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1.
Org Lett ; 23(22): 8994-8999, 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34723542

RESUMO

Suzuki cross-coupling of benzylic and unactivated aliphatic fluorides with aryl- and alkenylboronic acids has been achieved via mechanistically distinct Pd and Ni catalyzed pathways that outperform competing protodeboronation, ß-hydride elimination, and homocoupling processes. The utility is demonstrated with more than 20 examples including heterocyclic structures, 1,1-disubstituted and trans-1,2-disubstituted alkenes, and by the incorporation of acetonitrile into functionalized (hetero)arenes.

2.
Nat Commun ; 12(1): 6451, 2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34750404

RESUMO

The advances of high-throughput experimentation technology and chemometrics have revolutionized the pace of scientific progress and enabled previously inconceivable discoveries, in particular when used in tandem. Here we show that the combination of chirality sensing based on small-molecule optical probes that bind to amines and amino alcohols via dynamic covalent or click chemistries and powerful chemometric tools that achieve orthogonal data fusion and spectral deconvolution yields a streamlined multi-modal sensing protocol that allows analysis of the absolute configuration, enantiomeric composition and concentration of structurally analogous-and therefore particularly challenging-chiral target compounds without laborious and time-consuming physical separation. The practicality, high accuracy, and speed of this approach are demonstrated with complicated quaternary and octonary mixtures of varying chemical and chiral compositions. The advantages over chiral chromatography and other classical methods include operational simplicity, increased speed, reduced waste production, low cost, and compatibility with multiwell plate technology if high-throughput analysis of hundreds of samples is desired.

3.
Transl Psychiatry ; 11(1): 511, 2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34620830

RESUMO

Major depressive disorder (MDD) is associated with abnormal neural circuitry. It can be measured by assessing functional connectivity (FC) at resting-state functional MRI, that may help identifying neural markers of MDD and provide further efficient diagnosis and monitor treatment outcomes. The main aim of the present study is to investigate, in an unbiased way, functional alterations in patients with MDD using a large multi-center dataset from the PsyMRI consortium including 1546 participants from 19 centers ( www.psymri.com ). After applying strict exclusion criteria, the final sample consisted of 606 MDD patients (age: 35.8 ± 11.9 y.o.; females: 60.7%) and 476 healthy participants (age: 33.3 ± 11.0 y.o.; females: 56.7%). We found significant relative hypoconnectivity within somatosensory motor (SMN), salience (SN) networks and between SMN, SN, dorsal attention (DAN), and visual (VN) networks in MDD patients. No significant differences were detected within the default mode (DMN) and frontoparietal networks (FPN). In addition, alterations in network organization were observed in terms of significantly lower network segregation of SMN in MDD patients. Although medicated patients showed significantly lower FC within DMN, FPN, and SN than unmedicated patients, there were no differences between medicated and unmedicated groups in terms of network organization in SMN. We conclude that the network organization of cortical networks, involved in processing of sensory information, might be a more stable neuroimaging marker for MDD than previously assumed alterations in higher-order neural networks like DMN and FPN.


Assuntos
Conectoma , Transtorno Depressivo Maior , Adulto , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/tratamento farmacológico , Feminino , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Vias Neurais/diagnóstico por imagem , Descanso , Adulto Jovem
4.
Artigo em Inglês | MEDLINE | ID: mdl-34679202

RESUMO

(Pseudo)halogenated quinones react smoothly with chiral amines, amino alcohols, and amino acids toward push-pull conjugates with optical sensing and switching applications. The chiroptically active conjugates serve as redox switches between two reversibly interconverting states with remarkably different UV and CD signatures. Addition of sodium borohydride generates a hydroquinone derivative that is quantitatively re-oxidized to the original quinone upon exposure to air. This chiroptical quinone/hydroquinone redox switch system combines several attractive features such as simple set-up, use of inexpensive chemicals, short response time, and thermal and photochemical stability. A conceptually new sensing approach that is based on integrated chiroptical amplification and redox switching enables on-the-fly deconvolution of otherwise overlapping CD spectra and is used for quantitative er analysis of challenging samples containing constitutional isomers in varying enantiomeric compositions.

5.
Chirality ; 33(12): 891-898, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34598313

RESUMO

The 2-Aryl-2-fluoroacetonitriles have garnered increasing interest as versatile building blocks in asymmetric synthesis. However, the configurational stability of these organofluorines is poorly understood and analytical methods that can be used to differentiate between their enantiomers remain underdeveloped. In this study, baseline high performance liquid chromatography (HPLC) enantioseparation of ten 2-aryl-2-fluoroacetonitriles was achieved by screening frequently used chiral stationary phases. While Chiralcel OD, Chiralpak AD, and Chiralpak AS proved to be most broadly useful, preparative separation of the enantiomers of 2-(2-naphthyl)-2-fluoroacetonitrile was possible on Chiralcel OJ. This enabled racemization studies at various temperatures and in the presence of organic bases which showed that this compound is configurationally stable under neutral conditions upon heating to 130°C for 6 h but undergoes complete racemization within 10 h in the presence of stoichiometric amounts of a guanidine base at room temperature. The racemization is likely to proceed via formation of an achiral keteniminate intermediate and obeys reversible first-order reaction kinetics with a half-life time of 87.7 min in ethanolic hexanes at 23.2°C. Racemization is significantly slower and occurs with a half-life time of 23.1 h at 22.4°C when the guanidine is replaced with a weaker amidine base.

6.
Metabolites ; 11(9)2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34564439

RESUMO

Ubiquitin Specific Protease-13 (USP13) promotes protein de-ubiquitination and is poorly understood in neurodegeneration. USP13 is upregulated in Alzheimer's disease (AD) and Parkinson's disease (PD), and USP13 knockdown via shRNA reduces neurotoxic proteins and increases proteasome activity in models of neurodegeneration. We synthesized novel analogues of spautin-1 which is a non-specific USP13 inhibitor but unable to penetrate the brain. Our synthesized small molecule compounds are able to enter the brain, more potently inhibit USP13, and significantly reduce alpha-synuclein levels in vivo and in vitro. USP13 inhibition in transgenic mutant alpha-synuclein (A53T) mice increased the ubiquitination of alpha-synuclein and reduced its protein levels. The data suggest that novel USP13 inhibitors improve neurodegenerative pathology via antagonism of de-ubiquitination, thus alleviating neurotoxic protein burden in neurodegenerative diseases.

7.
Artigo em Inglês | MEDLINE | ID: mdl-34587013

RESUMO

Visual Question Answering systems target answering open-ended textual questions given input images. They are a testbed for learning high-level reasoning with a primary use in HCI, for instance assistance for the visually impaired. Recent research has shown that state-of-the-art models tend to produce answers exploiting biases and shortcuts in the training data, and sometimes do not even look at the input image, instead of performing the required reasoning steps. We present VisQA, a visual analytics tool that explores this question of reasoning vs. bias exploitation. It exposes the key element of state-of-the-art neural models - attention maps in transformers. Our working hypothesis is that reasoning steps leading to model predictions are observable from attention distributions, which are particularly useful for visualization. The design process of VisQA was motivated by well-known bias examples from the fields of deep learning and vision-language reasoning and evaluated in two ways. First, as a result of a collaboration of three fields, machine learning, vision and language reasoning, and data analytics, the work lead to a better understanding of bias exploitation of neural models for VQA, which eventually resulted in an impact on its design and training through the proposition of a method for the transfer of reasoning patterns from an oracle model. Second, we also report on the design of VisQA, and a goal-oriented evaluation of VisQA targeting the analysis of a model decision process from multiple experts, providing evidence that it makes the inner workings of models accessible to users.

8.
J Vis ; 21(8): 23, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34431965

RESUMO

Short-latency saccades are often biased toward salient objects or toward the center of images, for example, when inspecting photographs of natural scenes. Here, we measured the contribution of salient objects and central fixation bias to visual selection over time. Participants made saccades to images containing one salient object on a structured background and were instructed to either look at (i) the image center, (ii) the salient object, or (iii) at a cued position halfway in between the two. Results revealed, first, an early involuntary bias toward the image center irrespective of strategic behavior or the location of objects in the image. Second, the salient object bias was stronger than the center bias and prevailed over the latter when they directly competed for visual selection. In a second experiment, we tested whether the center bias depends on how well the image can be segregated from the monitor background. We asked participants to explore images that either did or did not contain a salient object while we manipulated the contrast between image background and monitor background to make the image borders more or less visible. The initial orienting toward the image was not affected by the image-monitor contrast, but only by the presence of objects-with a strong bias toward the center of images containing no object. Yet, a low image-monitor contrast reduced this center bias during the subsequent image exploration.

9.
Cogn Neurodyn ; 15(4): 547-568, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34367360

RESUMO

Humans and other primates are equipped with a foveated visual system. As a consequence, we reorient our fovea to objects and targets in the visual field that are conspicuous or that we consider relevant or worth looking at. These reorientations are achieved by means of saccadic eye movements. Where we saccade to depends on various low-level factors such as a targets' luminance but also crucially on high-level factors like the expected reward or a targets' relevance for perception and subsequent behavior. Here, we review recent findings how the control of saccadic eye movements is influenced by higher-level cognitive processes. We first describe the pathways by which cognitive contributions can influence the neural oculomotor circuit. Second, we summarize what saccade parameters reveal about cognitive mechanisms, particularly saccade latencies, saccade kinematics and changes in saccade gain. Finally, we review findings on what renders a saccade target valuable, as reflected in oculomotor behavior. We emphasize that foveal vision of the target after the saccade can constitute an internal reward for the visual system and that this is reflected in oculomotor dynamics that serve to quickly and accurately provide detailed foveal vision of relevant targets in the visual field.

10.
Am J Case Rep ; 22: e931195, 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34315846

RESUMO

BACKGROUND Extrahepatic and extrapulmonary localizations of cystic echinococcosis (CE) are rare and the incidence of splenic involvement is seen in 1.0% to 3.3% of all cases in the endemic areas of the Middle East and Asia. The diagnostic pathway consists of a detailed travel history, physical examination, abdominal ultrasonography, computed tomography, and serological tests. The efficacy of perioperative administration of albendazole (400 mg twice a day) has been proven; however, the appropriate surgical procedure for the treatment of giant, centrally located splenic hydatid cysts remains controversial. CASE REPORT We present the case of a 49-year-old woman referred to our hospital for a suspected isolated splenic hydatid cyst causing a compression of the right kidney, stomach, and the tail of the pancreas. She reported chronic pain in the left upper quadrant and a history of contact with animals. She underwent open splenectomy via a medial to lateral approach to minimize manipulation of the spleen. In addition, she received perioperative parasitostatic drug therapy with albendazole. The postoperative period was uneventful and the histologic analysis confirmed the diagnosis. CONCLUSIONS The spleen is a rare location for isolated CE, especially in non-endemic areas and must be considered in the differential diagnosis of splenic cystic masses. Surgical resection remains the most effective treatment that completely resolves this condition. A comparison of randomized trials is needed to compare the recurrence rates between splenectomy and spleen-preserving procedures in the treatment of giant splenic hydatid cysts.


Assuntos
Equinococose , Esplenopatias , Animais , Equinococose/diagnóstico , Equinococose/cirurgia , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Baço , Esplenectomia , Esplenopatias/cirurgia , Vísceras
11.
Meteorit Planet Sci ; 56(4): 844-893, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34295141

RESUMO

The June 2, 2018, impact of asteroid 2018 LA over Botswana is only the second asteroid detected in space prior to impacting over land. Here, we report on the successful recovery of meteorites. Additional astrometric data refine the approach orbit and define the spin period and shape of the asteroid. Video observations of the fireball constrain the asteroid's position in its orbit and were used to triangulate the location of the fireball's main flare over the Central Kalahari Game Reserve. 23 meteorites were recovered. A consortium study of eight of these classifies Motopi Pan as a HED polymict breccia derived from howardite, cumulate and basaltic eucrite, and diogenite lithologies. Before impact, 2018 LA was a solid rock of ~156 cm diameter with high bulk density ~2.85 g/cm3, a relatively low albedo pv ~ 0.25, no significant opposition effect on the asteroid brightness, and an impact kinetic energy of ~0.2 kt. The orbit of 2018 LA is consistent with an origin at Vesta (or its Vestoids) and delivery into an Earth-impacting orbit via the v6 resonance. The impact that ejected 2018 LA in an orbit towards Earth occurred 22.8 ± 3.8 Ma ago. Zircons record a concordant U-Pb age of 4563 ± 11 Ma and a consistent 207Pb/206Pb age of 4563 ± 6 Ma. A much younger Pb-Pb phosphate resetting age of 4234 ± 41 Ma was found. From this impact chronology, we discuss what is the possible source crater of Motopi Pan and the age of Vesta's Veneneia impact basin.

12.
MRS Adv ; : 1-4, 2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34075322

RESUMO

Abstract: With the Covid-19-based global pandemic that started in the beginning of 2020, the vital importance of accelerated, reliable and affordable virus testing systems has once again become clearer. Besides, we all learned very well that the disposable biochips, to be used in these in vitro diagnostic (IVD) testing systems, supposed to be produced in large amounts in a very short time to be widely available for the use of humanity to save more and more lives. That is why; roll-to-roll (R2R) polymer structuring manners offer such large quantities for the production of in vitro biochips. Our technology, based on R2R UV nanoimprint lithography (UV-NIL), has superior features. Via our pilot line, robust 7500 biochip components per 100 meter of a flexible, polymer foil coated with a UV curable photo-resin (i.e., parts with capillary fluidic channels or optical structures for IVDs) can be generated. This study shows an example of a prototype of a R2R UV-NIL generated chip: a foil, capillary flow-based IVD biochip for multiplexed DNA detection purposes (i.e., a Lab-on-a-Foil device). The biochip performance was further increased dramatically by integrating UV-NIL produced retro-reflective microstructures, which reflects the light back, to its design to enhance optical signal detection in a commercial IVD device, detecting DNA on a chemiluminescent-reaction basis.

14.
Sci Rep ; 11(1): 9331, 2021 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-33927227

RESUMO

Motor adaptation maintains movement accuracy over the lifetime. Saccadic eye movements have been used successfully to study the mechanisms and neural basis of adaptation. Using behaviorally irrelevant targets, it has been shown that saccade adaptation is driven by errors only in a brief temporal interval after movement completion. However, under natural conditions, eye movements are used to extract information from behaviorally relevant objects and to guide actions manipulating these objects. In this case, the action outcome often becomes apparent only long after movement completion, outside the supposed temporal window of error evaluation. Here, we show that saccade adaptation can be driven by error signals long after the movement when using behaviorally relevant targets. Adaptation occurred when a task-relevant target appeared two seconds after the saccade, or when a retro-cue indicated which of two targets, stored in visual working memory, was task-relevant. Our results emphasize the important role of visual working memory for optimal movement control.


Assuntos
Adaptação Fisiológica , Memória de Curto Prazo , Desempenho Psicomotor , Movimentos Sacádicos , Adulto , Feminino , Humanos , Masculino , Adulto Jovem
15.
Org Biomol Chem ; 19(19): 4248-4253, 2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-33885685

RESUMO

The efficiency and scope of two acyclic π-wall extended cucurbiturils, M2 and M3, exhibiting rapidly interconverting helical conformers for chiroptical sensing of amines, amino acids, alcohols, and terpenes at micromolar concentrations in water is evaluated. The formation of 1 : 1 host-guest complexes results in spontaneous induction of circular dichroism signals that can be used for accurate determination of the absolute configuration and enantiomeric composition of the analyte based on a simple mix-and-measure protocol.

16.
Mult Scler ; 27(10): 1564-1576, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33205682

RESUMO

BACKGROUND: In multiple sclerosis, impact of treatment on disability progression can be confounded if treatment also reduces relapses. OBJECTIVE: To distinguish siponimod's direct effects on disability progression from those on relapses in the EXPAND phase 3 trial. METHODS: Three estimands, one based on principal stratum and two on hypothetical scenarios (no relapses, or equal relapses in both treatment arms), were defined to determine the extent to which siponimod's effects on 3- and 6-month confirmed disability progression were independent of on-study relapses. RESULTS: Principal stratum analysis estimated that siponimod reduced the risk of 3- and 6-month confirmed disability progression by 14%-20% and 29%-33%, respectively, compared with placebo in non-relapsing patients. In the hypothetical scenarios, risk reductions independent of relapses were 14%-18% and 23% for 3- and 6-month confirmed disability progression, respectively. CONCLUSION: By controlling the confounding impact of on-study relapses on confirmed disability progression, these statistical approaches provide a methodological framework to assess treatment effects on disability progression in relapsing and non-relapsing patients. The analyses support that siponimod may be useful for treating secondary progressive multiple sclerosis in patients with or without relapses.

17.
Neurology ; 96(3): e376-e386, 2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33328324

RESUMO

OBJECTIVE: To investigate the effects of siponimod on cognitive processing speed in patients with secondary progressive (SP) multiple sclerosis (MS), by means of a predefined exploratory and post hoc analysis of the Exploring the Efficacy and Safety of Siponimod in Patients With Secondary Progressive Multiple Sclerosis (EXPAND) study, a randomized controlled trial comparing siponimod and placebo. METHODS: EXPAND was a double-blind, placebo-controlled phase 3 trial involving 1,651 patients with SPMS randomized (2:1) to either siponimod 2 mg/d or placebo. Cognitive function was assessed with the Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test (PASAT), and Brief Visuospatial Memory Test-Revised (BVMT-R) administered at baseline, 6-month intervals, and end of treatment. RESULTS: Between-group differences in mean change from baseline in SDMT scores were significantly better in siponimod- vs placebo-treated patients at month 12 (difference 1.08 [95% confidence interval 0.23-1.94]; p = 0.0132), month 18 (1.23 [0.25-2.21); p = 0.0135), and month 24 (2.30 [1.11-3.50]; p = 0.0002). Siponimod-treated patients were at significantly lower risk for having a 4-point sustained decrease in SDMT score (hazard ratio [HR] 0.79 [0.65-0.96]; p = 0.0157), while their chance for having a 4-point sustained increase in SDMT score was higher (HR 1.28 [1.05-1.55]; p = 0.0131). PASAT and BVMT-R scores did not differ significantly between the 2 treatment groups (all p > 0.28). CONCLUSION: Siponimod had a significant benefit on SDMT in patients with SPMS. Siponimod-treated patients were at significantly lower risk for having a ≥4-point decrease in SDMT score and had a significantly higher chance for having a ≥4-point increase in SDMT score, a magnitude of change accepted as clinically meaningful. CLINICALTRIALSGOV IDENTIFIER: NCT01665144. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, for patients with SPMS, siponimod had a significant benefit on cognitive processing speed.


Assuntos
Azetidinas/uso terapêutico , Compostos de Benzil/uso terapêutico , Cognição/efeitos dos fármacos , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Moduladores do Receptor de Esfingosina 1 Fosfato/uso terapêutico , Adulto , Azetidinas/farmacologia , Compostos de Benzil/farmacologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Crônica Progressiva/psicologia , Testes Neuropsicológicos , Moduladores do Receptor de Esfingosina 1 Fosfato/farmacologia
18.
Chem Soc Rev ; 49(23): 8543-8583, 2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33073285

RESUMO

Ynamides are among the most powerful building blocks in organic synthesis and have become invaluable starting materials for the construction of multifunctional compounds and challenging architectures that would be difficult to prepare otherwise. The rapidly growing popularity originates from the unique reactivity and ease of manipulation of the polarized ynamide triple bond, the advance of practical methods for making them, and the simplicity of storage and handling. These attractive features and the demonstration of numerous synthetic applications have spurred the development of intriguing asymmetric reaction strategies during the last decade. An impressive variety of chemo-, regio- and stereoselective carbon-carbon and carbon-heteroatom bond forming reactions with ynamides have been developed and now significantly enrich the toolbox of synthetic chemists. This review provides a comprehensive overview of asymmetric ynamide chemistry since 2010 with a focus on the general scope, current limitations, stereochemical reaction control and mechanistic aspects.

19.
Org Biomol Chem ; 18(42): 8629-8632, 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33094775

RESUMO

The cyclization reaction between ortho-phthalaldehyde and l-homocysteine coincides with the generation of a pronounced positive CD signal at approximately 335 nm. Under identical conditions, other amino acids including cysteine produce very weak CD responses. This unusual substrate specificity allows accurate chiroptical analysis of the enantiomeric composition of homocysteine samples in the presence of cysteine without the need for time-consuming chromatographic separation. This significantly simplifies and speeds up ee determination at reduced solvent waste production.

20.
Hum Mol Genet ; 29(17): 2882-2898, 2020 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-32776088

RESUMO

The role of Discoidin Domain Receptors (DDRs) is poorly understood in neurodegeneration. DDRs are upregulated in Alzheimer's and Parkinson's disease (PD), and DDRs knockdown reduces neurotoxic protein levels. Here we show that potent and preferential DDR1 inhibitors reduce neurotoxic protein levels in vitro and in vivo. Partial or complete deletion or inhibition of DDR1 in a mouse model challenged with α-synuclein increases autophagy and reduces inflammation and neurotoxic proteins. Significant changes of cerebrospinal fluid microRNAs that control inflammation, neuronal injury, autophagy and vesicular transport genes are observed in PD with and without dementia and Lewy body dementia, but these changes are attenuated or reversed after treatment with the DDR1 inhibitor, nilotinib. Collectively, these data demonstrate that DDR1 regulates autophagy and reduces neurotoxic proteins and inflammation and is a therapeutic target in neurodegeneration.


Assuntos
Receptor com Domínio Discoidina 1/genética , Doença por Corpos de Lewy/tratamento farmacológico , Doenças Neurodegenerativas/genética , Doença de Parkinson/tratamento farmacológico , alfa-Sinucleína/genética , Doença de Alzheimer/complicações , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Receptor com Domínio Discoidina 1/antagonistas & inibidores , Modelos Animais de Doenças , Humanos , Inflamação/complicações , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/patologia , Doença por Corpos de Lewy/genética , Doença por Corpos de Lewy/patologia , Camundongos , MicroRNAs/genética , Doenças Neurodegenerativas/patologia , Doença de Parkinson/complicações , Doença de Parkinson/genética , Doença de Parkinson/patologia , Pirimidinas/farmacologia
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