Biochemical properties of sheep colostrum and its potential benefits for lamb survival: a review.

Colostrum is the initial secretion of the mammary glands following parturition, which offers main food, protection, and biological active substances for the new born. The most threatening episode of neonate's life is the initial two weeks after birth. This period is associated with high neonatal mortality and morbidity. These worthwhile losses lead to a poor prolificacy rate, low profitability, and ultimately poor performance in animal production. Hence, both diseases and mortality cause valuable losses in terms of production and economic losses. The survival of neonate is correlated with their immune status and passive immune transfer (PIT). Colostrum provides the primary source of nutrition and immunity (PIT) that protects neonates against infections. It must be given as soon as possible after birth since its immunoglobulins are absorbed within the first 16-27 hours after birth, ideally within 2-4 hours. As a result, immunoglobulin (PIT) is the most important component of distressing infectious immunity, and a passable concentration of immunoglobulin in the blood of newborn lambs is linked to their health and survival rate. In this review, we summarized the importance of colostrum in early life and its association with neonatal lamb's survival, profitability and productivity of sheep farming.

Achieving focal invariance in different background refractive indices through a dual-environment metalens.

A conventional metalens is designed with a fixed working environment, and its focal length depends on the background refractive index. In this study, we propose a dual-environment metalens that can maintain the same focal length in both media of air and water. The metalens consists of 16 types of meta-atoms with different geometries, which can cover the 0-2π phase range in both air and water. We perform finite-difference time-domain simulations to investigate the metalens and demonstrate that its focal length remains unchanged, regardless of whether the background medium is air or water. Furthermore, we investigated the optical forces within the focal field of the metalens in both air and water, indicating its potential trapping capability in these media. Our method provides a new insight into dual-environment metasurfaces and advances the methodology of electromagnetic structures in extensive applications.

Realizing multi-function absorptions through arbitrary octagonal meta-atoms.

Metasurface absorbers (MA) typically exhibit a single type of absorption function due to their regular structures. In this study, we propose an irregular MA structure with octagonal meta-atoms. The presence of eight vertices in each meta-atom allows for tunable coordinates and offers a multitude of degrees of freedom in terms of geometry. As a result, the proposed MA exhibits diverse functionalities, including perfect absorption, multi-peaks absorption, and high absorption with a filtering window. To predict the geometric parameters of the MA structure based on a given target absorption spectrum, as well as the inverse design of the structure using the absorption spectrum as input, we employ a deep neural network combined with the particle swarm optimization algorithm. Remarkably, the mean-square error for spectrum prediction and inverse design of the MA structure is found to be as low as 0.0008 and 0.0031, respectively. This study opens up new possibilities for designing irregular electromagnetic structures and holds great potential for applications in multifunctional metasurfaces and metamaterials.

Structure and biochemical characterization of l-2-hydroxyglutarate dehydrogenase and its role in the pathogenesis of l-2-hydroxyglutaric aciduria.

l-2-hydroxyglutarate dehydrogenase (L2HGDH) is a mitochondrial membrane-associated metabolic enzyme, which catalyzes the oxidation of l-2-hydroxyglutarate (l-2-HG) to 2-oxoglutarate (2-OG). Mutations in human L2HGDH lead to abnormal accumulation of l-2-HG, which causes a neurometabolic disorder named l-2-hydroxyglutaric aciduria (l-2-HGA). Here, we report the crystal structures of Drosophila melanogaster L2HGDH (dmL2HGDH) in FAD-bound form and in complex with FAD and 2-OG and show that dmL2HGDH exhibits high activity and substrate specificity for l-2-HG. dmL2HGDH consists of an FAD-binding domain and a substrate-binding domain, and the active site is located at the interface of the two domains with 2-OG binding to the re-face of the isoalloxazine moiety of FAD. Mutagenesis and activity assay confirmed the functional roles of key residues involved in the substrate binding and catalytic reaction and showed that most of the mutations of dmL2HGDH equivalent to l-2-HGA-associated mutations of human L2HGDH led to complete loss of the activity. The structural and biochemical data together reveal the molecular basis for the substrate specificity and catalytic mechanism of L2HGDH and provide insights into the functional roles of human L2HGDH mutations in the pathogeneses of l-2-HGA.

Single-shot measurement of the Jones matrix for anisotropic media using four-channel digital polarization holography.

Dynamic measurement of the Jones matrix is crucial in investigating polarization light fields, which have wide applications in biophysics, chemistry, and mineralogy. However, acquiring the four elements of the Jones matrix instantly is difficult, hindering the characterization of random media and transient processes. In this study, we propose a single-shot measurement method of the Jones matrix for anisotropic media called "four-channel digital polarization holography" (FC-DPH). The FC-DPH system is created by a slightly off-axis superposition of reference light waves, which are modulated by a spatial light modulator (SLM), and signal light waves that pass through a Ronchi grating. The SLM enables flexible adjustment of the spatial carrier frequency, which can be adapted to different anisotropic media. The four elements of the Jones matrix can be obtained from the interferogram through the inverse Fourier transform. Optical experiments on anisotropic objects validate the feasibility and accuracy of the proposed method.

Lactate dehydrogenase D is a general dehydrogenase for D-2-hydroxyacids and is associated with D-lactic acidosis.

Mammalian lactate dehydrogenase D (LDHD) catalyzes the oxidation of D-lactate to pyruvate. LDHD mutations identified in patients with D-lactic acidosis lead to deficient LDHD activity. Here, we perform a systematic biochemical study of mouse LDHD (mLDHD) and determine the crystal structures of mLDHD in FAD-bound form and in complexes with FAD, Mn2+ and a series of substrates or products. We demonstrate that mLDHD is an Mn2+-dependent general dehydrogenase which exhibits catalytic activity for D-lactate and other D-2-hydroxyacids containing hydrophobic moieties, but no activity for their L-isomers or D-2-hydroxyacids containing hydrophilic moieties. The substrate-binding site contains a positively charged pocket to bind the common glycolate moiety and a hydrophobic pocket with some elasticity to bind the varied hydrophobic moieties of substrates. The structural and biochemical data together reveal the molecular basis for the substrate specificity and catalytic mechanism of LDHD, and the functional roles of mutations in the pathogenesis of D-lactic acidosis.

Molecular basis for the functional roles of the multimorphic T95R mutation of IRF4 causing human autosomal dominant combined immunodeficiency.

Interferon regulatory factor 4 (IRF4) is a transcription factor that regulates the development and function of immune cells. Recently, a new multimorphic mutation T95R was identified in the IRF4 DNA-binding domain (DBD) in patients with autosomal dominant combined immune deficiency. Here, we characterized the interactions of the wild-type IRF4-DBD (IRF4-DBDWT) and T95R mutant (IRF4-DBDT95R) with a canonical DNA sequence and several noncanonical DNA sequences. We found that compared to IRF4-DBDWT, IRF4-DBDT95R exhibits higher binding affinities for both canonical and noncanonical DNAs, with the highest preference for the noncanonical GATA sequence. The crystal structures of IRF4-DBDWT in complex with the GATA sequence and IRF4-DBDT95R in complexes with both canonical and noncanonical DNAs were determined, showing that the T95R mutation enhances the interactions of IRF4-DBDT95R with the canonical and noncanonical DNAs to achieve higher affinity and specificity. Collectively, our data provide the molecular basis for the gain-of-function and new function of IRF4T95R.

Spatio-temporal structuring control of a vectorial focal field.

Focal field modulation has attracted a lot of interest due to its potential in many applications such as optical tweezers or laser processing, and it has recently been facilitated by spatial light modulators (SLMs) owing to their dynamic modulation abilities. However, capabilities for manipulating focal fields are limited by the space-bandwidth product of SLMs. This difficulty can be alleviated by taking advantage of the high-speed modulation ability of digital micromirror devices (DMDs), i.e., trading time for space to achieve fine focus shaping. In this paper, we propose a new, to the best of our knowledge, technique for achieving four-dimensional focal field modulation, which allows for independent manipulation of the focal field's parameters (including amplitude, phase, and polarization) in both the space and time domains. This technique combines a DMD and a vector field synthesis system based on a 4-f system. The high-speed modulation ability of DMDs enables versatile focus patterns to be fast switchable during the exposure time of the detector, forming multiple patterns in a single recording frame. By generating different kinds of focal spots and lines at different moments during the exposure time of the detector, we can finally get complete multifocal spots and lines. Our proposed method is effective at improving the flexibility and speed of the focal field modulation, which is beneficial to applications.

Molecular insights into the catalysis and regulation of mammalian NAD-dependent isocitrate dehydrogenases.

Eukaryotic NAD-dependent isocitrate dehydrogenases (NAD-IDHs) are mitochondria-localized enzymes which catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate using NAD as a cofactor. In mammals, NAD-IDHs (or IDH3) consist of three types of subunits (α, ß, and γ), and exist as (α2ßγ)2 heterooctamer. Mammalian NAD-IDHs are regulated allosterically and/or competitively by a diversity of metabolites including citrate, ADP, ATP, NADH, and NADPH, which are associated with cellular metabolite flux, energy demands, and redox status. Proper assembly of the component subunits is essential for the catalysis and regulation of the enzymes. Recently, crystal structures of human IDH3 have been solved in apo form and in complex with various ligands, revealing the molecular mechanisms for the assembly, catalysis, and regulation of the enzyme.

Protein-metabolite interactomics of carbohydrate metabolism reveal regulation of lactate dehydrogenase.

Metabolic networks are interconnected and influence diverse cellular processes. The protein-metabolite interactions that mediate these networks are frequently low affinity and challenging to systematically discover. We developed mass spectrometry integrated with equilibrium dialysis for the discovery of allostery systematically (MIDAS) to identify such interactions. Analysis of 33 enzymes from human carbohydrate metabolism identified 830 protein-metabolite interactions, including known regulators, substrates, and products as well as previously unreported interactions. We functionally validated a subset of interactions, including the isoform-specific inhibition of lactate dehydrogenase by long-chain acyl-coenzyme A. Cell treatment with fatty acids caused a loss of pyruvate-lactate interconversion dependent on lactate dehydrogenase isoform expression. These protein-metabolite interactions may contribute to the dynamic, tissue-specific metabolic flexibility that enables growth and survival in an ever-changing nutrient environment.

The Accuracy and Clinical Relevance of the Multi-echo Dixon Technique for Evaluating Changes to Hepatic Steatosis in Patients with Non-alcoholic Fatty Liver Disease Treated with Formulated Food.

PURPOSE: The Multi-echo Dixon (ME-Dixon) is a non-invasive quantitative MRI technique to diagnose non-alcoholic fatty liver disease (NAFLD). In this study, the hydrogen proton MR spectroscopy (1H-MRS) was used as a reference to explore the accuracy of the ME-Dixon technique in evaluating hepatic steatosis in NAFLD patients after ingesting formulated food and its correlation with changes in clinical indicators. METHODS: Twenty-seven patients with NAFLD were enrolled. Fifteen patients completed 12 weeks of treatment with prebiotics and dietary fiber. In addition, abdominal MRI scans and blood tests were performed before and after treatment. The MRI-proton density fat fraction (MRI-PDFF) and MRS-PDFF were measured using the ME-Dixon and 1H-MRS techniques. The Bland-Altman method and Pearson correlation analysis were used to test the consistency of the two techniques for measuring the liver fat content and the changed values. Besides, correlation analysis was conducted between the MRI-PDFF value and metabolic indicators. RESULTS: In the PDFF quantification of 42 person-times and the monitoring of the PDFF change in 15 patients under treatment, there was a good consistency and a correlation between MRI and MRS. At baseline, MRI-PDFF was positively correlated with insulin resistance index (HOMA-IR), fatty liver index (FLI), and liver enzymes. After treatment, the changes in MRI-PDFF were positively correlated with the recovery degree of FLI and liver enzymes. CONCLUSION: ME-Dixon has a good consistency and a correlation with MRS in quantifying the liver fat content and monitoring the treatment effect, which may be used as an accurate indicator for clinical monitoring of changes in the liver fat content.

Breaking symmetry restriction of chirality through spin-decoupled phase modulation utilizing non-mirror-symmetric meta-atoms.

The geometric phase in metasurfaces follows a symmetry restriction of chirality, which dictates that the phases of two orthogonal circularly polarized waves are identical but have opposite signs. In this study, we propose a general mechanism to disrupt this symmetric restriction on the chirality of orthogonal circular polarizations by introducing mirror-symmetry-breaking meta-atoms. This mechanism introduces a new degree of freedom in spin-decoupled phase modulation without necessitating the rotation of the meta-atom. To demonstrate the feasibility of this concept, we design what we believe is a novel meta-atom with a QR-code structure and successfully showcase circular-polarization multiplexing metasurface holography. Our investigation offers what we believe to be a novel understanding of the chirality in geometric phase within the realm of nanophotonics. Moreover, it paves the way for the development of what we believe will be novel design methodologies for electromagnetic structures, enabling applications in arbitrary wavefront engineering.

Structures of a constitutively active mutant of human IDH3 reveal new insights into the mechanisms of allosteric activation and the catalytic reaction.

Human NAD-dependent isocitrate dehydrogenase or IDH3 (HsIDH3) catalyzes the decarboxylation of isocitrate into α-ketoglutarate in the tricarboxylic acid cycle. It consists of three types of subunits (α, ß, and γ) and exists and functions as the (αßαγ)2 heterooctamer. HsIDH3 is regulated allosterically and/or competitively by numerous metabolites including CIT, ADP, ATP, and NADH. Our previous studies have revealed the molecular basis for the activity and regulation of the αß and αγ heterodimers. However, the molecular mechanism for the allosteric activation of the HsIDH3 holoenzyme remains elusive. In this work, we report the crystal structures of the αß and αγ heterodimers and the (αßαγ)2 heterooctamer containing an α-Q139A mutation in the clasp domain, which renders all the heterodimers and the heterooctamer constitutively active in the absence of activators. Our structural analysis shows that the α-Q139A mutation alters the hydrogen-bonding network at the heterodimer-heterodimer interface in a manner similar to that in the activator-bound αγ heterodimer. This alteration not only stabilizes the active sites of both αQ139Aß and αQ139Aγ heterodimers in active conformations but also induces conformational changes of the pseudo-allosteric site of the αQ139Aß heterodimer enabling it to bind activators. In addition, the αQ139AICT+Ca+NADßNAD structure presents the first pseudo-Michaelis complex of HsIDH3, which allows us to identify the key residues involved in the binding of cofactor, substrate, and metal ion. Our structural and biochemical data together reveal new insights into the molecular mechanisms for allosteric regulation and the catalytic reaction of HsIDH3.

Functional Epoxy Elastomer Integrating Self-Healing Capability and Degradability for a Flexible Stretchable Strain Sensor.

With the rapid development of flexible electronics and the increasing deterioration of the natural environment, functional and environmentally friendly flexible strain sensors have become one of the frontier research hotspots. Here, we propose a novel strategy to synthesize a functional epoxy elastomer integrating self-healing capability and degradability for flexible stretchable strain sensors. A carboxyl-terminated epoxy prepolymer was first synthesized using carboxyl-terminated PEG (PEG-COOH), 2,2'-dithiodibenzoic acid (DTSA), and 1,4-butanediol diglycidyl ether (BDDE), and then crosslinked by epoxidized soybean oil (ESO) to yield an epoxy elastomer. The obtained elastomer exhibited not only high tensile stress (5.07 MPa), large stretchability (477%), and high healing efficiency (92.5%) but also superior degradability in alkaline aqueous solution. The elastomer-based stretchable strain sensor with microstructure showed high sensitivity (GF = 176.71) and was successfully applied for detecting human motions and recognizing objects with various shapes. Moreover, the healed sensor could restore stable sensing ability. The prepared functional epoxy elastomer is of great significance for the preparation of environmentally friendly and high-performance sensors and is promising for applications in the fields of healthcare monitoring, intelligent robots, and wearable electronics.

Correlation analysis of epicardial adipose tissue and ventricular myocardial strain in Chinese amateur marathoners using cardiac magnetic resonance.

BACKGROUND: The volume of epicardial adipose tissue (EAT) is associated with an increased incidence of cardiovascular disease (CVD); however, only a few studies have examined its effect on the myocardial function of endurance in athletes. The association between the EAT and the variation of myocardial function is still unclear in amateur marathoners. Consequently, by using some sedentary individuals as the control, this study aims to evaluate the correlation between the EAT volume and the myocardial strain in the left and right ventricles of Chinese amateur marathoners by cardiac magnetic resonance (CMR). METHODS: A total of 30 amateur marathoners were included as the exercise group and 20 sedentary people as a control group. All participants received the cardiac magnetic resonance (CMR) to measure the left and right ventricular end-diastolic volume, end-systolic volume and volume index, stroke volume and index, cardiac output index, ejection fraction and myocardial mass, the EAT volume, global radial, circumferential, and longi-tudinal strains, and the strain rates of left and right ventricular myocardium. RESULTS: There was a significant difference in the EAT volume (EATV) index between the exercise group and the control group (26.82±11.76ml/m2 vs 37.82±17.15ml/m2, P = 0.01). Results from the multivariate linear regression analysis showed that BMI (standardized ß = 0.458; P < 0.001) had an independent positive correlation with the EATV index. The EATV index was negatively correlated with the left ventricular global radial strain (GRS) (r = -0.505; P = 0.004) in the exercise group, while it is negatively correlated with right ventricular GRS (r = -0.492; P = 0.027) and positively correlated with global longitudinal strain (GLS) (r = 0.601; P = 0.005) in the control group. In the exercise group, the multivariate linear regression analysis showed that the EATV index (standardized ß = -0.429; P = 0.021) was an independent determinant of the left ventricular GRS, and being a male (standardized ß = 0.396; P = 0.029) was an independent determinant of the right ventricular GLS. CONCLUSION: The EATV index is independently correlated with the left ventricular GRS in the amateur Chinese marathoners, also, the amateur marathon reduces the EATV index and increases the left ventricular myocardial mass, which consequently reduces the adverse effects on myocardial function.

Molecular mechanism of S-adenosylmethionine sensing by SAMTOR in mTORC1 signaling.

The mechanistic target of rapamycin-mLST8-raptor complex (mTORC1) functions as a central regulator of cell growth and metabolism in response to changes in nutrient signals such as amino acids. SAMTOR is an S-adenosylmethionine (SAM) sensor, which regulates the mTORC1 activity through its interaction with the GTPase-activating protein activity toward Rags-1 (GATOR1)-KPTN, ITFG2, C12orf66 and SZT2-containing regulator (KICSTOR) complex. In this work, we report the crystal structures of Drosophila melanogaster SAMTOR in apo form and in complex with SAM. SAMTOR comprises an N-terminal helical domain and a C-terminal SAM-dependent methyltransferase (MTase) domain. The MTase domain contains the SAM-binding site and the potential GATOR1-KICSTOR-binding site. The helical domain functions as a molecular switch, which undergoes conformational change upon SAM binding and thereby modulates the interaction of SAMTOR with GATOR1-KICSTOR. The functional roles of the key residues and the helical domain are validated by functional assays. Our structural and functional data together reveal the molecular mechanism of the SAM sensing of SAMTOR and its functional role in mTORC1 signaling.

Neutralization mechanism of a human antibody with pan-coronavirus reactivity including SARS-CoV-2.

Frequent outbreaks of coronaviruses underscore the need for antivirals and vaccines that can counter a broad range of coronavirus types. We isolated a human antibody named 76E1 from a COVID-19 convalescent patient, and report that it has broad-range neutralizing activity against multiple α- and ß-coronaviruses, including the SARS-CoV-2 variants. 76E1 also binds its epitope in peptides from γ- and δ-coronaviruses. 76E1 cross-protects against SARS-CoV-2 and HCoV-OC43 infection in both prophylactic and therapeutic murine animal models. Structural and functional studies revealed that 76E1 targets a unique epitope within the spike protein that comprises the highly conserved S2' site and the fusion peptide. The epitope that 76E1 binds is partially buried in the structure of the SARS-CoV-2 spike trimer in the prefusion state, but is exposed when the spike protein binds to ACE2. This observation suggests that 76E1 binds to the epitope at an intermediate state of the spike trimer during the transition from the prefusion to the postfusion state, thereby blocking membrane fusion and viral entry. We hope that the identification of this crucial epitope, which can be recognized by 76E1, will guide epitope-based design of next-generation pan-coronavirus vaccines and antivirals.

Unique binding pattern for a lineage of human antibodies with broad reactivity against influenza A virus.

Most structurally characterized broadly neutralizing antibodies (bnAbs) against influenza A viruses (IAVs) target the conserved conformational epitopes of hemagglutinin (HA). Here, we report a lineage of naturally occurring human antibodies sharing the same germline gene, VH3-48/VK1-12. These antibodies broadly neutralize the major circulating strains of IAV in vitro and in vivo mainly by binding a contiguous epitope of H3N2 HA, but a conformational epitope of H1N1 HA, respectively. Our structural and functional studies of antibody 28-12 revealed that the continuous amino acids in helix A, particularly N49HA2 of H3 HA, are critical to determine the binding feature with 28-12. In contrast, the conformational epitope feature is dependent on the discontinuous segments involving helix A, the fusion peptide, and several HA1 residues within H1N1 HA. We report that this antibody was initially selected by H3 (group 2) viruses and evolved via somatic hypermutation to enhance the reactivity to H3 and acquire cross-neutralization to H1 (group 1) virus. These findings enrich our understanding of different antigenic determinants of heterosubtypic influenza viruses for the recognition of bnAbs and provide a reference for the design of influenza vaccines and more effective antiviral drugs.