. With the addition of a data acquisition board, spatially-resolved current-voltage measurements (I'V spectroscopy) were obtained. The new techniques were first used with different materials in order to test their functioning, limits and resolution. After that, the electrical characterization techniques were used to study semiconductor samples grown by chemical beam epitaxy, with particular interest in strained films with self-assembled nanostructures. Electrostatic force microscopy was used for surface potential (difference in the work function of two different materials) measurements in order to determine the Fermi level energy of our samples. In this case the data acquisition board was used to directly provide the surface potential, similarly to the Kelvin-Probe technique. Although our results could not spatially resolve the surface nanostructures in our samples, different surface potential values were measured for the different samples, and were interpreted as a result of the presence of the strained film. Current measurements as well as I'V spectroscopy for InAs/InP samples have shown a Schottky-type contact for the metalized tip and dot, due to the oxidation of the sample surface caused by exposure to air. Current variations over different regions of the same dot were attributed to the tip-sample convolution. Using the atomic force microscope as a nanolithography tool, we have developed the initial processing steps to produce devices with the epitaxial nanostructures. This will allow electrical transport experiments at temperatures lower than 300K Mestrado Física Mestre em Física

Most previous studies that examined the effect of anxiety on hostility towards a distinct group have focused on cases in which we hate those we are afraid of. The current study, on the other hand, examines the relationship between anxiety in one domain and hostility towards a distinct group that is not the source of that anxiety. We focus here on symptoms of anxiety during the COVID-19 pandemic, which have become increasingly frequent, and show that the implications of such mental difficulties are far-reaching, posing a threat to relationships between ideological groups. In two studies conducted in both Israel and the United States, we found that high levels of anxiety during the COVID-19 epidemic are associated with higher levels of hatred towards ordinary people from the respective political outgroups, lower levels of willingness to sustain interpersonal relations with these people (i.e., greater social distancing), and greater willingness to socially exclude them. This relationship was mediated by the perception of threat posed by the political outgroup. This study is the first to show that mental difficulty driven by an external threat can be a fundamental factor that explains levels of intergroup hostility.

Enhancement of Wnt signaling is fundamental for stem cell function during intestinal regeneration. Molecular modules control Wnt activity by regulating signal transduction. CD44 is such a positive regulator and a Wnt target gene. While highly expressed in intestinal crypts and used as a stem cell marker, its role during intestinal homeostasis and regeneration remains unknown. Here we propose a CD44 positive-feedback loop that boosts Wnt signal transduction, thus impacting intestinal regeneration. Excision of Cd44 in Cd44

The main protease (Mpro) of SARS-CoV-2 is a current target for the inhibition of viral replication. Through a combined Docking and Density Functional Theory (DFT) approach, we investigated in-silico the molecular mechanism by which ebselen (IUPAC: 2-phenyl-1,2-benzoselenazol-3-one), the most famous and pharmacologically active organoselenide, inhibits Mpro. For the first time, we report on a mechanistic investigation in an enzyme for the formation of the covalent -S-Se- bond between ebselen and a key enzymatic cysteine. The results highlight the strengths and weaknesses of ebselen and provide hints for a rational drug design of bioorganic selenium-based inhibitors.

Mitochondria are essential regulators of cellular energy and metabolism, and have a crucial role in sustaining the growth and survival of cancer cells. A central function of mitochondria is the synthesis of ATP by oxidative phosphorylation, known as mitochondrial bioenergetics. Mitochondria maintain oxidative phosphorylation by creating a membrane potential gradient that is generated by the electron transport chain to drive the synthesis of ATP1. Mitochondria are essential for tumour initiation and maintaining tumour cell growth in cell culture and xenografts2,3. However, our understanding of oxidative mitochondrial metabolism in cancer is limited because most studies have been performed in vitro in cell culture models. This highlights a need for in vivo studies to better understand how oxidative metabolism supports tumour growth. Here we measure mitochondrial membrane potential in non-small-cell lung cancer in vivo using a voltage-sensitive, positron emission tomography (PET) radiotracer known as 4-[18F]fluorobenzyl-triphenylphosphonium (18F-BnTP)4. By using PET imaging of 18F-BnTP, we profile mitochondrial membrane potential in autochthonous mouse models of lung cancer, and find distinct functional mitochondrial heterogeneity within subtypes of lung tumours. The use of 18F-BnTP PET imaging enabled us to functionally profile mitochondrial membrane potential in live tumours. A positron emission tomography imaging tracer is developed to image mitochondrial function in vivo, and application of this tracer to a mouse model of lung cancer identifies distinct functional mitochondrial heterogeneity between tumour cells.

Exposure of mitochondrial parkinsonian neurotoxin 1-methyl-4-phenylpyridinium ion (MPP+) to PC-12 cells results in significant cell death, decreases lysosomal acidity, and inhibits autophagic flux. Biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) of ≈100 nm diameter localize to the lysosome, degrade, and subsequently release their acidic components to acidify the local lysosomal environment. The performance of PLGA NPs with different lysosomal pH modulating capabilities is investigated in PC-12 cells under MPP+ induced mitochondrial toxicity. PLGA NPs perform in a compositional dependent manner, where NPs with a higher glycolic acid to lactic acid ratio content degrade faster and yield greater degrees of lysosomal pH modulation as well as autophagic flux modulation in PC-12 cells under MPP+ insult. These results show that slight compositional changes of the polymeric NP give rise to differing degrees of lysosomal acidification in PC-12 cells and afford improved cellular degradative a...

This chapter presents an overview of recent work on cultural intermediaries and the ‘creative class’ in relation to social inequality. The chapter looks at Britain’s ‘creative class’ in relation to workforce patterns, tastes, social attitudes, and their faith in the transformative power of culture. Ultimately the chapter suggests we need caution when thinking about the impact of cultural intermediaries on social inequality.

The prevailing dogma is that thermogenic brown adipose tissue (BAT) contributes to improvements in glucose homeostasis in obesogenic animal models, though much of the evidence supporting this premise is from thermostressed rodents. Determination of whether modulation of the BAT morphology/function drives changes in glucoregulation at thermoneutrality requires further investigation. We used loss- and gain-of-function approaches including genetic manipulation of the lipolytic enzyme Pnpla2, change in environmental temperature, and lifestyle interventions to comprehensively test the premise that a thermogenic-like BAT phenotype is coupled with enhanced glucose tolerance in female mice. In contrast to this hypothesis, we found that 1) compared to mice living at thermoneutrality, enhanced activation of BAT and its thermogenic phenotype via chronic mild cold stress does not improve glucose tolerance in obese mice, 2) silencing of the Pnpla2 in interscapular BAT causes a brown-to-white phenotypic shift accompanied with inflammation but does not disrupt glucose tolerance in lean mice, and 3) exercise and low-fat diet improve glucose tolerance in obese mice but these effects do not track with a thermogenic BAT phenotype. Collectively, these findings indicate that a thermogenic-like BAT phenotype is not linked to heightened glucose tolerance in female mice.

Objective Mitochondria are organelles primarily responsible for energy production, and recent evidence indicates that alterations in size, shape, location, and quantity occur in response to fluctuations in energy supply and demand. We tested the impact of acute and chronic exercise on mitochondrial dynamics signaling and determined the impact of the mitochondrial fission regulator Dynamin related protein (Drp)1 on exercise performance and muscle adaptations to training. Methods Wildtype and muscle-specific Drp1 heterozygote (mDrp1+/−) mice, as well as dysglycemic (DG) and healthy normoglycemic men (control) performed acute and chronic exercise. The Hybrid Mouse Diversity Panel, including 100 murine strains of recombinant inbred mice, was used to identify muscle Dnm1L (encodes Drp1)-gene relationships. Results Endurance exercise impacted all aspects of the mitochondrial life cycle, i.e. fission-fusion, biogenesis, and mitophagy. Dnm1L gene expression and Drp1Ser616 phosphorylation were markedly increased by acute exercise and declined to baseline during post-exercise recovery. Dnm1L expression was strongly associated with transcripts known to regulate mitochondrial metabolism and adaptations to exercise. Exercise increased the expression of DNM1L in skeletal muscle of healthy control and DG subjects, despite a 15% ↓(P = 0.01) in muscle DNM1L expression in DG at baseline. To interrogate the role of Dnm1L further, we exercise trained male mDrp1+/− mice and found that Drp1 deficiency reduced muscle endurance and running performance, and altered muscle adaptations in response to exercise training. Conclusion Our findings highlight the importance of mitochondrial dynamics, specifically Drp1 signaling, in the regulation of exercise performance and adaptations to endurance exercise training., Highlights • Skeletal muscle expression of the mitochondrial fission regulator Dnm1L (encodes Drp1) is increased in mice and men during acute exercise. • DNM1L expression is reduced in muscle from dysglycemic vs. normoglycemic men at rest and during exercise. • Phospho-Drp1Ser616 (activation) is elevated in muscle from male and female mice during acute exercise and returns to baseline during post-exercise recovery. • Dnm1L expression is critical for exercise performance and muscle adaptations in response to endurance exercise training.

HIG2A promotes cell survival under hypoxia and mediates the assembly of complex III and complex IV into respiratory chain supercomplexes. In the present study, we show that human HIGD2A and mouse Higd2a gene expressions are regulated by hypoxia, glucose, and the cell cycle-related transcription factor E2F1. The latter was found to bind the promoter region of HIGD2A. Differential expression of the HIGD2A gene was found in C57BL/6 mice in relation to tissue and age. Besides, the silencing of HIGD2A evidenced the modulation of mitochondrial dynamics proteins namely, OPA1 as a fusion protein increases, while FIS1, a fission protein, decreases. Besides, the mitochondrial membrane potential (ΔΨm) increased. The protein HIG2A is localized in the mitochondria and nucleus. Moreover, we observed that the HIG2A protein interacts with OPA1. Changes in oxygen concentration, glucose availability, and cell cycle regulate HIGD2A expression. Alterations in HIGD2A expression are associated with changes in mitochondrial physiology.

The law of Deuteronomy 23:2-9 (MT), stipulating who is to be excluded from the Assembly of God, envisaged a need to explain its absolute exclusion of two foreign nations (the Ammonites and the Moabites), alongside its more lenient approach towards members of two other foreign nations (the Edomites and the Egyptians), as expressed in their temporal exclusion from the Assembly. The eternal exclusion of the Ammonites and the Moabites is justified by their historical, unfriendly treatment of Israel on its march from Egypt to the Promised Land. The immediate question, however, is whether the other two nations mentioned in this law treated Israel any better, prior to that march and during its course. Indeed, answering this question in the negative appears to be the goal of another Pentateuchal text, Numbers 20:14-21. Underlying the criticism of Deuteronomy 23:4-9 in Numbers 20:14-21 is the Priestly-Deuteronomic fundamental controversy over the meaning of the covenant of circumcision.

Objective: Despite progress in treating relapsing multiple sclerosis (MS), effective inhibition of nonrelapsing progressive MS is an urgent, unmet, clinical need. Animal models of MS, such as experimental autoimmune encephalomyelitis (EAE), provide valuable tools to examine the mechanisms contributing to disease and may be important for developing rational therapeutic approaches for treatment of progressive MS. It has been suggested that myelin oligodendrocyte glycoprotein (MOG) peptide residues 35-55 (MOG35-55)-induced EAE in nonobese diabetic (NOD) mice resembles secondary progressive MS. The objective was to determine whether the published data merits such claims. Methods: Induction and monitoring of EAE in NOD mice and literature review. Results: It is evident that the NOD mouse model lacks validity as a progressive MS model as the individual course seems to be an asynchronous, relapsing-remitting neurodegenerative disease, characterized by increasingly poor recovery from relapse. The seemingly progressive course seen in group means of clinical score is an artifact of data handling and interpretation. Interpretation: Although MOG35-55-induced EAE in NOD mice may provide some clues about approaches to block neurodegeneration associated with the inflammatory penumbra as lesions form, it should not be used to justify trials in people with nonactive, progressive MS. This adds further support to the view that drug studies in animals should universally adopt transparent raw data deposition as part of the publication process, such that claims can adequately be interrogated. This transparency is important if animal-based science is to remain a credible part of translational research in MS.

Changes to mitochondrial architecture are associated with various adaptive and pathogenic processes. However, quantification of changes to mitochondrial structures is limited by the yet unmet challenge of defining the borders of each individual mitochondrion within an image. Here, we describe a novel method for segmenting primary brown adipocyte (BA) mitochondria images. We describe a granular approach to quantifying subcellular structures, particularly mitochondria in close proximity to lipid droplets: peridroplet mitochondria. In addition, we lay out a novel machine-learning-based mitochondrial segmentation method that eliminates the bias of manual mitochondrial segmentation and improves object recognition compared to conventional thresholding analyses. By applying these methods, we discovered a significant difference between cytosolic and peridroplet BA mitochondrial H

Multiple sclerosis (MS) is an autoimmune disease targeting the central nervous system, characterized by an unpredictable disease course and a wide range of symptoms. Emotional and cognitive deficits are now recognized as primary disease manifestations and not simply the consequence of living with a chronic condition, raising questions regarding the efficacy of current therapeutics for these specific symptoms. Mechanisms underlying psychiatric sequelae in MS are believed to be similar to those underlying pathogenesis, that is mediated by cytokines and other inflammatory mediators. To gain insight into the pathogenesis of MS depression, we performed behavioral assays in the murine experimental autoimmune encephalomyelitis (EAE) MS model, in the presence or absence of immunomodulation using the drug FTY720, an analogue of the lipid signaling molecule sphingosine-1-phosphate (S1P). Specifically, mice were challenged with the elevated plus maze (EPM) test, a validated experimental paradigm for rodent-specific anxiety-like behavior. FTY720 treatment failed to ameliorate anxiety-like symptoms, irrespective of dosage. On the other hand, it was effective in reducing inflammatory infiltration, microglial reactivity and levels of pro-inflammatory molecules in the hippocampus, confirming the anti-inflammatory capacity of treatment. To explore the absence of FTY720 effect on behavior, we confirmed expression of S1P receptors (S1PR) S1PR1, S1PR3 and S1PR5 in the hippocampus and mapped the dynamics of these receptors in response to drug treatment alone, or in combination with EAE induction. We identified a complex pattern of responses, differing between (1) receptors, (2) dosage and (3) hippocampal sub-field. FTY720 treatment in the absence of EAE resulted in overall downregulation of S1PR1 and S1PR3, while S1PR5 exhibited a dose-dependent upregulation. EAE induction alone resulted in overall downregulation of all three receptors. On the other hand, combined FTY720 and EAE showed generally no effect on S1PR1 and S1PR3 expression except for the fimbrium region, but strong upregulation of S1PR5 over the range of doses examined. These data illustrate a hitherto undescribed complexity of S1PR response to FTY720 in the hippocampus, independent of drug effect on effector immune cells, but simultaneously emphasize the need to explore novel treatment strategies to specifically address mood disorders in MS.

Metal-mediated [2+2+2] cycloadditions of unsaturated molecules to cyclic and polycyclic organic compounds are a versatile synthetic route affording good yields and selectivity under mild conditions. In the last two decades, in silico investigations have unveiled important details about the mechanism and the energetics of the whole catalytic cycle. Particularly, a number of computational studies address the topic of half-sandwich catalysts which, due to their structural fluxionality, have been widely employed, since the 1980s. In these organometallic species, the metal is coordinated to an aromatic ring, typically the ubiquitous cyclopentadienyl anion, C5H5 –(Cp) or to the Cp moiety of a larger polycyclic aromatic ligand (Cp′). During the catalytic process, the metal continuously ‘slips’ on the ring, changing its hapticity. This phenomenon of metal slippage and its implications for the catalyst’s performance are discussed in this work, referring to the most important computational mechanistic studies reported in literature for Rh(I) half-metallocenes, with the purpose of providing hints for a rational design of this class of compounds.1 Introduction2 Mechanism of Metal-Catalyzed Acetylene [2+2+2] Cycloaddition to Benzene and the Problem of the Indenyl Effect2.1 Acetylene-Acetonitrile [2+2+2] Co-cycloaddition to 2-Methylpyridine: Evidence of the Indenyl Effect2.2 Heteroaromatic Catalysts and the Evidence of a Reverse Indenyl Effect2.3 Booth’s Mechanistic Hypothesis and the Evidence of the Indenyl Effect3 Structure–Reactivity Correlation: The Slippage-Span Model4 Conclusions and Perspectives