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Li, C.

Publications and source records attributed to Li, C..

At least 667 records · Page 37Linked to original sources

The role of B cells in immune cell activation in polycystic ovary syndrome

Variations in B cell numbers are associated with polycystic ovary syndrome (PCOS) through unknown mechanisms. Here we demonstrate that B cells are not central mediators of PCOS pathology and that their frequencies are altered as a direct effect of androgen receptor activation. Hyperandrogenic women with PCOS have increased frequencies of age-associated double-negative B memory cells and increased levels of circulating immunoglobulin M (IgM). However, the transfer of serum IgG from women into wild-type female mice induces only an increase in body weight. Furthermore, RAG1 knock-out mice, which lack mature T- and B cells, fail to develop any PCOS-like phenotype. In wild-type mice, co-treatment with flutamide, an androgen receptor antagonist, prevents not only the development of a PCOS-like phenotype but also alterations of B cell frequencies induced by dihydrotestosterone (DHT). Finally, B cell-deficient mice, when exposed to DHT, are not protected from developing a PCOS-like phenotype. These results urge further studies on B cell functions and their effects on autoimmune comorbidities highly prevalent among women with PCOS. SummaryAndrogen receptor activation alters B cell frequencies and functionality as the transfer of human PCOS IgG increase weight in female mice. Lack of B cells does not protect from the development of a PCOS phenotype, suggesting an unrecognized role for B cells in PCOS autoimmune comorbidities. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/525671v2_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@15802fborg.highwire.dtl.DTLVardef@12bd154org.highwire.dtl.DTLVardef@1bc14a9org.highwire.dtl.DTLVardef@f08d2b_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

The complete chloroplast genome sequence of Akebia trifoliata and a comparative analysis within the Ranales clade

The complete nucleotide sequence of the Akebia trifoliata chloroplast (cp) genome was reported and characterized in this study. The cp genome is a closed circular molecule of 157 949 bp, composed of a pair of IR regions of 26 149 bp, one LSC region of 86 595 bp, and one SSC region of 19 056 bp. The GC contents of the LSC, SSC, and IR regions, and the whole cp genome are 37.11%, 33.62%, 43.08% and 38.66%, respectively. The cp genome contains 130 predicted functional genes, including 85 PCGs of 79 107 bp, 37 tRNA and 8 rRNA genes of 11 851 bp. 168 SSRs and 23 long repeats were identified in the cp genome. The results revealed that 21 891 codons characterize the coding capacity of 85 protein-coding genes in Akebia trifoliata, 10.84% and 1.20% of the codons coded for leucine and cysteine respectively. The usage of the start codon exhibited no bias in the A. trifoliata cp genome. Phylogenetic analysis suggest that A. trifoliata is most closely related to S. japonica, which then formed a cluster with N. dormestica and M. saniculifolia to form subgroup of Ranunculales. Our study provides information on mangrove plant species in coastal intertidal zones.

plant biology↗

MANF stimulates autophagy and restores mitochondrial homeostasis to treat toxic proteinopathy

Misfolded protein aggregates may cause toxic proteinopathy, including autosomal dominant tubulointerstitial kidney disease due to uromodulin mutations (ADTKD-UMOD), one of the leading hereditary kidney diseases, and Alzheimers disease etc. There are no targeted therapies. ADTKD is also a genetic form of renal fibrosis and chronic kidney disease, which affects 500 million people worldwide. For the first time, in our newly generated mouse model recapitulating human ADTKD-UMOD carrying a leading UMOD deletion mutation, we show that autophagy/mitophagy and mitochondrial biogenesis are severely impaired, leading to cGAS- STING activation and tubular injury. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a novel endoplasmic reticulum stress-regulated secreted protein. We provide the first study that inducible tubular overexpression of MANF after the onset of disease stimulates autophagy/mitophagy and clearance of the misfolded UMOD, and promotes mitochondrial biogenesis through p-AMPK enhancement, resulting in protection of kidney function. Conversely, genetic ablation of endogenous MANF upregulated in the mutant mouse and human tubular cells worsens autophagy suppression and kidney fibrosis. Together, we discover MANF as a novel biotherapeutic protein and elucidate previously unknown mechanisms of MANF in regulating organelle homeostasis to treat ADTKD, which may have broad therapeutic application to treat various proteinopathies.

cell biology↗

Wheat plant height locus RHT25 encodes a PLATZ transcription factor that interacts with DELLA (RHT1)

Plant height is an important agronomic trait with a significant impact on grain yield, as demonstrated by the positive effect of the REDUCED HEIGHT (RHT) dwarfing alleles (Rht1b) on lodging and harvest index in the "Green Revolution" wheat varieties. However, these gibberellic acid (GA) insensitive alleles also reduce coleoptile length, biomass production, and yield potential in some environments, triggering the search for alternative GA-sensitive dwarfing genes. Here we report the identification, validation and characterization of the gene underlying the GA-sensitive dwarfing locus RHT25 in wheat. This gene, designated as PLATZ-A1 (TraesCS6A02G156600), is expressed mainly in the elongating stem and developing spike and encodes a plant-specific AT-rich sequence- and zinc-binding protein (PLATZ). Natural and induced loss-of-function mutations in PLATZ-A1 reduce plant height and its over-expression increases it, demonstrating that PLATZ-A1 is the causative gene of RHT25. PLATZ-A1 interacts physically and genetically with RHT1 (DELLA), and both genes have stronger effects on plant height in the presence of the wildtype than in the presence of the mutant allele of the other gene. These results suggest that PLATZ1 can modulate the effect of DELLA on wheat plant height. We identified four natural truncation mutations and one promoter insertion in PLATZ-A1 that are more frequent in modern varieties than in landraces, suggesting positive selection during wheat breeding. These mutations can be used to fine-tune wheat plant height and, in combination with other GA-sensitive dwarfing genes, to replace the GA-insensitive Rht1b alleles to search for grain yield improvements beyond those of the Green Revolution varieties. Significance StatementWe have identified and characterized a previously unknown gene controlling plant height in wheat and named it PLATZ1. Mutations in PLATZ1 reduce plant height while its overexpression results in taller plants. PLATZ1 is expressed mainly in elongating stems and developing spikes and interacts physically and genetically with the "Green Revolution" dwarfing gene REDUCED HEIGHT 1 (RHT1). We discovered five natural mutants in the A genome copy of PLATZ1 in common wheat that have been favored during breeding, suggesting an overall positive effect on wheat performance. These mutations can be used to fine-tune wheat plant height and, eventually, to replace the RHT1 dwarfing alleles that impose limitations on planting depth and grain yield potential in some environments.

plant biology↗

Ultrasensitive Proteomics Depicted an In-depth Landscape for Mouse Embryo

In recent years, single-cell or low-input multi-omics techniques have brought a revolution in the study of pre-implantation embryo development. However, single-cell or low-input proteome research in this field is relatively underdeveloped, due to the limited source of mammalian embryo samples, the objective reality of high abundance zona pellucida proteins, and the lack of hypersensitive proteome technology. Here, a comprehensive solution of ultrasensitive proteome technology was developed for single-cell or low-input mouse embryos. Both deep coverage route and high-throughput route could significantly reduce the starting material and enhance the proteomic depth without any customized instrument. Using the deep coverage route, an average of 2,665 or 4,585 protein groups can be identified from 1 or 20 mouse zygotes respectively. Using the high-throughput route, 300 single mouse zygotes can be analysis in 8 days with an average of 2,371 proteins identified. With its popularization, we believe researchers can choose deep coverage or high-throughput technology routes according to their own conditions.

systems biology↗

Interplay between acetylation and ubiquitination of imitation switch chromatin remodeler Isw1 confers multidrug resistance in Cryptococcus neoformans

Cryptococcus neoformans poses a threat to human health, but anticryptococcal therapy is hampered by the emergence of drug resistance, whose underlying mechanisms remain poorly understood. Herein, we discovered that Isw1, an imitation switch chromatin remodeling ATPase, functions as a master modulator of genes responsible for multidrug resistance in C. neoformans. Cells with the disrupted ISW1 gene exhibited profound resistance to multiple antifungal drugs. Mass spectrometry analysis revealed that Isw1 is both acetylated and ubiquitinated, suggesting that an interplay between these two modification events exists to govern Isw1 function. Mutagenesis studies of acetylation and ubiquitination sites revealed that the acetylation status of Isw1K97 coordinates with its ubiquitination processes at Isw1K113 and Isw1K441 through modulating the interaction between Isw1 and Cdc4, an E3 ligase. Additionally, clinical isolates of C. neoformans overexpressing the degradation-resistant ISW1K97Q allele showed impaired drug-resistant phenotypes. Collectively, our studies revealed a sophisticated acetylation-Isw1-ubiquitination regulation axis that controls multidrug resistance in C. neoformans.

microbiology↗

Category-induced global effects of feature-based attention in human visual system

Global effects of FBA are generally limited to stimuli sharing the same or similar features, as hypothesized in the "feature-similarity gain model". Visual perception, however, often reflects categories acquired via experience; whether the global-FBA effect can be induced by the categorized features remains unclear. Here human subjects were trained to classify motion-directions into two discrete categories and performed a classical motion-based attention task. We found a category-induced global-FBA effect in both the MT+ and frontoparietal areas, where attention to a motion-direction globally spread to unattended motion-directions within the same category, but not to those in a different category. Effective connectivity analysis showed that the category-induced global-FBA effect in MT+ was derived by feedback from the IFJ. Altogether, our results reveal for the first time a category-induced global-FBA effect and identify a source for this effect in human prefrontal cortex, implying that FBA is of greater ecological significance than previously thought.

neuroscience↗

Designing epitope-focused vaccines via antigen reorientation

A major challenge in vaccine development, especially against rapidly evolving viruses, is the ability to focus the immune response toward evolutionarily conserved antigenic regions to confer broad protection. For example, while many broadly neutralizing antibodies against influenza have been found to target the highly conserved stem region of hemagglutinin (HA-stem), the immune response to seasonal influenza vaccines is predominantly directed to the immunodominant but variable head region (HA-head), leading to narrow-spectrum efficacy. Here, we first introduce an approach to controlling antigen orientation based on the site-specific insertion of short stretches of aspartate residues (oligoD) that facilitates antigen-binding to alum adjuvants. We demonstrate the generalizability of this approach to antigens from the Ebola virus, SARS-CoV-2, and influenza and observe enhanced antibody responses following immunization in all cases. Next, we use this approach to reorient HA in an "upside down" configuration, which we envision increases HA-stem exposure, therefore also improving its immunogenicity compared to HA-head. When applied to HA of H2N2 A/Japan/305/1957, the reoriented H2 HA (reoH2HA) on alum induced a stem-directed antibody response that cross-reacted with both group 1 and 2 influenza A HAs. Our results demonstrate the possibility and benefits of antigen reorientation via oligoD insertion, which represents a generalizable immunofocusing approach readily applicable for designing epitope-focused vaccine candidates. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=83 SRC="FIGDIR/small/521291v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@185f949org.highwire.dtl.DTLVardef@b132a9org.highwire.dtl.DTLVardef@174fcc8org.highwire.dtl.DTLVardef@17fb872_HPS_FORMAT_FIGEXP M_FIG C_FIG Seasonal influenza vaccines induce a biased antibody response against the variable head of hemagglutinin, whereas conserved epitopes on the stem are a target for universal vaccines. Here we show that reorienting HA in an "upside-down" configuration sterically occludes the head and redirects the antibody response to the more exposed stem, thereby inducing broad cross-reactivity against hemagglutinins from diverse influenza strains.

immunology↗

Perinuclear force regulates SUN2 dynamics and distribution on the nuclear envelope for proper nuclear mechanotransduction

The trans-luminal LINC (Linker of Nucleoskeleton and Cytoskeleton) complex plays a central role in nuclear mechanotransduction by coupling the nucleus with cytoskeleton. High spatial density and active dynamics of LINC complex have hindered its precise characterization for the understanding of underlying mechanisms how the linkages sense and respond to mechanical stimuli. In this study, we focus on SUN2, a core component of LINC complex interconnecting the nuclear lamina and actin cytoskeleton and apply single molecule super-resolution imaging to reveal how SUN2 responds to actomyosin contractility. Using stochastic optical reconstruction microscopy (STORM), we quantitated the distribution pattern and density of SUN2 on the basal nuclear membrane. We found that SUN2 undergoes bidirectional translocation between ER and nuclear membrane in response to actomyosin contractility, suggesting that dynamic constrained force on SUN2 is required for its proper distribution. Furthermore, single molecule imaging unveils interesting dynamics of SUN2 molecules that are regulated by both actomyosin contractility and laminA/C network, whereas SUN2 oligomeric states are not affected by actomyosin contractility. Lastly, the mechanical response of SUN2 to actomyosin contractility was found to regulate expression of mechano-sensitive genes located in lamina-associated domains (LADs) and perinuclear heterochromatin. Taken together, our results reveal how SUN2 responds to mechanical cues at the single-molecule level, providing new insights into the mechanism of nuclear mechanotransduction.

cell biology↗

Nucleic acid sensing by STING induces an interferon-like antiviral response in a marine invertebrate

The cytosolic detection of pathogen derived nucleic acids has evolved as an essential strategy for host innate immune defense in mammals. The stimulator of interferon genes (STING) functions as a crucial signaling adaptor, linking the cytosolic detection of DNA by cyclic GMP-AMP (cGAMP) synthase (cGAS) to the downstream Type I interferon (IFN) signaling axis. However, this process remains elusive in invertebrates. Herein, we demonstrated that a STING ortholog from a marine invertebrate (shrimp) Litopenaeus vannamei can directly sense DNA to activate an interferon-like antiviral response. Unlike STING homologs exclusively functioning as a sensor for cyclic dinucleotides (CDNs) in other eukaryotic organisms, shrimp STING can bind to double-stranded DNA (dsDNA) in addition to CDNs, including 2'3'-cGAMP. In vivo, shrimp STING can directly sense DNA nucleic acids from an infected virus, accelerate IRF dimerization, nuclear translocation and induce the expression of an interferon functional analog protein (Vago4), and finally establish an antiviral state. Surprisingly, the shrimp cGAS-like homolog is not involved in dsDNA-intrigued and STING-dependent IRF-Vago axis activation. Taken together, our results uncovered a novel dsDNA-STING-IKK{varepsilon}-IRF-Vago antiviral axis in an arthropod, and provided some novel insights into the functional origin of a DNA-sensing pathway in evolution.

immunology↗

The compact CasPi (Cas12l) bracelet "provides" a unique structural platform for DNA manipulation

CRISPR-Cas modules serve as the adaptive nucleic-acid immune systems for prokaryotes, and provide versatile tools for nucleic-acid manipulation in various organisms. Here, we discovered a new miniature type V system, CRISPR-Cas{pi} (Cas12l) ([~]860 aa), from the environmental metagenome. Complexed with a large guide-RNA ([~]170 nt) comprising the tracrRNA and crRNA, Cas{pi} (Cas12l) recognizes a unique 5 C-rich PAM for DNA cleavage under a broad range of biochemical conditions, and generates gene editing in mammalian cells. Cryo-EM study reveals a bracelet architecture of Cas{pi} effector encircling the DNA target at 3.4-[A] resolution, substantially different from the canonical two-lobe architectures of Cas12 and Cas9 nucleases. And the large guide-RNA serves as a two-arm scaffold for effector assembly. Our study expands the knowledge of DNA targeting mechanisms by CRISPR effectors, and offers an efficient but compact platform for DNA manipulations.

biophysics↗

Identification of Barley Enhancers across Genome via STARR-seq

Enhancers are DNA sequences that can strengthen transcription initiation. However, the global identification of plant enhancers is complicated due to uncertainty in the distance and orientation of enhancers, especially in species with large genomes. In this study, we performed self-transcribing active regulatory region sequencing (STARR-seq) for the first time to identify enhancers across the barley genome. A total of 7323 enhancers were successfully identified, and among 45 randomly selected enhancers, over 75% were effective as validated by a dual-luciferase reporter assay system in the lower epidermis of tobacco leaves. Interestingly, up to 53.5% of the barley enhancers were repetitive sequences, especially transposable elements (TEs), thus reinforcing the vital role of repetitive enhancers in gene expression. Both the common active transcription marker H3K4me3 and repressive histone marker H3K27me3 were abundant among the barley STARR-seq enhancers. In addition, the functional range of barley STARR-seq enhancers seemed much broader than that of rice or maize and extended to {+/-} 100 KB of the gene body, and this finding was consistent with the high expression levels of genes in the genome. This work specifically depicts the unique features of barley enhancers and provides available barley enhancers for further utilization.

genomics↗

COMBINe: Automated Detection and Classification of Neurons and Astrocytes in Tissue Cleared Mouse Brains

Tissue clearing renders entire organs transparent to enable combination with light sheet fluorescence microscopy and accelerate whole tissue imaging. Yet, challenges remain in analyzing the large resulting 3D datasets that consist of terabytes of images and information on millions of labeled cells. Previous work has established pipelines for automated analysis of tissue cleared mouse brains. However, they have focused on single color channels and/or detection of nuclear localized signals, in relatively low-resolution images. To address this gap, we present an automated workflow to map labeled neurons and astrocytes in the genetically distinct Mosaic Analysis with Double Markers (MADM) mouse forebrains. We named the workflow COMBINe (Cell detectiOn in Mouse BraIN) as it combines modules from multiple pipelines. With RetinaNet in its core, we quantitatively analyzed the regional and subregional effects of MADM-based deletion of the Epidermal growth factor receptor on neuronal and astrocyte populations in the mouse forebrain.

neuroscience↗

Multiplex Epigenome Editing of MECP2 to Rescue Rett Syndrome Neurons

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by loss-of-function heterozygous mutations of Methyl CpG-binding Protein 2 (MECP2) on the X chromosome in girls. Reactivation of the silent wild-type MECP2 allele from the inactive X chromosome (Xi) represents a promising therapeutic opportunity for female patients with RTT. Here, we applied a multiplex epigenome editing approach to reactivate MECP2 from Xi in RTT human embryonic stem cells (hESCs) and derived neurons. Demethylation of the MECP2 promoter by dCas9-Tet1 with target sgRNA reactivated MECP2 from Xi in RTT hESCs without detectable off-target effects at the transcriptional level. Neurons derived from methylation-edited RTT hESCs maintained MECP2 reactivation and reversed the smaller soma size and electrophysiological abnormalities, two hallmarks of RTT. In RTT neurons, insulation of the methylation edited MECP2 locus by dCpf1-CTCF with target CRISPR RNA enhanced MECP2 reactivation and rescued RTT-related neuronal defects, providing a proof-of-concept study for epigenome editing to treat RTT and potentially other dominant X-linked diseases. One-Sentence SummaryReactivation of MECP2 from the inactive X chromosome by multiplex epigenome editing rescues Rett syndrome neurons in vitro.

physiology↗

Widely targeted metabolomic analysis reveals differences in volatile metabolites among four Angelica species

Angelica L. has attracted global interest for its traditional medicinal uses and commercial values. However, few studies have focused on the metabolomic differences among the Angelica species. In this study, employing the widely targeted metabolomics based on gas chromatography-tandem mass spectrometry, the metabolomes of four Angelica species were analyzed (Angelica sinensis (Oliv.) Diels (A. sinensis), Angelica biserrata (R.H.Shan & Yuan) C.Q.Yuan & R.H.Shan (A. biserrata), Angelica dahurica (Hoffm.) Benth. & Hook.f. ex Franch. & Sav. (A. dahurica), Angelica keiskei Koidz. (A. keiskei)). A total of 698 volatile metabolites were identified and classified into fifteen different categories. The metabolomic analysis indicated that 7-hydroxycoumarin and Z-ligustilide were accumulated at significantly higher levels in A. sinensis, whereas the opposite pattern was observed for bornyl acetate. In addition, a high correspondence between the dendrogram of metabolite contents and phylogenetic positions was detected in the four species. This study provides a biochemical map for the exploitation, application and development of the Angelica species as medicinal plants or health-related dietary supplements.

plant biology↗

Assembly of 43 diverse human Y chromosomes reveals extensive complexity and variation

The prevalence of highly repetitive sequences within the human Y chromosome has led to its incomplete assembly and systematic omission from genomic analyses. Here, we present long-read de novo assemblies of 43 diverse Y chromosomes spanning 180,000 years of human evolution, including two from deep-rooted African Y lineages, and report remarkable complexity and diversity in chromosome size and structure, in contrast with its low level of base substitution variation. The size of the Y chromosome assemblies varies extensively from 45.2 to 84.9 Mbp and include, on average, 81 kbp of novel sequence per Y chromosome. Half of the male-specific euchromatic region is subject to large inversions with a >2-fold higher recurrence rate compared to inversions in the rest of the human genome. Ampliconic sequences associated with these inversions further show differing mutation rates that are sequence context-dependent and some ampliconic genes show evidence for concerted evolution with the acquisition and purging of lineage-specific pseudogenes. The largest heterochromatic region in the human genome, the Yq12, is composed of alternating arrays of DYZ1 and DYZ2 repeat units that show extensive variation in the number, size and distribution of these arrays, but retain a 1:1 copy number ratio of the monomer repeats, consistent with the notion that functional or evolutionary forces are acting on this chromosomal region. Finally, our data suggests that the boundary between the recombining pseudoautosomal region 1 and the non-recombining portions of the X and Y chromosomes lies 500 kbp distal to the currently established boundary. The availability of sequence-resolved Y chromosomes from multiple individuals provides a unique opportunity for identifying new associations of specific traits with Y-chromosomal variants and garnering novel insights into the evolution and function of complex regions of the human genome.

genomics↗

Organization, genomic targeting and assembly of three distinct SWI/SNF chromatin remodeling complexes in Arabidopsis

Switch defective/sucrose non-fermentable (SWI/SNF) complexes are evolutionarily conserved multi-subunit machines that play vital roles in chromatin architecture regulation for modulating gene expression via sliding or ejection of nucleosomes in eukaryotes. In plants, perturbations of SWI/SNF subunits often result in severe developmental disorders. However, the subunit composition, pathways of assembly, and genomic targeting of the plant SWI/SNF complexes remain undefined. Here, we reveal the organization, genomic targeting and assembly of three distinct Arabidopsis SWI/SNF complexes: BRAHMA-Associated SWI/SNF complexes (BAS), SPLAYED-Associated SWI/SNF complexes (SAS) and MINUSCULE-Associated SWI/SNF complexes (MAS). We show that BAS complexes are equivalent to human ncBAF, whereas SAS and MAS complexes evolve in multiple subunits unique to plants, suggesting a plant-specific functional evolution of SWI/SNF complexes. We further demonstrate overlapping and specific genomic targeting of the three plant SWI/SNF complexes on chromatin and reveal that SAS complexes are necessary for the correct genomic localization of the BAS complexes. Finally, we define the role of core module subunit in the assembly of the plant SWI/SNF complexes and highlight that ATPase module subunit is required for global complex stability and the interaction of core module subunits in SAS and BAS complexes in Arabidopsis. Together, our work highlights the divergence of SWI/SNF chromatin remodelers during the eukaryote evolution and provides a comprehensive landscape for understanding the plant SWI/SNF complexes organization, assembly, genomic targeting, and function. One-sentence summaryComprehensively define the organization, genomic targeting and assembly of three distinct SWI/SNF chromatin remodeling complexes in Arabidopsis

plant biology↗

A novel method revealing animal evolutionary relationships based on milk Mid-infrared

Mid-infrared spectra (MIRS) can effectively reflect the chemical bonds in milk, which has been widely used in dairy herd improvement. However, the relationship between MIRS and animal evolution remains largely unclear. This study firstly found great differences in MIRS and the components of milk by analyzing MIRS information of 12 different mammal species. A five-level discriminant model of evolutionary level based on MIRS was established with a test set kappa coefficient >0.97. In addition, a regression model of genetic distance was also established to estimate the genetic distance of different animal species with a correlation coefficient of R >0.94. These results showed that this method could be used for accurate mammalian evolutionary relationship assessment. We further clarified the potential relationship between MIRS and genes, such as PPP3CA and SCD that could change MIRS by regulating specific milk components. In conclusion, we expand the application of MIRS in animal species identification and evolution research and provide new perspectives for the research on the formation mechanism of different animal milk special components.

evolutionary biology↗