The human vaginal microbiome is dominated by bacteria from the genus
, which create an acidic environment thought to protect women against sexually transmitted pathogens and opportunistic infections. ...Strikingly, lactobacilli dominance appears to be unique to humans; while the relative abundance of lactobacilli in the human vagina is typically >70%, in other mammals lactobacilli rarely comprise more than 1% of vaginal microbiota. Several hypotheses have been proposed to explain humans' unique vaginal microbiota, including humans' distinct reproductive physiology, high risk of STDs, and high risk of microbial complications linked to pregnancy and birth. Here, we test these hypotheses using comparative data on vaginal pH and the relative abundance of lactobacilli in 26 mammalian species and 50 studies (
= 21 mammals for pH and 14 mammals for lactobacilli relative abundance). We found that non-human mammals, like humans, exhibit the lowest vaginal pH during the period of highest estrogen. However, the vaginal pH of non-human mammals is never as low as is typical for humans (median vaginal pH in humans = 4.5; range of pH across all 21 non-human mammals = 5.4-7.8). Contrary to disease and obstetric risk hypotheses, we found no significant relationship between vaginal pH or lactobacilli relative abundance and multiple metrics of STD or birth injury risk (
-values ranged from 0.13 to 0.99). Given the lack of evidence for these hypotheses, we discuss two alternative explanations: the common function hypothesis and a novel hypothesis related to the diet of agricultural humans. Specifically, with regard to diet we propose that high levels of starch in human diets have led to increased levels of glycogen in the vaginal tract, which, in turn, promotes the proliferation of lactobacilli. If true, human diet may have paved the way for a novel, protective microbiome in human vaginal tracts. Overall, our results highlight the need for continuing research on non-human vaginal microbial communities and the importance of investigating both the physiological mechanisms and the broad evolutionary processes underlying human lactobacilli dominance.
The secretory pathway is responsible for the synthesis, folding, and delivery of a diverse array of cellular proteins. Secretory protein synthesis begins in the endoplasmic reticulum (ER), which is ...charged with the tasks of correctly integrating nascent proteins and ensuring correct post-translational modification and folding. Once ready for forward traffic, proteins are captured into ER-derived transport vesicles that form through the action of the COPII coat. COPII-coated vesicles are delivered to the early Golgi via distinct tethering and fusion machineries. Escaped ER residents and other cycling transport machinery components are returned to the ER via COPI-coated vesicles, which undergo similar tethering and fusion reactions. Ultimately, organelle structure, function, and cell homeostasis are maintained by modulating protein and lipid flux through the early secretory pathway. In the last decade, structural and mechanistic studies have added greatly to the strong foundation of yeast genetics on which this field was built. Here we discuss the key players that mediate secretory protein biogenesis and trafficking, highlighting recent advances that have deepened our understanding of the complexity of this conserved and essential process.
Among children and young adults with the Dravet syndrome, a developmental disorder that is associated with treatment-resistant seizures, cannabidiol reduced the frequency of convulsive seizures but ...caused sleepiness and elevated liver enzymes in some patients.
Seizures are difficult to control in the Dravet syndrome, a rare genetic form of epileptic encephalopathy primarily due to loss-of-function mutations in the
SCN1A
gene. Interest in cannabidiol for the treatment of epilepsy was generated by media reports of efficacy in children with the Dravet syndrome.
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Four small trials of cannabidiol had yielded mixed results.
2
–
5
A series of in vitro and in vivo preclinical models of seizure showed that cannabidiol had activity against convulsive seizures.
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Subsequently, the safety and effectiveness of a standardized oral solution of cannabidiol was tested in an open-label trial involving 214 children and young adults . . .
Low molecular weight synthetic peptides have been demonstrated to be effective catalysts for an increasingly wide array of asymmetric transformations. In many cases, these peptide-based catalysts ...have enabled novel multifunctional substrate activation modes and unprecedented selectivity manifolds. These features, along with their ease of preparation, modular and tunable structures, and often biomimetic attributes make peptides well-suited as chiral catalysts and of broad interest. Many examples of peptide-catalyzed asymmetric reactions have appeared in the literature since the last survey of this broad field in Chemical Reviews (Chem. Rev. 2007, 107, 5759–5812). The overarching goal of this new Review is to provide a comprehensive account of the numerous advances in the field. As a corollary to this goal, we survey the many different types of catalytic reactions, ranging from acylation to C–C bond formation, in which peptides have been successfully employed. In so doing, we devote significant discussion to the structural and mechanistic aspects of these reactions that are perhaps specific to peptide-based catalysts and their interactions with substrates and/or reagents.
Protein-protein interactions play critical roles in biology, but the structures of many eukaryotic protein complexes are unknown, and there are likely many interactions not yet identified. We take ...advantage of advances in proteome-wide amino acid coevolution analysis and deep-learning–based structure modeling to systematically identify and build accurate models of core eukaryotic protein complexes within the
proteome. We use a combination of RoseTTAFold and AlphaFold to screen through paired multiple sequence alignments for 8.3 million pairs of yeast proteins, identify 1505 likely to interact, and build structure models for 106 previously unidentified assemblies and 806 that have not been structurally characterized. These complexes, which have as many as five subunits, play roles in almost all key processes in eukaryotic cells and provide broad insights into biological function.
Protein damage contributes prominently to cellular aging. To address whether this occurs at a specific period during aging or accumulates gradually, we monitored the biochemical, cellular, and ...physiological properties of folding sensors expressed in different tissues of C. elegans. We observed the age-dependent misfolding and loss of function of diverse proteins harboring temperature-sensitive missense mutations in all somatic tissues at the permissive condition. This widespread failure in proteostasis occurs rapidly at an early stage of adulthood, and coincides with a severely reduced activation of the cytoprotective heat shock response and the unfolded protein response. Enhancing stress responsive factors HSF-1 or DAF-16 suppresses misfolding of these metastable folding sensors and restores the ability of the cell to maintain a functional proteome. This suggests that a compromise in the regulation of proteostatic stress responses occurs early in adulthood and tips the balance between the load of damaged proteins and the proteostasis machinery. We propose that the collapse of proteostasis represents an early molecular event of aging that amplifies protein damage in age-associated diseases of protein conformation.
Many cellular membrane-bound structures exhibit distinct curvature that is driven by the physical properties of their lipid and protein constituents. Here we review how cells manipulate and control ...this curvature in the context of dynamic events such as vesicle-mediated membrane traffic. Lipids and cargo proteins each contribute energy barriers that must be overcome during vesicle formation. In contrast, protein coats and their associated accessory proteins drive membrane bending using a variety of interdependent physical mechanisms. We survey the energy costs and drivers involved in membrane curvature, and draw a contrast between the stochastic contributions of molecular crowding and the deterministic assembly of protein coats. These basic principles also apply to other cellular examples of membrane bending events, including important disease-related problems such as viral egress.
Eukaryotic cells employ membrane-bound carriers to transport cargo between compartments in a process essential to cell functionality. Carriers are generated by coat complexes that couple cargo ...capture to membrane deformation. The COPII coat mediates export from the endoplasmic reticulum by assembling in inner and outer layers, yielding carriers of variable shape and size that allow secretion of thousands of diverse cargo. Despite detailed understanding of COPII subunits, the molecular mechanisms of coat assembly and membrane deformation are unclear. Here we present a 4.9 Å cryo-tomography subtomogram averaging structure of in vitro-reconstituted membrane-bound inner coat. We show that the outer coat (Sec13-Sec31) bridges inner coat subunits (Sar1-Sec23-Sec24), promoting their assembly into a tight lattice. We directly visualize the membrane-embedded Sar1 amphipathic helix, revealing that lattice formation induces parallel helix insertions, yielding tubular curvature. We propose that regulators like the procollagen receptor TANGO1 modulate this mechanism to determine vesicle shape and size.
Long known as a coat system that generates small transport vesicles from the endoplasmic reticulum (ER), the COPII coat also drives ER export of cargo proteins that are too large to be contained ...within these canonical carriers. With crystal and cryo-EM structures giving an atomic level view of coat architecture, current advances in the field have focused on understanding how the coat adapts to the different geometries of the underlying cargo. Combined with a growing appreciation for the specific roles of individual COPII paralogs in diverse aspects of mammalian physiology, the field is poised to understand how coat assembly and post-translational modification permits structural rigidity but geometric flexibility to handle the diverse cargoes that exit the ER.
This article contributes to the attachment versus differentiation debate, bringing the conversation to parent–child relationships. While attachment theory's (AT) approach emphasizes bonding, Bowen ...family systems theory's (BFST) differentiation approach emphasizes emotional boundaries. They both suggest that balancing autonomy and connection is important, but AT conceptualizes this in terms of the parent's ability to meet the child's needs for autonomy and connection, while BFST conceptualizes this in terms of the parent's and child's ability to be connected due to mutual respect for each other's emotional boundaries. They similarly recognize that: (1) emotionally mature parents respect children individuality, (2) emotionally immature parents may project their needs and wishes onto children, and (3) emotionally mature parents focus on calming themselves to help their children to be calm. They differ in that: (1) BFST suggests that children may project their needs and wishes onto their parents and intrude on their parents' emotional boundaries, and AT does not conceptualize this; (2) BFST suggests that caregiver over‐involvement may be experienced as positive for a child and program them to be excessively needy, and AT suggests that caregiver over‐involvement is negative for children and neediness is caused by under‐involved caregiving; and (3) BFST suggests that therapists should not try to be a parent to their clients as this can replicate the fusion that the client experienced with their parents, and AT suggests that therapists should try to be like a good parent to their clients to help them to develop more secure attachment styles.
本文对情感依恋与个体分离两者之间的争论带来新的研究，并开启在亲子关系方面的对话。依恋理论(AT)的方法强调联结，Bowen鲍恩家庭系统理论(BFST)的区分方法强调情感边界。他们都认为，自主性和联结平衡好很重要，但AT的概念是父母满足孩子自主性和联结需求的能力，而BFST的概念是父母和孩子由于相互尊重彼此的情感边界而建立联系的能力。他们同样认识到:1) 情感成熟的父母尊重孩子的个体性；2) 情感不成熟的父母可能会把自己的需求和愿望投射到孩子身上，3) 情感成熟的父母专注于让自己平静下来，帮助孩子平静下来。它们的不同之处在于: 1) BFST表明，儿童可能会将他们的需求和愿望投射到父母身上，并侵入父母的情感边界，而AT没有将这此观点概念化；2) BFST认为看护者的过度投入可能会对儿童产生积极的体验，并将他们训练成为过度提需求；AT表明，看护者的过度投入对儿童是有消极作用的，而非常需要父母的状态则是由关注和照顾不足造成的；3) BFST建议治疗师不应该试图成为来访者的家长一样，因为这可能会复制来访者与他们的父母的融合关系，AT建议治疗师应该尝试像一个好父母一样帮助他们的来访者发展更安全的依恋方式方法。.
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