RESUMO
Semiochemicals can be used to manipulate insect behaviour for sustainable pest management strategies, but their high volatility is a major issue for their practical implementation. Inclusion of these molecules within porous materials is a potential solution to this issue, as it can allow for a slower and more controlled release. In this work, we demonstrate that a series of Zr(IV) and Al(III) metal-organic frameworks (MOFs) with channel-type pores enable controlled release of three semiochemicals over 100â days by pore size design, with the uptake and rate of release highly dependent on the pore size. Insight from grand canonical Monte Carlo simulations indicates that this is due to weaker MOF-guest interactions per guest molecule as the pore size increases. These MOFs are all stable post-release and can be reloaded to show near-identical re-release profiles. These results provide valuable insight on the diffusion behaviour of volatile guests in MOFs, and for the further development of porous materials for sustainable agriculture applications.
RESUMO
Humans are adept at identifying spectral patterns, such as vowels, in different rooms, at different sound levels, or produced by different talkers. How this feat is achieved remains poorly understood. Two psychoacoustic analogs of spectral pattern recognition are spectral profile analysis and spectrotemporal ripple direction discrimination. This study tested whether pattern-recognition abilities observed previously at low frequencies are also observed at extended high frequencies. At low frequencies (center frequency â¼500 Hz), listeners were able to achieve accurate profile-analysis thresholds, consistent with prior literature. However, at extended high frequencies (center frequency â¼10 kHz), listeners' profile-analysis thresholds were either unmeasurable or could not be distinguished from performance based on overall loudness cues. A similar pattern of results was observed with spectral ripple discrimination, where performance was again considerably better at low than at high frequencies. Collectively, these results suggest a severe deficit in listeners' ability to analyze patterns of intensity across frequency in the extended high-frequency region that cannot be accounted for by cochlear frequency selectivity. One interpretation is that the auditory system is not optimized to analyze such fine-grained across-frequency profiles at extended high frequencies, as they are not typically informative for everyday sounds.
Assuntos
Estimulação Acústica , Limiar Auditivo , Psicoacústica , Humanos , Adulto Jovem , Feminino , Masculino , Adulto , Sinais (Psicologia) , Percepção da Fala/fisiologia , Espectrografia do Som , Percepção Sonora , Reconhecimento Fisiológico de ModeloRESUMO
Accurate pitch perception of harmonic complex tones is widely believed to rely on temporal fine structure information conveyed by the precise phase-locked responses of auditory-nerve fibers. However, accurate pitch perception remains possible even when spectrally resolved harmonics are presented at frequencies beyond the putative limits of neural phase locking, and it is unclear whether residual temporal information, or a coarser rate-place code, underlies this ability. We addressed this question by measuring human pitch discrimination at low and high frequencies for harmonic complex tones, presented either in isolation or in the presence of concurrent complex-tone maskers. We found that concurrent complex-tone maskers impaired performance at both low and high frequencies, although the impairment introduced by adding maskers at high frequencies relative to low frequencies differed between the tested masker types. We then combined simulated auditory-nerve responses to our stimuli with ideal-observer analysis to quantify the extent to which performance was limited by peripheral factors. We found that the worsening of both frequency discrimination and F0 discrimination at high frequencies could be well accounted for (in relative terms) by optimal decoding of all available information at the level of the auditory nerve. A Python package is provided to reproduce these results, and to simulate responses to acoustic stimuli from the three previously published models of the human auditory nerve used in our analyses.
Assuntos
Nervo Coclear , Percepção da Altura Sonora , Estimulação Acústica/métodos , Nervo Coclear/fisiologia , Humanos , Percepção da Altura Sonora/fisiologiaRESUMO
Solvent-free synthesis by using a vibratory ball mill (VBM) offers the chance to access new chemical reactivity, whilst reducing solvent waste and minimising reaction times. Herein, we report the core functionalisation of N,N'-bis(2-ethylhexyl)-2,6-dibromo-1,4,5,8-naphthalenetetracarboxylic acid (Br2 -NDI) by using Suzuki, Sonogashira and Buchwald-Hartwig coupling reactions. The products of these reactions are important building blocks in many areas of organic electronics including organic light-emitting diodes (OLEDs), organic field-effect transistors (OFETs) and organic photovoltaic cells (OPVCs). The reactions proceed in as little as 1â h, use commercially available palladium sources (frequently Pd(OAc)2 ) and are tolerant to air and atmospheric moisture. Furthermore, the real-world potential of this green VBM protocol is demonstrated by the double Suzuki coupling of a monobromo(NDI) residue to a bis(thiophene) pinacol ester. The resulting dimeric NDI species has been demonstrated to behave as an electron acceptor in functioning OPVCs.
RESUMO
A cheap, conventional, sealed heating reactor proved to be a useful alternative to a microwave reactor in the synthesis of a >20-member MIDA boronate library (MIDA = N-methyliminodiacetic acid). Reaction times were 10 min and work-ups were minimal, saving on energy and solvent usage.
Assuntos
Ácidos Borônicos , Calefação , Estrutura MolecularRESUMO
The global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has called for an urgent need for dedicated antiviral therapeutics. Metal complexes are commonly underrepresented in compound libraries that are used for screening in drug discovery campaigns, however, there is growing evidence for their role in medicinal chemistry. Based on previous results, we have selected more than 100â structurally diverse metal complexes for profiling as inhibitors of two relevant SARS-CoV-2 replication mechanisms, namely the interaction of the spike (S) protein with the ACE2 receptor and the papain-like protease PLpro . In addition to many well-established types of mononuclear experimental metallodrugs, the pool of compounds tested was extended to approved metal-based therapeutics such as silver sulfadiazine and thiomersal, as well as polyoxometalates (POMs). Among the mononuclear metal complexes, only a small number of active inhibitors of the S/ACE2 interaction was identified, with titanocene dichloride as the only strong inhibitor. However, among the gold and silver containing complexes many turned out to be very potent inhibitors of PLpro activity. Highly promising activity against both targets was noted for many POMs. Selected complexes were evaluated in antiviral SARS-CoV-2 assays confirming activity for gold complexes with N-heterocyclic carbene (NHC) or dithiocarbamato ligands, a silver NHC complex, titanocene dichloride as well as a POM compound. These studies might provide starting points for the design of metal-based SARS-CoV-2 antiviral agents.
Assuntos
Antivirais/farmacologia , Proteases Semelhantes à Papaína de Coronavírus/antagonistas & inibidores , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Enzima de Conversão de Angiotensina 2 , SARS-CoV-2/efeitos dos fármacosRESUMO
Adaptive resistance is a major limitation in the use of targeted therapies for cancer. Using real time biomass tracking, we demonstrate the isolation and identification of rare (1% fraction) diffuse large B cell lymphoma cells resistant to the PI3K inhibitor idelalisib, from an otherwise sensitive population. This technique allows direct study of these rare, drug tolerant cells.
Assuntos
Linfoma Difuso de Grandes Células B , Fosfatidilinositol 3-Quinases , Biomassa , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologiaRESUMO
Fundamental frequency differences (ΔF0) between competing talkers aid in the perceptual segregation of the talkers (ΔF0 benefit), but the underlying mechanisms remain incompletely understood. A model of ΔF0 benefit based on harmonic cancellation proposes that a masker's periodicity can be used to cancel (i.e., filter out) its neural representation. Earlier work suggested that an octave ΔF0 provided little benefit, an effect predicted by harmonic cancellation due to the shared periodicity of masker and target. Alternatively, this effect can be explained by spectral overlap between the harmonic components of the target and masker. To assess these competing explanations, speech intelligibility of a monotonized target talker, masked by a speech-shaped harmonic complex tone, was measured as a function of ΔF0, masker spectrum (all harmonics or odd harmonics only), and masker temporal envelope (amplitude modulated or unmodulated). Removal of the masker's even harmonics when the target was one octave above the masker improved speech reception thresholds by about 5 dB. Because this manipulation eliminated spectral overlap between target and masker components but preserved shared periodicity, the finding is consistent with the explanation for the lack of ΔF0 benefit at the octave based on spectral overlap, but not with the explanation based on harmonic cancellation.
Assuntos
Percepção Auditiva/fisiologia , Audição/fisiologia , Mascaramento Perceptivo/fisiologia , Percepção da Fala/fisiologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Ruído , Inteligibilidade da Fala/fisiologia , Teste do Limiar de Recepção da Fala/métodos , Adulto JovemRESUMO
We report the development of high-speed live-cell interferometry (HSLCI), a new multisample, multidrug testing platform for directly measuring tumor therapy response via real-time optical cell biomass measurements. As a proof of concept, we show that HSLCI rapidly profiles changes in biomass in BRAF inhibitor (BRAFi)-sensitive parental melanoma cell lines and in their isogenic BRAFi-resistant sublines. We show reproducible results from two different HSLCI platforms at two institutions that generate biomass kinetic signatures capable of discriminating between BRAFi-sensitive and -resistant melanoma cells within 24 h. Like other quantitative phase imaging (QPI) modalities, HSLCI is well-suited to noninvasive measurements of single cells and cell clusters, requiring no fluorescence or dye labeling. HSLCI is substantially faster and more sensitive than field-standard growth inhibition assays, and in terms of the number of cells measured simultaneously, the number of drugs tested in parallel, and temporal measurement range, it exceeds the state of the art by more than 10-fold. The accuracy and speed of HSLCI in profiling tumor cell heterogeneity and therapy resistance are promising features of potential tools to guide patient therapeutic selections.
Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Interferometria/métodos , Melanoma/classificação , Inibidores de Proteínas Quinases/farmacologia , Biomassa , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Humanos , Cinética , Melanoma/genética , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
Harmonic complex tones are easier to detect in noise than inharmonic complex tones, providing a potential perceptual advantage in complex auditory environments. Here, we explored whether the harmonic advantage extends to other auditory tasks that are important for navigating a noisy auditory environment, such as amplitude- and frequency-modulation detection. Sixty young normal-hearing listeners were tested, divided into two equal groups with and without musical training. Consistent with earlier studies, harmonic tones were easier to detect in noise than inharmonic tones, with a signal-to-noise ratio (SNR) advantage of about 2.5 dB, and the pitch discrimination of the harmonic tones was more accurate than that of inharmonic tones, even after differences in audibility were accounted for. In contrast, neither amplitude- nor frequency-modulation detection was superior with harmonic tones once differences in audibility were accounted for. Musical training was associated with better performance only in pitch-discrimination and frequency-modulation-detection tasks. The results confirm a detection and pitch-perception advantage for harmonic tones but reveal that the harmonic benefits do not extend to suprathreshold tasks that do not rely on extracting the fundamental frequency. A general theory is proposed that may account for the effects of both noise and memory on pitch-discrimination differences between harmonic and inharmonic tones.
RESUMO
To investigate the role of spectral pattern information in the perception of foreign-accented speech, we measured the effects of spectral shifts on judgments of talker discrimination, perceived naturalness, and intelligibility when listening to Mandarin-accented English and native-accented English sentences. In separate conditions, the spectral envelope and fundamental frequency (F0) contours were shifted up or down in three steps using coordinated scale factors (multiples of 8% and 30%, respectively). Experiment 1 showed that listeners perceive spectrally shifted sentences as coming from a different talker for both native-accented and foreign-accented speech. Experiment 2 demonstrated that downward shifts applied to male talkers and the largest upward shifts applied to all talkers reduced the perceived naturalness, regardless of accent. Overall, listeners rated foreign-accented speech as sounding less natural even for unshifted speech. In Experiment 3, introducing spectral shifts further lowered the intelligibility of foreign-accented speech. When speech from the same foreign-accented talker was shifted to simulate five different talkers, increased exposure failed to produce an improvement in intelligibility scores, similar to the pattern observed when listeners actually heard five foreign-accented talkers. Intelligibility of spectrally shifted native-accented speech was near ceiling performance initially, and no further improvement or decrement was observed. These experiments suggest a mechanism that utilizes spectral envelope and F0 cues in a talker-dependent manner to support the perception of foreign-accented speech.
Assuntos
Percepção da Fala , Fala , Cognição , Humanos , Julgamento , Idioma , Masculino , Inteligibilidade da FalaRESUMO
The pentafluorosulfanyl (-SF5 ) functional group is of increasing interest as a bioisostere in medicinal chemistry. A library of SF5 -containing compounds, including amide, isoxazole, and oxindole derivatives, was synthesised using a range of solution-based and solventless methods, including microwave and ball-mill techniques. The library was tested against targets including human dihydroorotate dehydrogenase (HDHODH). A subsequent focused approach led to synthesis of analogues of the clinically used disease modifying anti-rheumatic drugs (DMARDs), Teriflunomide and Leflunomide, considered for potential COVID-19 use, where SF5 bioisostere deployment led to improved inhibition of HDHODH compared with the parent drugs. The results demonstrate the utility of the SF5 group in medicinal chemistry.
Assuntos
Química Farmacêutica , Di-Hidro-Orotato Desidrogenase , Amidas , Di-Hidro-Orotato Desidrogenase/antagonistas & inibidores , HumanosRESUMO
The long-term sustainability of the high-energy physics (HEP) research software ecosystem is essential to the field. With new facilities and upgrades coming online throughout the 2020s, this will only become increasingly important. Meeting the sustainability challenge requires a workforce with a combination of HEP domain knowledge and advanced software skills. The required software skills fall into three broad groups. The first is fundamental and generic software engineering (e.g., Unix, version control, C++, and continuous integration). The second is knowledge of domain-specific HEP packages and practices (e.g., the ROOT data format and analysis framework). The third is more advanced knowledge involving specialized techniques, including parallel programming, machine learning and data science tools, and techniques to maintain software projects at all scales. This paper discusses the collective software training program in HEP led by the HEP Software Foundation (HSF) and the Institute for Research and Innovation in Software in HEP (IRIS-HEP). The program equips participants with an array of software skills that serve as ingredients for the solution of HEP computing challenges. Beyond serving the community by ensuring that members are able to pursue research goals, the program serves individuals by providing intellectual capital and transferable skills important to careers in the realm of software and computing, inside or outside HEP.
RESUMO
DNA length polymorphisms are found in many serious diseases, and assessment of their length and abundance is often critical for accurate diagnosis. However, measuring their length and frequency in a mostly wild-type background, as occurs in many situations, remains challenging due to their variable and repetitive nature. To overcome these hurdles, we combined two powerful techniques, digital polymerase chain reaction (dPCR) and high-speed atomic force microscopy (HSAFM), to create a simple, rapid, and flexible method for quantifying both the size and proportion of DNA length polymorphisms. In our approach, individual amplicons from each dPCR partition are imaged and sized directly. We focused on internal tandem duplications (ITDs) located within the FLT3 gene, which are associated with acute myeloid leukemia and often indicative of a poor prognosis. In an analysis of over 1.5 million HSAFM-imaged amplicons from cell line and clinical samples containing FLT3-ITDs, dPCR-HSAFM returned the expected variant length and variant allele frequency, down to 5% variant samples. As a high-throughput method with single-molecule resolution, dPCR-HSAFM thus represents an advance in HSAFM analysis and a powerful tool for the diagnosis of length polymorphisms.
Assuntos
Leucemia Mieloide Aguda , Análise de Sequência de DNA/métodos , Tirosina Quinase 3 Semelhante a fms/genética , DNA/genética , Frequência do Gene , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Microscopia de Força Atômica , Reação em Cadeia da PolimeraseRESUMO
Prompt and repeated assessments of tumor sensitivity to available therapeutics could reduce patient morbidity and mortality by quickly identifying therapeutic resistance and optimizing treatment regimens. Analysis of changes in cancer cell biomass has shown promise in assessing drug sensitivity and fulfilling these requirements. However, a major limitation of previous studies in solid tumors, which comprise 90% of cancers, is the use of cancer cell lines rather than freshly isolated tumor material. As a result, existing biomass protocols are not obviously extensible to real patient tumors owing to potential artifacts that would be generated by the removal of cells from their microenvironment and the deleterious effects of excision and purification. In this present work, we show that simple excision of human triple-negative breast cancer (TNBC) tumors growing in immunodeficient mouse, patient-derived xenograft (PDX) models, followed by enzymatic disaggregation into single cell suspension, is enabling for rapid and accurate biomass accumulation-based predictions of in vivo sensitivity to the chemotherapeutic drug carboplatin. We successfully correlate in vitro biomass results with in vivo treatment results in three TNBC PDX models that have differential sensitivity to this drug. With a maximum turnaround time of 40 h from tumor excision to useable results and a fully-automated analysis pipeline, the assay described here has significant potential for translation to clinical practice.