Solution structure of the hypothetical protein Mth677 from Methanobacterium thermoautotrophicum: a novel alpha+beta fold

The structure of Mth677, a hypothetical protein from Methanobacterium thermoautotrophicum (Mth), has been determined by using heteronuclear nuclear magnetic resonance (NMR) methods on a double-labeled (15)N-(13)C sample. Mth677 adopts a novel alpha+beta fold, consisting of two alpha-helices (one N terminal and one C terminal) packed on the same side of a central beta-hairpin. This structure is likely shared by its three orthologs, detected in three other Archaebacteria. There are no clear features in the sequences of these proteins or in the genome organization of Mth to make a reliable functional assignment to this protein. However, the structural similarity to Escherichia coli MinE, the protein which controls that division occurs at the midcell site, lends support to the proposal that Mth677 might be, in Mth, the counterpart of the topological specificity domain of MinE in E. coli.     

Nitric Oxide Sustains IL-1β Expression in Human Dendritic Cells Enhancing Their Capacity to Induce IL-17–Producing T-Cells

The role played by lung dendritic cells (DCs) which are influenced by external antigens and by their redox state in controlling inflammation is unclear. We studied the role played by nitric oxide (NO) in DC maturation and function. Human DCs were stimulated with a long-acting NO donor, DPTA NONOate, prior to exposure to lipopolysaccharide (LPS). Dose-and time-dependent experiments were performed with DCs with the aim of measuring the release and gene expression of inflammatory cytokines capable of modifying T-cell differentiation, towardsTh1, Th2 and Th17 cells. NO changed the pattern of cytokine release by LPS-matured DCs, dependent on the concentration of NO, as well as on the timing of its addition to the cells during maturation. Addition of NO before LPS-induced maturation strongly inhibited the release of IL-12, while increasing the expression and release of IL-23, IL-1β and IL-6, which are all involved in Th17 polarization. Indeed, DCs treated with NO efficiently induced the release of IL-17 by T-cells through IL-1β. Our work highlights the important role that NO may play in sustaining inflammation during an infection through the preferential differentiation of the Th17 lineage.     

Tail regression induced by elevated retinoic acid signaling in amphioxus larvae occurs by tissue remodeling,not cell death

The vitamin A derived morphogen retinoic acid (RA) is known to function in the regulation of tissue proliferation and differentiation. Here, we show that exogenous RA applied to late larvae of the invertebrate chordate amphioxus can reverse some differentiated states. Although treatment with the RA antagonist BMS009 has no obvious effect on late larvae of amphioxus, administration of excess RA alters the morphology of the posterior end of the body. The anus closes over, and gut contents accumulate in the hindgut. In addition, the larval tail fin regresses, although little apoptosis takes place. This fin normally consists of columnar epidermal cells, each characterized by a ciliary rootlet running all the way from an apical centriole to the base of the cell and likely contributing substantial cytoskeletal support. After a few days of RA treatment, the rootlet becomes disrupted, and the cell shape changes from columnar to cuboidal. Transmission electron microscopy (TEM) shows fragments of the rootlet in the basal cytoplasm of the cuboidal cell. A major component of the ciliary rootlet in amphioxus is the protein Rootletin, which is encoded by a single AmphiRootletin gene. This gene is highly expressed in the tail epithelial cells of control larvae, but becomes downregulated after about a day of RA treatment, and the breakup of the ciliary rootlet soon follows. The effect of excess RA on these epidermal cells of the larval tail in amphioxus is unlike posterior regression in developing zebrafish, where elevated RA signaling alters connective tissues of mesodermal origin. In contrast, however, the RA‐induced closure of the amphioxus anus has parallels in the RA‐induced caudal regression syndrome of mammals.     

An encounter between a pelagic shark and giant cephalopod

An oceanic whitetip shark (Carcharhinus longimanus) was observed off the coast of Kona, Hawaii, with scars caused by the tentacles of a large cephalopod. While the exact species could not be confirmed, candidate species include the giant squid (Architeuthis dux) or species from the genera Thysanoteuthis (flying squids) and Megalocranchia (glass squids). Telemetry shows C. longimanus will dive within the mesopelagic zone and may interact with or even forage for large cephalopods.     

Annual breeding in a captive smalltooth sawfish,Pristis pectinata

The critically endangered smalltooth sawfish Pristis pectinata reproduces biennially in central west Florida, U.S.A. Here we demonstrate that smalltooth sawfish are physiologically capable of reproducing annually in a captive environment. The smalltooth sawfish are held in an open system, with abiotic conditions that vary naturally with the surrounding environment in The Bahamas. This suggests wild smalltooth sawfish may also be capable of annual reproduction provided there are adequate prey resources, limited competition and mate availability.     

Longtail tuna,Thunnus tonggol (Bleeker, 1851): a global review of population dynamics,ecology, fisheries,and considerations for future conservation and management

Longtail tuna (Thunnus tonggol) is a neritic species that supports commercial, artisanal and recreational fisheries throughout the Indo-Pacific region. Historically receiving little attention by commercial fisheries, the global annual catch of longtail tuna has steadily risen from around 30,000 t in the early 1980s to exceeding 200,000 t since 2004, reaching a peak of 291,264 t in 2007, and was 281,613 t in 2017. Catches of longtail tuna in the Indian Ocean now exceed catches of principal commercial target species, such as albacore and bigeye tunas. A sequence of stock assessments undertaken throughout the species’ range since the late 1980s persistently indicated that at least three of the four stocks defined in this paper are likely to have been, and most likely are currently, subject to overfishing and overfished as a result of excess fishing effort on this relatively slow-growing and long-lived tuna species. As the spawning biomass of principal tuna target species continue to decline in both the Indian and western and central Pacific Oceans, the increasing catches of longtail tuna, other neritic tunas, and seerfishes is worrisome. Few conservation and management measures (CMMs) are currently in place specifically for longtail tuna, although in recent years some coastal States, Regional Fishery Bodies, and tuna Regional Fisheries Management Organisations have begun to develop initiatives to improve the catch and biological data quality for longtail tuna and sympatric species of neritic tunas and tuna-like species. This paper provides a global review of biological, ecological and fishery information to provide researchers, fishery managers and policy makers with the most current information from which to begin to guide future stock assessment and the development of CMMs for longtail tuna.

     

Long‐term caloric restriction ameliorates deleterious effects of aging on white and brown adipose tissue plasticity

Age‐related increased adiposity is an important contributory factor in the development of insulin resistance (IR) and is associated with metabolic defects. Caloric restriction (CR) is known to induce weight loss and to decrease adiposity while preventing metabolic risk factors. Here, we show that moderate 20% CR delays early deleterious effects of aging on white and brown adipose tissue (WAT and BAT, respectively) function and improves peripheral IR. To elucidate the role of CR in delaying early signs of aging, young (3 months), middle‐aged (12 months), and old (20 months) mice fed al libitum and middle‐aged and old mice subjected to early‐onset CR were used. We show that impaired plasticity of subcutaneous WAT (scWAT) contributes to IR, which is already evident in middle‐aged mice. Moreover, alteration of thyroid axis status with age is an important factor contributing to BAT dysfunction in middle‐aged animals. Both defects in WAT and BAT/beige cells are ameliorated by CR. Accordingly, CR attenuated the age‐related decline in scWAT function and decreased the extent of fibro‐inflammation. Furthermore, CR promoted scWAT browning. In brief, our study identifies the contribution of scWAT impairment to age‐associated metabolic dysfunction and identifies browning in response to food restriction, as a potential therapeutic strategy to prevent the adverse metabolic effects in middle‐aged animals.     

Specific antibody binding to the APP672–699 region shifts APP processing from α- to β-cleavage

Alzheimer''s disease (AD), a progressive neurodegenerative disorder that is the most common cause of dementia in the elderly, is characterized by the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles, as well as a progressive loss of synapses and neurons in the brain. The major pertinacious component of amyloid plaques is Aβ, a variably sized peptide derived from the integral membrane protein amyloid precursor protein (APP). The Aβ region of APP locates partly within its ecto- and trans-membrane domains. APP is cleaved by three proteases, designated as α-, β-, and γ-secretases. Processing by β- and γ-secretase cleaves the N- and C-terminal ends of the Aβ region, respectively, releasing Aβ, whereas α-secretase cleaves within the Aβ sequence, releasing soluble APPα (sAPPα). The γ-secretase cleaves at several adjacent sites to yield Aβ species containing 39–43 amino acid residues. Both α- and β-cleavage sites of human wild-type APP are located in APP_672–699 region (ectodomain of β-C-terminal fragment, ED-β-CTF or ED-C99). Therefore, the amino acid residues within or near this region are definitely pivotal for human wild-type APP function and processing. Here, we report that one ED-C99-specific monoclonal antibody (mAb_ED-C99) blocks human wild-type APP endocytosis and shifts its processing from α- to β-cleavage, as evidenced by elevated accumulation of cell surface full-length APP and β-CTF together with reduced sAPPα and α-CTF levels. Moreover, mAb_ED-C99 enhances the interactions of APP with cholesterol. Consistently, intracerebroventricular injection of mAb_ED-C99 to human wild-type APP transgenic mice markedly increases membrane-associated β-CTF. All these findings suggest that APP_672–699 region is critical for human wild-type APP processing and may provide new clues for the pathogenesis of sporadic AD.Abnormal functioning and/or processing of amyloid precursor protein (APP), a type I membrane protein, has a pivotal role in the pathogenesis of Alzheimer''s disease (AD).^{1, 2, 3} APP is cleaved by three proteases, designated as α-, β-, and γ-secretases (Supplementary Figure S1). The major fraction (>90%) of wild-type APP is proteolyzed by α-secretase that cleaves wild-type APP between residues APP₆₈₇ and APP₆₈₈ within the amyloid-β (Aβ) sequence, releasing soluble APPα (sAPPα) and α-C-terminal fragment (α-CTF, C83). Only a minority (<10%) of all wild-type APP molecules undergo β-cleavage at the β-cleavage site (between residues APP₆₇₁ and APP₆₇₂) generating sAPPβ and β-CTF (C99), the latter of which is subsequently processed by γ-secretase complex to generate a mixture of Aβ peptides primarily 40 or 42 residues in length (Aβ_1-40/42).^{4, 5} The β-secretase cleaves APP in addition at a β′-site (between residues APP₆₈₁ and APP₆₈₂) to generate C89 that is further processed by γ-secretase to produce truncated Aβ_11–40/42 species.⁶Both α- and β-cleavage sites of wild-type APP are located in APP_672–699 region (the ectodomain of β-CTF, ED-β-CTF, or ED-C99; Supplementary Figure S1). Therefore, the amino acid residues within or near this region are definitely pivotal for wild-type APP function and processing. Previous studies have identified that mutation in ED-C99 region can affect the physiological processing of APP and contribute to pathological features of familial AD (fAD). For example, Swedish APP carrying APP_670/671 mutation (KM→NL) is cleaved by β-secretase over 50-fold more efficiently than wild-type APP.⁷ APP₆₇₃ mutation (A→V) and APP₆₉₃ mutation (E→G) can enhance Aβ production and accelerate formation of amyloid fibrils.^{8, 9, 10} APP₆₈₂ mutation (E→K) blocks APP β′-site and shifts cleavage to β-site, thus increasing Aβ_1–40/42 production.⁶ Although sporadic AD (sAD), the more common type of AD comprising 90 to 95% of all AD cases, lacks mutations in the APP gene, region-specific protein modifications within the ED-C99 region may affect wild-type APP processing similarly to APP gene mutations. For example, phosphorylation of ED-C99 at the threonine 687 (of APP₇₇₀ isoform, or corresponding threonine 668 of APP₇₅₁ isoform; Supplementary Figure S1) facilitates APP processing by γ-secretase.¹¹ Therefore, the elucidation of potential influences of region-specific modifications, induced by either endogenous or exogenous molecules, on wild-type APP processing would be especially critical for clarifying the mechanisms underlying the pathogenesis of sAD.To confirm this hypothesis, we used one mouse monoclonal antibody specifically recognizing ED-C99 (mAb_ED-C99) with its epitope at APP_674–679 (Supplementary Figure S1). The influences of mAb_ED-C99 binding on human wild-type APP processing were evaluated in vitro using Chinese hamster ovary cells expressing human wild-type APP (CHO/APP_wt cells) and cortical neurons derived from human wild-type APP transgenic (TgAPP_wt) mice. The in vitro effects of ED-C99 binding with mAb_ED-C99 on wild-type APP processing were further evaluated and confirmed in vivo using TgAPP_wt mice and 5 × FAD transgenic mice (Tg6799 line).