Structure-based computational design of antibody mimetics: challenges and perspectives.

The design of antibody mimetics holds great promise for revolutionizing therapeutic interventions by offering alternatives to conventional antibody therapies. Structure-based computational approaches have emerged as indispensable tools in the rational design of those molecules, enabling the precise manipulation of their structural and functional properties. This review covers the main classes of designed antigen-binding motifs, as well as alternative strategies to develop tailored ones. We discuss the intricacies of different computational protein-protein interaction design strategies, showcased by selected successful cases in the literature. Subsequently, we explore the latest advancements in the computational techniques including the integration of machine and deep learning methodologies into the design framework, which has led to an augmented design pipeline. Finally, we verse onto the current challenges that stand in the way between high-throughput computer design of antibody mimetics and experimental realization, offering a forward-looking perspective into the field and the promises it holds to biotechnology.

Physicochemical and Sensory Properties of Arabica Coffee Beans of Arara cv. Dried Using Different Methods.

The coffee fruit is preferably harvested at the cherry stage, with high moisture and metabolic activity, and must then undergo a drying process for better preservation of the bean and its sensory attributes. In this context, this study aimed to characterize the final quality of the Arara cultivar Arabica coffee processed using the wet method and subjected to six drying methods: three conducted at the agro-industrial establishment (fixed-bed dryer, rotary drum dryer, and combined drying) and three laboratory-scale methods (convective oven, cast-tape drying, and suspended terrace). Drying was carried out to reduce the coffee's moisture content from an initial value of 46.2% on a wet basis (w.b.) to a final average value of 11.35% (w.b.). The fruits of in natura demucilaged coffee and the processed dry coffee beans were characterized for moisture, ash content, nitrogen compounds, lipids, total titratable acidity, organic acids, sugars, and the instrumental color of the beans. The sensory profile of the Arabica coffee was evaluated by five coffee specialists using the methodology proposed by the Specialty Coffee Association (SCA), and all the coffees were classified as a specialty.

Inverse design of a polarization demultiplexer for on-chip path-entangled photon-pair sources based on single quantum dots.

Epitaxial quantum dots can emit polarization-entangled photon pairs. If orthogonal polarizations are coupled to independent paths, then the photons will be path-entangled. Through inverse design with adjoint method optimization, we design a quantum dot polarization demultiplexer, a nanophotonic geometry that efficiently couples orthogonally polarized transition dipole moments of a single quantum dot to two independent waveguides. We predict 95% coupling efficiency, cross talk less than 0.1%, and Purcell radiative rate enhancement factors over 11.5 for both dipoles, with sensitivity to dipole misalignment and orientation comparable to that of conventional nanophotonic geometries. We anticipate our design will be valuable for the implementation of triggered, high-rate sources of path-entangled photon-pairs on chip.

Ultra-low loss quantum photonic circuits integrated with single quantum emitters.

The scaling of many photonic quantum information processing systems is ultimately limited by the flux of quantum light throughout an integrated photonic circuit. Source brightness and waveguide loss set basic limits on the on-chip photon flux. While substantial progress has been made, separately, towards ultra-low loss chip-scale photonic circuits and high brightness single-photon sources, integration of these technologies has remained elusive. Here, we report the integration of a quantum emitter single-photon source with a wafer-scale, ultra-low loss silicon nitride photonic circuit. We demonstrate triggered and pure single-photon emission into a Si3N4 photonic circuit with ≈ 1 dB/m propagation loss at a wavelength of ≈ 930 nm. We also observe resonance fluorescence in the strong drive regime, showing promise towards coherent control of quantum emitters. These results are a step forward towards scaled chip-integrated photonic quantum information systems in which storing, time-demultiplexing or buffering of deterministically generated single-photons is critical.

Resolution of the curse of dimensionality in single-cell RNA sequencing data analysis.

Single-cell RNA sequencing (scRNA-seq) can determine gene expression in numerous individual cells simultaneously, promoting progress in the biomedical sciences. However, scRNA-seq data are high-dimensional with substantial technical noise, including dropouts. During analysis of scRNA-seq data, such noise engenders a statistical problem known as the curse of dimensionality (COD). Based on high-dimensional statistics, we herein formulate a noise reduction method, RECODE (resolution of the curse of dimensionality), for high-dimensional data with random sampling noise. We show that RECODE consistently resolves COD in relevant scRNA-seq data with unique molecular identifiers. RECODE does not involve dimension reduction and recovers expression values for all genes, including lowly expressed genes, realizing precise delineation of cell fate transitions and identification of rare cells with all gene information. Compared with representative imputation methods, RECODE employs different principles and exhibits superior overall performance in cell-clustering, expression value recovery, and single-cell-level analysis. The RECODE algorithm is parameter-free, data-driven, deterministic, and high-speed, and its applicability can be predicted based on the variance normalization performance. We propose RECODE as a powerful strategy for preprocessing noisy high-dimensional data.

Nutritional and physicochemical quality of formulations based on colostrum and bovine whey.

The objective of this study was to investigate the nutritional quality of bovine colostrum and whey mixtures. Five whey with bovine colostrum formulations were prepared (90:10; 80:20; 70:30; 60:40 and 50:50 whey:colostrum v:v) to be subjected to low-temperature pasteurization (63°C to 65°C for 30 minutes) and freeze-drying. The samples underwent chemical composition characterization, fatty acid profile analysis, determination of contamination by Enterobacteriaceae, pH, and Dornic acidity measurements before and after vat pasteurization. The amount of protein, fat, total solids, defatted dry extract, Brix and density increased as the bovine colostrum concentration increased. The level of saturated fatty acids and the thrombogenicity and atherogenicity indices reduced, while unsaturated fatty acids increased as the level of added bovine colostrum increased. The low-temperature pasteurization of the formulations was possible and effective, eliminating contamination by Enterobacteriaceae in the samples. Mixing bovine colostrum and whey reduced the colostrum viscosity, allowing a successful pasteurization procedure. Due to colostrum composition, the formulations yielded a higher nutritional value when compared to whey alone. The parameters applied in the formulation of mixtures of bovine colostrum and whey resulted in valuable ingredients for preparing novel dairy products.

The ongoing evolution of variants of concern and interest of SARS-CoV-2 in Brazil revealed by convergent indels in the amino (N)-terminal domain of the spike protein.

Mutations at both the receptor-binding domain (RBD) and the amino (N)-terminal domain (NTD) of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike (S) glycoprotein can alter its antigenicity and promote immune escape. We identified that SARS-CoV-2 lineages circulating in Brazil with mutations of concern in the RBD independently acquired convergent deletions and insertions in the NTD of the S protein, which altered the NTD antigenic-supersite and other predicted epitopes at this region. Importantly, we detected the community transmission of different P.1 lineages bearing NTD indels ∆69-70 (which can impact several SARS-CoV-2 diagnostic protocols), ∆144 and ins214ANRN, and a new VOI N.10 derived from the B.1.1.33 lineage carrying three NTD deletions (∆141-144, ∆211, and ∆256-258). These findings support that the ongoing widespread transmission of SARS-CoV-2 in Brazil generates new viral lineages that might be more resistant to antibody neutralization than parental variants of concern.

Immune evasion of SARS-CoV-2 variants of concern is driven by low affinity to neutralizing antibodies.

SARS-CoV-2 VOC immune evasion is mainly due to lower cross-reactivity from previously elicited class I/II neutralizing antibodies, while increased affinity to hACE2 plays a minor role. The affinity between antibodies and VOCs is impacted by remodeling of the electrostatic surface potential of the Spike RBDs. The P.3 variant is a putative VOC.

The ongoing evolution of variants of concern and interest of SARS-CoV-2 in Brazil revealed by convergent indels in the amino (N)-terminal domain of the Spike protein

Mutations at both the receptor-binding domain (RBD) and the amino (N)-terminal domain (NTD) of the SARS-CoV-2 Spike (S) glycoprotein can alter its antigenicity and promote immune escape. We identified that SARS-CoV-2 lineages circulating in Brazil with mutations of concern in the RBD independently acquired convergent deletions and insertions in the NTD of the S protein, which altered the NTD antigenic-supersite and other predicted epitopes at this region. These findings support that the ongoing widespread transmission of SARS-CoV-2 in Brazil is generating new viral lineages that might be more resistant to neutralization than parental variants of concern.

The influence of larval density on triacylglycerol content in Aedes aegypti (Linnaeus) (Diptera: Culicidae).

Given the importance of Aedes aegypti as an arbovirus vector, understanding the impact of population density during larval development is fundamental to improve control methods. The aims of this study were to analyze the effects of larval density on the triacylglycerol (TAG) reserves, fecundity, and the size of mosquitos. To evaluate the influence of density on the amount of TAG in the different stages of development of A. aegypti, the larvae were reared in densities of 0.04, 0.32, and 0.8 larvae/ml, represented by D1, D2, and D3, respectively. Larval rearing density affected the amount of TAG in the different developmental stages of this insect. The group reared with the highest population density (D3) presented greater storage of TAG, except when analyzing the amount of TAG µg/protein in the fat body of blood-fed females. In addition, it was possible to observe higher resistance to fasting and a greater number of eggs laid. Insects reared in D2 and D3 were larger than those in the D1 group. This study provides interesting data for future investigations on how the density of larval rearing affects the lipid metabolism for synthesis and mobilization of TAG stored in A. aegypti and how it influences size and reproduction.

SARS-CoV-2 VOCs immune evasion from previously elicited neutralizing antibodies is mainly driven by lower cross-reactivity due to spike RBD electrostatic surface changes.

O rápido espalhamento das novas variantes do novo coronavírus SARS-CoV-2, como exemplificado pela alta prevalência da variante P.1 ainda nos dois primeiros meses após seu surgimento, junto a relatos de reinfecção causada por estas variantes, levanta para a ciência a questão de quais seriam os mecanismos por trás deste cenário. É de especial interesse para estas pesquisas o estudo das mutações no genoma das variantes ­ em particular, no gene da glicoproteína Spike (proteína S), que promove a entrada nas células humanas a partir da interação com a Enzima Conversora de Angiotensina 2 (hACE2), molécula que atua como receptor do vírus. A capacidade de se ligar à hACE2 pode tornar-se maior ou menor de acordo com as alterações na estrutura da proteína S, que variam entre linhagens do SARS-CoV-2 e cada uma de suas variantes. Essas alterações na estrutura da proteína S podem também resultar em uma menor capacidade de anticorpos gerados em resposta a uma infecção ­ ou, possivelmente, mesmo após a vacinação ­ de se ligarem à proteína S e neutralizar a capacidade do vírus de causar infecção. A presente publicação ­ agora também disponível em sua versão revisada por pares ­ investiga estes dois possíveis efeitos das mutações da proteína S detectadas em variantes como a P.1, variantes da linhagem B.1.351 e a B.1.1.7: a de uma interação "mais forte" com o receptor hACE2 ou a de uma interação "mais fraca" com os anticorpos anti-proteína-S. No link do ChemRxiv ainda em estágio pre-print, antes da revisão por pesquisadores independentes, o artigo descreve uma série de experimentos feitos com modelagem computacional das moléculas envolvidas (hACE2, anticorpos e as diversas "versões" da proteína S, referentes a cada uma das variantes estudadas). Com base na simulação computacional da interação entre as moléculas, foi possível verificar que a alteração da estrutura da proteína S não teve efeitos marcantes na interação com o receptor hACE2. Por outro lado, ao simular a interação dos anticorpos gerados em resposta a linhagens iniciais do SARS-CoV-2 com a proteína S das novas variantes, foi possível ver que há uma diminuição na ligação entre as moléculas, um achado que aponta para um potencial de "escape" da resposta imune. Segundo essa hipótese, as novas variantes seriam mais eficazes em fugir da neutralização proporcionada por anticorpos, e este seria um mecanismo mais relevante para explicar seu rápido espalhamento pela população. É importante ressaltar que, baseados em algumas medidas de afinidade entre variações da proteína S e o receptor hACE2, outros grupos de pesquisa previamente sugeriram que o aumento da transmissibilidade estaria relacionado com uma maior afinidade entre a proteína viral e o receptor humano, em contraste com os resultados do presente estudo. Contudo, estes estudos não exploraram a interação das diferentes proteínas S com os anticorpos neutralizantes. O artigo aponta ainda a nova variante denominada P.3 como uma potencial Variante de Preocupação (VOC), tendo em vista que a maioria dos anticorpos analisados no estudo não foram capazes de se ligar eficientemente à proteína S desta linhagem nas simulações realizadas.

Temperament and performance of Nellore bulls classified for residual feed intake in a feedlot system.

This study aimed to evaluate the performance in feedlot and temperament of Nellore bulls classified by residual feed intake. The residual feed intake was calculated as the difference between the observed and predicted dry matter intake. Bulls classified as low residual feed intake had lower dry matter intake (kg day-1) and dry matter intake (g kg-1 d-1) of body weight, and were more efficient in feed conversion ratio than those classified as medium and high. The average daily gain didn't differ among residual feed intake classes and was 1.69 kg day-1, 1.82 kg day-1 and 1.71 kg day-1 for bulls classified as low, medium, or high, respectively. The residual feed intake was positively associated with dry matter intake, feed conversion ratio and subcutaneous fat thickness. The subcutaneous fat thickness was lower in bulls classified as low residual feed intake than in those with medium and high. No differences were observed in flight speed and reactivity score among residual feed intake classes. Overall, we concluded that bulls classified as low residual feed intake consumed less dry matter than high, with no differences in average daily gain, temperamentand had better feed efficiency, albeit their subcutaneous fat thickness was lower.

Lipid metabolism in insect disease vectors.

More than a third of the world population is at constant risk of contracting some insect-transmitted disease, such as Dengue fever, Zika virus disease, malaria, Chagas' disease, African trypanosomiasis, and others. Independent of the life cycle of the pathogen causing the disease, the insect vector hematophagous habit is a common and crucial trait for the transmission of all these diseases. This lifestyle is unique, as hematophagous insects feed on blood, a diet that is rich in protein but relatively poor in lipids and carbohydrates, in huge amounts and low frequency. Another unique feature of these insects is that blood meal triggers essential metabolic processes, as molting and oogenesis and, in this way, regulates the expression of various genes that are involved in these events. In this paper, we review current knowledge of the physiology and biochemistry of lipid metabolism in insect disease vectors, comparing with classical models whenever possible. We address lipid digestion and absorption, hemolymphatic transport, and lipid storage by the fat body and ovary. In this context, both de novo fatty acid and triacylglycerol synthesis are discussed, including the related fatty acid activation process and the intracellular lipid binding proteins. As lipids are stored in order to be mobilized later on, e.g. for flight activity or survivorship, lipolysis and ß-oxidation are also considered. All these events need to be finely regulated, and the role of hormones in this control is summarized. Finally, we also review information about infection, when vector insect physiology is affected, and there is a crosstalk between its immune system and lipid metabolism. There is not abundant information about lipid metabolism in vector insects, and significant current gaps in the field are indicated, as well as questions to be answered in the future.

Ancient Observation of Spinal Cord Injury: The Case of the Assyrian Lion.

The description of paraplegia is considered a milestone in the history of neurology. The Egyptians provided excellent descriptions of spinal cord injuries, the Bible has several references to paraplegia, and, more recently, the pioneers of neurology described the classic syndromes related to spinal injuries and paraplegia. Here, we describe an ancient observation by the Assyrian people of paraplegia in an animal. In ancient Assyria, lion hunting was a ritualized activity conducted for political and religious purposes. The Lion Hunt of Ashurbanipal, a series of Assyrian palace reliefs from the North Palace at Nineveh dating from approximately 645 BCE, which is now in the British Museum in London, UK, shows King Ashurbanipal hunting lions. Applying modern knowledge of mammalian dermatomes to the images, we reveal a detailed and precise observation of paraplegia after spinal cord injury.

Study of the pedestal process for reducing sidewall scattering in photonic waveguides.

In this work we investigate the principles of an alternative method for defining sidewall in optical waveguides fabricated using planar technology. The efficiency of this method is demonstrated through simulations and experimental results regarding propagation losses of a solid core ARROW waveguide fabricated on silicon substrate. It is well known that waveguides fabricated using sidewalls etched via Reactive Ion Etching (RIE) can present high sidewall roughness, especially if metallic hard-masks are used. This is largely responsible for the undesirable losses observed in these waveguides. The basic strategy of the proposed method is to do the etching step, in the fabrication of the waveguides, before the deposition of the core, so as to have the lower cladding layer and part of the silicon substrate etched away. Only after this, is the core of the waveguide deposited. This results in a waveguide sustained by a silicon pedestal. With this process, losses as low as 0.45 dB cm-1 for multimode and 0.84 dB cm-1 for single mode waveguides are obtained. The numerical simulations demonstrate that roughness in sidewalls implicates in propagation losses which are at least five times larger that those in the bulk of the material, thus corroborating the idea behind the proposed method.

Lethal and sublethal effects of essential oil of Lippia sidoides (Verbenaceae) and monoterpenes on Chagas´ disease vector Rhodnius prolixus

The aim of this study was to identify the composition of the essential oil from leaves of Lippia sidoides (EOLS), a typical shrub commonly found in the dry northeast of Brazil, popularly known as “alecrim-pimenta”. Additionally, we investigated the nymphicidal, ovicidal, phagoinhibitory and excretion effects of EOLS, its major constituent thymol and its isomer carvacrol, on fourth instar nymphs and eggs of Rhodnius prolixus, the Chagas’ disease vector. The nymphicidal and ovicidal activity of thymol, carvacrol, and EOLS was assessed by tests using impregnated Petri dishes. The lethal concentration values (LC50) for EOLS, carvacrol, and thymol were 54.48, 32.98, and 9.38 mg/cm2, respectively. The ovicidal test showed that both carvacrol and thymol (50 mg/cm2) inhibited hatching (50% and 23.3%, respectively), while treatments with 10 mg/cm2 or 50 mg/cm2 EOLS did not affect the hatching rate at all (80% and 90%, respectively). We observed an anti-feeding effect in insects fed with blood containing natural products at the higher concentrations (100 µg/mL). Finally, excretion rate was affected by EOLS and carvacrol, but not by thymol. These findings offer novel insights into basic physiological processes that make the tested natural compounds interesting candidates for new types of insecticides.

Lethal and sublethal effects of essential oil of Lippia sidoides (Verbenaceae) and monoterpenes on Chagas' disease vector Rhodnius prolixus.

The aim of this study was to identify the composition of the essential oil from leaves of Lippia sidoides (EOLS), a typical shrub commonly found in the dry northeast of Brazil, popularly known as "alecrim-pimenta". Additionally, we investigated the nymphicidal, ovicidal, phagoinhibitory and excretion effects of EOLS, its major constituent thymol and its isomer carvacrol, on fourth instar nymphs and eggs of Rhodnius prolixus, the Chagas' disease vector. The nymphicidal and ovicidal activity of thymol, carvacrol, and EOLS was assessed by tests using impregnated Petri dishes. The lethal concentration values (LC50) for EOLS, carvacrol, and thymol were 54.48, 32.98, and 9.38 mg/cm2, respectively. The ovicidal test showed that both carvacrol and thymol (50 mg/cm2) inhibited hatching (50% and 23.3%, respectively), while treatments with 10 mg/cm2 or 50 mg/cm2 EOLS did not affect the hatching rate at all (80% and 90%, respectively). We observed an anti-feeding effect in insects fed with blood containing natural products at the higher concentrations (100 µg/mL). Finally, excretion rate was affected by EOLS and carvacrol, but not by thymol. These findings offer novel insights into basic physiological processes that make the tested natural compounds interesting candidates for new types of insecticides.

The duration of gonadotropin stimulation does not alter the clinical pregnancy rate in IVF or ICSI cycles.

BACKGROUND: Ovarian stimulation is an essential part of assisted reproduction treatments. Research on whether the duration of stimulation alters the success in assisted reproduction has not been conclusive. AIM: The purpose of the study was to establish whether the duration of ovarian stimulation alters the success in assisted reproduction treatments. METHODS: All fresh (non-donor) stimulation cycles performed in an academic tertiary referral ART centre over a period of 18 years, between 1st January 1997 and 31st December 2014, were identified. Data were prospectively and electronically collected. IVF and ICSI cycles were analysed independently. Each category was then subdivided into assisted reproduction cycles where the antagonist, long (down regulation) and flare protocol were used. Clinical pregnancy was the main outcome measured. A total of 10,478 stimulation cycles (6011 fresh IVF and 4467 fresh ICSI) reaching egg collection were included. RESULTS: We showed no significant difference in CP rates in IVF cycles for the long (p = 0.082), antagonist (p = 0.217) or flare (p = 0.741) protocol cycles or in ICSI cycles with the long (p = 0.223), antagonist (p = 0.766) or the flare (p = 0.690) protocol with regards the duration of stimulation. CONCLUSION: The duration of stimulation does not alter the CP rate in ICSI or IVF cycles using the long, antagonist or flare stimulation protocol.

Hierarchical structures of amorphous solids characterized by persistent homology.

This article proposes a topological method that extracts hierarchical structures of various amorphous solids. The method is based on the persistence diagram (PD), a mathematical tool for capturing shapes of multiscale data. The input to the PDs is given by an atomic configuration and the output is expressed as 2D histograms. Then, specific distributions such as curves and islands in the PDs identify meaningful shape characteristics of the atomic configuration. Although the method can be applied to a wide variety of disordered systems, it is applied here to silica glass, the Lennard-Jones system, and Cu-Zr metallic glass as standard examples of continuous random network and random packing structures. In silica glass, the method classified the atomic rings as short-range and medium-range orders and unveiled hierarchical ring structures among them. These detailed geometric characterizations clarified a real space origin of the first sharp diffraction peak and also indicated that PDs contain information on elastic response. Even in the Lennard-Jones system and Cu-Zr metallic glass, the hierarchical structures in the atomic configurations were derived in a similar way using PDs, although the glass structures and properties substantially differ from silica glass. These results suggest that the PDs provide a unified method that extracts greater depth of geometric information in amorphous solids than conventional methods.