Rare twin cysteine residues in the HIV-1 envelope variable region 1 link to neutralization escape and breadth development.

Identifying HIV-1 envelope (Env) traits associated with neutralization cross-reactivity is crucial for vaccine design. Variable loops 1 and 2 (V1V2), positioned at the Env trimer apex, are key regions linked to neutralization. We describe non-canonical cysteine (Cys) residues in V1 that are enriched in individuals with elite neutralization breadth. Analyzing over 65,000 V1 sequences from the CATNAP database, AMP trials, and longitudinal HIV-1 cohorts (SHCS, ZPHI, and CAPRISA), we found that Env variants with extra V1 Cys are present at low levels and fluctuate over time. Extra V1 Cys associate with elite plasma neutralization, and two additional Cys are preferred, suggesting stabilization through disulfide bonds. Among 34 broadly neutralizing antibody (bnAb)-inducer Envs, 17.6% had elongated V1 regions with extra Cys. These extra Cys moderately increased neutralization resistance and altered bnAb epitope accessibility. Collectively, altering epitope exposure alongside Env stabilization renders the V1 twin Cys motif a promising feature for HIV-1 bnAb immunogens

Measurement of double-differential charged-current Drell-Yan cross-sections at high transverse masses in pp collisions at √s = 13 TeV with the ATLAS detector

This paper presents a first measurement of the cross-section for the charged-current Drell-Yan process $pp\rightarrow W^{\pm} \rightarrow \ell^{\pm} \nu$ above the resonance region, where $\ell$ is an electron or muon. The measurement is performed for transverse masses, $m_{\text{T}}^{\text{W}}$, between 200 GeV and 5000 GeV, using a sample of 140 fb$^{-1}$ of $pp$ collision data at a centre-of-mass energy of $\sqrt{s}$ = 13 TeV collected by the ATLAS detector at the LHC during 2015-2018. The data are presented single differentially in transverse mass and double differentially in transverse mass and absolute lepton pseudorapidity. A test of lepton flavour universality shows no significant deviations from the Standard Model. The electron and muon channel measurements are combined to achieve a total experimental precision of 3% at low $m_{\text{T}}^{\text{W}}$. The single- and double differential $W$-boson charge asymmetries are evaluated from the measurements. A comparison to next-to-next-to-leading-order perturbative QCD predictions using several recent parton distribution functions and including next-to-leading-order electroweak effects indicates the potential of the data to constrain parton distribution functions. The data are also used to constrain four fermion operators in the Standard Model Effective Field Theory formalism, in particular the lepton-quark operator Wilson coefficient $c_{\ell q}^{(3)}.

Systems genomics in age-related macular degeneration

Genomic studies in age-related macular degeneration (AMD) have identified genetic variants that account for the majority of AMD risk. An important next step is to understand the functional consequences and downstream effects of the identified AMD-associated genetic variants. Instrumental for this next step are 'omics' technologies, which enable high-throughput characterization and quantification of biological molecules, and subsequent integration of genomics with these omics datasets, a field referred to as systems genomics.Single cell sequencing studies of the retina and choroid demonstrated that the majority of candidate AMD genes identified through genomic studies are expressed in non-neuronal cells, such as the retinal pigment epithelium (RPE), glia, myeloid and choroidal cells, highlighting that many different retinal and choroidal cell types contribute to the pathogenesis of AMD. Expression quantitative trait locus (eQTL) studies in retinal tissue have identified putative causal genes by demonstrating a genetic overlap between gene regulation and AMD risk. Linking genetic data to complement measurements in the systemic circulation has aided in understanding the effect of AMD-associated genetic variants in the complement system, and supports that protein QTL (pQTL) studies in plasma or serum samples may aid in understanding the effect of genetic variants and pinpointing causal genes in AMD. A recent epigenomic study fine-mapped AMD causal variants by determing regulatory regions in RPE cells differentiated from induced pluripotent stem cells (iPSC-RPE). Another approach that is being employed to pinpoint causal AMD genes is to produce synthetic DNA assemblons representing risk and protective haplotypes, which are then delivered to cellular or animal model systems.Pinpointing causal genes and understanding disease mechanisms is crucial for the next step towards clinical translation. Clinical trials targeting proteins encoded by the AMD-associated genomic loci C3, CFB, CFI, CFH, and ARMS2/HTRA1 are currently ongoing, and a phase III clinical trial for C3 inhibition recently showed a modest reduction of lesion growth in geographic atrophy. The EYERISK consortium recently developed a genetic test for AMD that allows genotyping of common and rare variants in AMD-associated genes. Polygenic risk scores (PRS) were applied to quantify AMD genetic risk, and may aid in predicting AMD progression.In conclusion, genomic studies represent a turning point in our exploration of AMD. The results of those studies now serve as a driving force for several clinical trials. Expanding to omics and systems genomics will further decipher function and causality from the associations that have been reported, and will enable the development of therapies that will lessen the burden of AMD

Systems genomics in age-related macular degeneration

Genomic studies in age-related macular degeneration (AMD) have identified genetic variants that account for the majority of AMD risk. An important next step is to understand the functional consequences and downstream effects of the identified AMD-associated genetic variants. Instrumental for this next step are ‘omics’ technologies, which enable high-throughput characterization and quantification of biological molecules, and subsequent integration of genomics with these omics datasets, a field referred to as systems genomics. Single cell sequencing studies of the retina and choroid demonstrated that the majority of candidate AMD genes identified through genomic studies are expressed in non-neuronal cells, such as the retinal pigment epithelium (RPE), glia, myeloid and choroidal cells, highlighting that many different retinal and choroidal cell types contribute to the pathogenesis of AMD. Expression quantitative trait locus (eQTL) studies in retinal tissue have identified putative causal genes by demonstrating a genetic overlap between gene regulation and AMD risk. Linking genetic data to complement measurements in the systemic circulation has aided in understanding the effect of AMD-associated genetic variants in the complement system, and supports that protein QTL (pQTL) studies in plasma or serum samples may aid in understanding the effect of genetic variants and pinpointing causal genes in AMD. A recent epigenomic study fine-mapped AMD causal variants by determing regulatory regions in RPE cells differentiated from induced pluripotent stem cells (iPSC-RPE). Another approach that is being employed to pinpoint causal AMD genes is to produce synthetic DNA assemblons representing risk and protective haplotypes, which are then delivered to cellular or animal model systems. Pinpointing causal genes and understanding disease mechanisms is crucial for the next step towards clinical translation. Clinical trials targeting proteins encoded by the AMD-associated genomic loci C3, CFB, CFI, CFH, and ARMS2/HTRA1 are currently ongoing, and a phase III clinical trial for C3 inhibition recently showed a modest reduction of lesion growth in geographic atrophy. The EYERISK consortium recently developed a genetic test for AMD that allows genotyping of common and rare variants in AMD-associated genes. Polygenic risk scores (PRS) were applied to quantify AMD genetic risk, and may aid in predicting AMD progression. In conclusion, genomic studies represent a turning point in our exploration of AMD. The results of those studies now serve as a driving force for several clinical trials. Expanding to omics and systems genomics will further decipher function and causality from the associations that have been reported, and will enable the development of therapies that will lessen the burden of AMD

Coesão e resistência ao cisalhamento relacionadas a atributos físicos e químicos de um Latossolo Amarelo de tabuleiro costeiro Cohesion and shear strength as related to physical and chemical properties of a Yellow Latosol of coastal plain

Os solos coesos de tabuleiros costeiros têm como característica peculiar horizontes minerais subsuperficiais, que apresentam consistência friável quando úmidos, porém, quando secos, têm consistência dura, muito dura ou extremamente dura. Este trabalho teve o objetivo de estudar o comportamento mecânico de horizontes coesos e não-coesos de um Latossolo Amarelo de tabuleiro costeiro por meio de características de cisalhamento relacionadas com propriedades físicas, químicas e teor de água do solo. Os resultados mostraram que a coesão do solo e a resistência ao cisalhamento aumentaram expressivamente com a redução do teor de água no horizonte coeso. Este horizonte apresentou os maiores valores de densidade do solo, microporosidade e óxidos de Fe, Si e Al, resultando em maiores valores de coesão do solo e resistência ao cisalhamento, em relação aos horizontes não-coesos. Os maiores valores de coesão do solo resultaram em maiores valores de resistência à penetração no horizonte coeso, em relação aos não-coesos. As características de cisalhamento (coesão do solo, ângulo de atrito interno e resistência ao cisalhamento) mostraram-se sensíveis à identificação de horizontes coesos em solos de tabuleiros costeiros.<br>The cohesive soils of Brazilian coastal plain have subsurface horizon with a peculiar characteristic - when wet the consistency is friablet, but of hard, very hard or extremely hard consistency when dry. The objective of this study was to evaluate the mechanical characteristics of cohesive and non-cohesive horizons of a Yellow Latosol of coastal tableland based on shear parameters related with soil physical and chemical properties and moisture. The results showed that soil cohesion and shear strength increased substantially with the reduction of the water content in the cohesive horizon. The cohesive horizon presented the highest values of bulk density, microporosity and Fe, Si and Al oxides, resulting in higher values of soil cohesion and shear strength as compared to the non-cohesive horizons. The highest values of soil cohesion resulted in greater resistance to penetration in the cohesive horizon in comparison to the non-cohesive horizons. The shear parameters (soil cohesion, internal friction angle and shear strength) proved sensitive for the identification of cohesive horizons in soils of coastal plains

Influência de diferentes sistemas de uso e manejo na coesão, resistência ao cisalhamento e óxidos de Fe, Si E Al em solo de tabuleiro costeiro de Alagoas Influence of different use and management systems on cohesion, shear strength and Fe, Si and Al oxides in coastal tableland soils of Alagoas state, Brazil

A tensão de cisalhamento e a coesão do solo constituem importantes propriedades físicas do solo, podendo ser influenciadas pelo sistema de manejo e óxidos de Fe, Si e Al do solo. Os efeitos de diferentes sistemas de manejo de solo cultivado com cana-de-açúcar na tensão de cisalhamento, ângulo de atrito interno, coesão do solo e nos teores de óxidos de Fe, Si e Al de um Argissolo Amarelo Coeso foram estudados em quatro áreas da Usina Triunfo, no Estado de Alagoas. Os tratamentos abrangeram: uma área irrigada, uma área não irrigada, uma com aplicação de vinhaça e uma sob floresta nativa, como condição original. Amostras foram tiradas de cada área a 0,2-0,4 m e 0,4-0,8 m de profundidade. Os sistemas sequeiro e irrigado promoveram os maiores aumentos na coesão, ângulo de atrito interno e resistência ao cisalhamento do solo. Os teores de água e de óxidos no solo influíram nos valores de coesão do solo, tendo sido os maiores valores deste atributo obtidos em solos com teores de água mais baixos e solos com maiores teores de óxidos.<br>The shear tension and soil cohesion are important soil physical properties. They are affected by management systems and the content of Fe, Si and Al oxides in the soil. The effects of different sugarcane management systems on the shear tension, angle of internal friction, soil cohesion, and the contents of Fe, Si and Al oxides in a Cohesive Yellow Argisol were studied in four areas of the Triunfo mill in Alagoas State, Brazil. The treatments consisted of an area cultivated with irrigation and another without irrigation, a site with vinasse application. A native forest area was included as reference for the original conditions. Samples were collected from each site at depths of 0.2-0.4 m and 0.4-0.8 m. The areas cultivated with and without irrigation promoted the greatest increase in soil cohesion, angle of internal friction and soil shear strength. The water and oxide contents affected the soil cohesion; the highest soil cohesion values were obtained in soils with the lowest water and the highest oxide contents