The transcriptional regulators that drive regulatory T (Treg) cell development and function remain partially understood. Helios (Ikzf2) and Eos (Ikzf4) are closely-related members of the Ikaros family of transcription factors. They are highly expressed in CD4+ Treg cells and functionally important for Treg cell biology, as mice deficient for either Helios or Eos are susceptible to autoimmune diseases. However, it remains unknown if these factors exhibit specific or partially redundant functions in Treg cells. Here we show that mice with germline deletions of both Ikzf2 and Ikzf4 are not very different from animals with single Ikzf2 or Ikzf4 deletions. Double knockout Treg cells differentiate normally, and efficiently suppress effector T cell proliferation in vitro. Both Helios and Eos are required for optimal Foxp3 protein expression. Surprisingly, Helios and Eos regulate different, largely non-overlapping, sets of genes. Only Helios is required for proper Treg cell aging, as Helios deficiency results in reduced Treg cell frequencies in the spleen of older animals. These results indicate that Helios and Eos are required for distinct aspects of Treg cell function.

[This corrects the article DOI: 10.3389/fendo.2022.981090.].

Acupoint specificity is a key scientific issue in acupuncture and moxibustion. Acupoint electric resistance is a commonly-used biophysical index to study the functional specificity of acupoints. The non-linear characteristics of acupoint electric resistance have great impacts on the measured values, but it has been greatly ignored. By analyzing the non-linear characteristics of acupoint resistance and its application in the study of acupoint function specificity, a new idea of introducing chaos theory and technology into the study of acupoint function is proposed.
穴位特异性是针灸学的关键科学问题，穴位电阻是常用的研究穴位功能特异性的生物物理指标，其非线性特征对测量值有很大影响，但并未得到足够重视。通过梳理与分析穴位电阻非线性特征及其在穴位功能特异性研究中的应用，提出将混沌理论与技术引入穴位功能研究的新思路。.

The thyroid hormone receptor-like (THR-like) family is the largest transcription factors family belonging to the nuclear receptor superfamily, which directly binds to DNA and regulates the gene expression and thereby controls various metabolic processes in a ligand-dependent manner. The THR-like family contains receptors THRs, RARs, VDR, PPARs, RORs, Rev-erbs, CAR, PXR, LXRs, and others. THR-like receptors are involved in many aspects of human health, including development, metabolism and homeostasis. Therefore, it is considered an important therapeutic target for various diseases such as osteoporosis, rickets, diabetes, etc.
In this study, we have performed an extensive sequence and structure analysis of the ligand-binding domain (LBD) of the THR-like family spanning multiple taxa. We have use different computational tools (information-theoretic measures; relative entropy) to predict the key residues responsible for fold and functional specificity in the LBD of the THR-like family. The MSA of THR-like LBDs was further used as input in conservation studies and phylogenetic clustering studies.
Phylogenetic analysis of the LBD domain of THR-like proteins resulted in the clustering of eight subfamilies based on their sequence homology. The conservation analysis by relative entropy (RE) revealed that structurally important residues are conserved throughout the LBDs in the THR-like family. The multi-harmony conservation analysis further predicted specificity in determining residues in LBDs of THR-like subfamilies. Finally, fold and functional specificity determining residues (residues critical for ligand, DBD and coregulators binding) were mapped on the three-dimensional structure of thyroid hormone receptor protein. We then compiled a list of natural mutations in THR-like LBDs and mapped them along with fold and function-specific mutations. Some of the mutations were found to have a link with severe diseases like hypothyroidism, rickets, obesity, lipodystrophy, epilepsy, etc.
Our study identifies fold and function-specific residues in THR-like LBDs. We believe that this study will be useful in exploring the role of these residues in the binding of different drugs, ligands, and protein-protein interaction among partner proteins. So this study might be helpful in the rational design of either ligands or receptors.

Akkermansia muciniphila has long been considered to be the only Akkermansia species in the human gut and has been extensively studied. The present study revealed the genomic architecture of Akkermansia in the human gut by analyzing 1,126 near-complete metagenome-assembled genomes, 84 publicly available genomes, and 1 newly sequenced Akkermansia glycaniphila strain from the human gut. We found that 1) the genomes of Akkermansia were clustered into four phylogroups with distinct interspecies similarity and different genomic characteristics and 2) A. glycaniphila GP37, a strain of Akkermansia, was isolated from the human gut, whereas previously, it had only been found in python. Amuc III was present in the Chinese population, and Amuc IV was mainly distributed in Western populations. A large number of gene functions, pathways, and carbohydrate-active enzymes were specifically associated with phylogroups. Our findings based on over a thousand genomes strengthened our previous knowledge and provided new insights into the population structure and ecology of Akkermansia in the human gut.

Sponge microbiomes are typically profiled by analyzing the community DNA of whole tissues, which does not distinguish the taxa residing within sponge cells from extracellular microbes. To uncover the endosymbiotic microbiome, we separated the sponge cells to enrich the intracellular microbes. The intracellular bacterial community of sponge Euryspongia arenaria was initially assessed by amplicon sequencing, which indicated that it hosts three unique phyla not found in the extracellular and bulk tissue microbiomes. These three phyla account for 66% of the taxonomically known genera in the intracellular microbiome. The shotgun metagenomic analysis extended the taxonomic coverage to viruses and eukaryotes, revealing the most abundant signature taxa specific to the intracellular microbiome. Functional KEGG pathway annotation demonstrated that the endosymbiotic microbiome hosted the greatest number of unique gene orthologs. The pathway profiles distinguished the intra- and extracellular microbiomes from the tissue and seawater microbiomes. Carbohydrate-active enzyme analysis further discriminated each microbiome based on their representative and dominant enzyme families. One pathway involved in digestion system and family esterase had a consistently higher level in intracellular microbiome and could statistically differentiate the intracellular microbiome from the others, suggesting that triacylglycerol lipases could be the key functional component peculiar to the endosymbionts. The identified higher abundance of lipase-related eggNOG categories further supported the lipid-hydrolyzing metabolism of endosymbiotic microbiota. Pseudomonas members, reported as lipase-producing bacteria, were only in the endosymbiotic microbiome, meanwhile Pseudomonas also showed a greater abundance intracellularly. Our study aided a comprehensive sponge microbiome that demonstrated the taxonomic and functional specificity of endosymbiotic microbiota. IMPORTANCE Sponges host abundant microbial symbionts that can produce an impressive number of novel bioactive metabolites. However, knowledge on intracellular (endosymbiotic) microbiota is scarce. We characterize the composition and function of the endosymbiotic microbiome by separation of sponge cells and enrichment of intracellular microbes. We uncover a noteworthy number of taxa exclusively in the endosymbiotic microbiome. We unlock the unique pathways and enzymes of endosymbiotic taxa. This study achieves a more comprehensive sponge microbial community profile, which demonstrates the structural and functional specificity of the endosymbiotic microbiome. Our findings not only open the possibility to reveal the low abundant and the likely missed microbiota when directly sequencing the sponge bulk tissues, but also warrant future in-depth exploration within single sponge cells.

Neuroimage studies have yielded evidence for a correlation between the left ventrolateral prefrontal cortex (VLPFC) and a specific type of cognitive reappraisal strategy, positive reappraisal. However, evidence is still lacking for a direct relation. We used single-pulse transcranial magnetic stimulation (TMS) over the left VLPFC at different time points to investigate the functional specificity of the left VLPFC in the success of positive reappraisal and the timing at which the left VLPC was involved in positive reappraisal. Fifteen participants engaged in a baseline experiment and in TMS experiments. All participants successfully reduced their negative emotional ratings using positive reappraisal in the baseline experiment. In the TMS experiments, participants performed the same task as in the baseline experiment but single-pulse TMS was applied over the left VLPFC at 300 ms or/and 3,300 ms after stimulus onset, as well as over the vertex as a control stimulation. Valence ratings of negative stimuli increased (unpleasantness reduction) when participants reappraised negative stimuli with TMS stimulation over the left VLPFC, regardless of the timing of the stimulation at 300 ms or/and at 3,300 ms after the stimulus onset, relative to the vertex stimulation and the baseline experiment. Our study provided evidence of the functional specificity of the left VLPFC in regulation of negative emotions using positive reappraisal. The left VLPFC was believed to be involved in different stages of positive reappraisal. The prominent facilitation effect of TMS over the left VLPFC makes it possible to consider potential applications in clinical practice for mood disorders.

The recent emergence of the novel SARS-CoV-2 in China and its rapid spread in the human population has led to a public health crisis worldwide. Like in SARS-CoV, horseshoe bats currently represent the most likely candidate animal source for SARS-CoV-2. Yet, the specific mechanisms of cross-species transmission and adaptation to the human host remain unknown. Here we show that the unsupervised analysis of conservation patterns across the β-CoV spike protein family, using sequence information alone, can provide valuable insights on the molecular basis of the specificity of β-CoVs to different host cell receptors. More precisely, our results indicate that host cell receptor usage is encoded in the amino acid sequences of different CoV spike proteins in the form of a set of specificity determining positions (SDPs). Furthermore, by integrating structural data, in silico mutagenesis and coevolution analysis we could elucidate the role of SDPs in mediating ACE2 binding across the Sarbecovirus lineage, either by engaging the receptor through direct intermolecular interactions or by affecting the local environment of the receptor binding motif. Finally, by the analysis of coevolving mutations across a paired MSA we were able to identify key intermolecular contacts occurring at the spike-ACE2 interface. These results show that effective mining of the evolutionary records held in the sequence of the spike protein family can help tracing the molecular mechanisms behind the evolution and host-receptor adaptation of circulating and future novel β-CoVs.

A hallmark of the aging process is increased connectivity between networks and decreased connectivity within networks, which to some extent reflects the reorganization of the brain networks during normal aging. Considering the brain as a complex dynamic system, emerging evidence suggests the time-varying connectivity patterns to be more informative of brain functions. However, the age effect on the dynamic reconfiguration of intrinsic resting state networks is still elusive. By tracking the ongoing formation and dissipation of putative functional modules across time and space, we explored the age-related changes of segregation and integration and further elucidated the underlying brain network dynamics mechanism during normal aging. Results showed that aging strongly weakened dynamic global segregation while enhanced dynamic global integration across the whole brain. Aging was associated with decreasing dynamic segregation of most networks (except the cerebellum) while increasing dynamic integration of only a few networks at the large-scale network level. Notably, the fronto-parietal network, the default mode network, the visual network, and a small group of nodes from these networks, whose dynamic segregation and integration, were both modulated by age. These findings provide direct evidence that there are remarkable changes of dynamic network architecture across the human adult lifespan and suggest the age-related modulations of dynamic segregation and integration intuitively reflect the adaptive changes of the functional dedifferentiation and compensation in older adults.

The heat shock protein 70 (Hsp70) family of molecular chaperones are crucial for the survival and pathogenicity of the main agent of malaria, Plasmodium falciparum. Hsp70 is central to cellular proteostasis and some of its isoforms are essential for survival of the malaria parasite. In addition, they are also implicated in the development of antimalarial drug resistance. For these reasons, they are thought to be potential drug targets, especially in antimalarial combination therapies. However, their high sequence conservation across species presents a hurdle with respect to their selective targeting. The human genome encodes 17 Hsp70 isoforms while P. falciparum encodes for only 6. The structural architecture of Hsp70s is typically characterized by a highly conserved N-terminal nucleotide-binding domain (NBD) and a less conserved C-terminal substrate-binding domain (SBD). The two domains are connected by a highly conserved linker. In spite of their fairly high sequence conservation, Hsp70s from various species possess unique signature motifs that appear to uniquely influence their function. In addition, their cooperation with co-chaperones further regulates their functional specificity. In the current review, bioinformatics tools were used to identify conserved and unique signature motifs in Hsp70s of P. falciparum versus their human counterparts. We discuss the common and distinctive structure-function features of these proteins. This information is important towards elucidating the prospects of selective targeting of parasite heat shock proteins as part of antimalarial design efforts.