Explore the vast range of titles available.

A sphingomyelin-binding motif is identified in the membrane-spanning domain of p24, a COPI machinery protein. Sphingolipid recognition by membrane proteins Sphingolipids are structural components of membranes, and some of them also act as intracellular second messengers. This work shows that one sphingomyelin species, known as SM18, directly and specifically interacts with the transmembrane domain of the COPI machinery protein p24. The interaction depends on a motif (VXXTLXXIY) within the membrane-spanning domain of p24, and bioinformatic analyses predict that this motif represents a conserved sphingolipid-binding cavity in a variety of other mammalian membrane proteins. Functioning and processing of membrane proteins critically depend on the way their transmembrane segments are embedded in the membrane 1 . Sphingolipids are structural components of membranes and can also act as intracellular second messengers. Not much is known of sphingolipids binding to transmembrane domains (TMDs) of proteins within the hydrophobic bilayer, and how this could affect protein function. Here we show a direct and highly specific interaction of exclusively one sphingomyelin species, SM 18, with the TMD of the COPI machinery protein p24 (ref. 2 ). Strikingly, the interaction depends on both the headgroup and the backbone of the sphingolipid, and on a signature sequence (VXXTLXXIY) within the TMD. Molecular dynamics simulations show a close interaction of SM 18 with the TMD. We suggest a role of SM 18 in regulating the equilibrium between an inactive monomeric and an active oligomeric state of the p24 protein 3 , 4 , which in turn regulates COPI-dependent transport. Bioinformatic analyses predict that the signature sequence represents a conserved sphingolipid-binding cavity in a variety of mammalian membrane proteins. Thus, in addition to a function as second messengers, sphingolipids can act as cofactors to regulate the function of transmembrane proteins. Our discovery of an unprecedented specificity of interaction of a TMD with an individual sphingolipid species adds to our understanding of why biological membranes are assembled from such a large variety of different lipids.

The allosteric communication between the pore domain, voltage sensors, and Ca 2+ binding sites in the calcium- and voltage-activated K + channel (BK) underlies its physiological role as the preeminent signal integrator in excitable systems. BK displays shallow voltage sensitivity with very fast gating charge kinetics, yet little is known about the molecular underpinnings of this distinctive behavior. Here, we explore the mechanistic basis of coupling between voltage-sensing domains (VSDs) and calcium sensors in Aplysia BK by locking the VSDs in their activated (R196Q and R199Q) and resting (R202Q) states, with or without calcium. Cryo-EM structures of these mutants reveal unique tilts at the S4 C-terminal end, together with large side-chain rotameric excursions of the gating charges. Notably, the VSD resting structure (R202Q) also revealed BK in its elusive, fully closed state, highlighting the reciprocal relation between calcium and voltage sensors. These structures provide a plausible path where voltage and Ca 2+ binding couple energetically and define the conformation of the pore domain and, thus, BK’s full functional range. The allosteric communication between the pore domain, voltage sensors, and Ca2+ binding sites in BK channels underlies its physiological role. Here, cryo-EM structures provide a plausible path where voltage and Ca2+ binding define the conformation of the pore domain.

The voltage-dependent motor protein prestin (also known as SLC26A5) is responsible for the electromotive behaviour of outer-hair cells and underlies the cochlear amplifier 1 . Knockout or impairment of prestin causes severe hearing loss 2 – 5 . Despite the key role of prestin in hearing, the mechanism by which mammalian prestin senses voltage and transduces it into cellular-scale movements (electromotility) is poorly understood. Here we determined the structure of dolphin prestin in six distinct states using single-particle cryo-electron microscopy. Our structural and functional data suggest that prestin adopts a unique and complex set of states, tunable by the identity of bound anions (Cl − or SO 4 2− ). Salicylate, a drug that can cause reversible hearing loss, competes for the anion-binding site of prestin, and inhibits its function by immobilizing prestin in a new conformation. Our data suggest that the bound anion together with its coordinating charged residues and helical dipole act as a dynamic voltage sensor. An analysis of all of the anion-dependent conformations reveals how structural rearrangements in the voltage sensor are coupled to conformational transitions at the protein–membrane interface, suggesting a previously undescribed mechanism of area expansion. Visualization of the electromotility cycle of prestin distinguishes the protein from the closely related SLC26 anion transporters, highlighting the basis for evolutionary specialization of the mammalian cochlear amplifier at a high resolution. Mammalian prestin underlies cellular electromotility by sensing the voltage through a dynamic senor and converting it to an in-plane area expansion.

Voltage gated potassium (Kv) channels regulate processes from cellular excitability to immune response and are major pharmaceutical targets. Despite recent structural advances, the closed state structure of the strictly coupled Kv1 family remains elusive. Here, we capture the structure of the Shaker potassium channel with a closed pore by uncoupling its voltage sensor domains from the pore domain. Structural determination of the uncoupled I384R mutant by single particle Cryo-EM reveals a fully closed pore coexisting with activated, non-relaxed voltage sensors. Comparison with the open pore structure suggests a roll-and-turn movement along the length of the pore-forming S6 helices, contrasting with canonical gating models based on limited movements of S6. These rotational-translational motions place two hydrophobic residues, one in the inner cavity and the other at the bundle crossing region, directly at the permeation pathway, limiting the pore radius to less than 1 Å. The selectivity filter is captured in a noncanonical state, partially expanded at G446, unlike previously described dilated or pinched filter conformations. Together, these findings suggest a reinterpretation of the mechanism of activation gating for strictly coupled Kv1 channels, highlighting the strictly sensor-pore coupling that underlies different functional states. Voltage-gated potassium channels control excitability, but their non-conductive structure remained elusive. Here, authors reveal the Shaker channel’s closed-pore structure, showing distinct “roll-and-turn” helix movements that redefine activation gating in the Kv1 family.

Mislabeling of seafood is a global phenomenon that can misrepresent the status and level of consumption of wild fish stocks while concealing the use of many other wild species or those originating from aquaculture and sold as substitutes. We conducted a DNA barcoding study in three cities within Mexico (Mazatlan, Mexico City and Cancun) and sequenced the COI gene in 376 fish samples sold as 48 distinct commercial names at fish markets, grocery stores, and restaurants. Our goal was to identify the main species sold, their mislabeling rates and the species most used as substitutes. Overall, the study-wide mislabeling rate was 30.8% (95% CI 26.4–35.6). Half of the samples collected belonged to five species traded globally (yellowfin tuna, Atlantic salmon, mahi, swai, and tilapia), most of them with important aquaculture or ranching production levels. These species were commonly used as substitutes for other species and showed low mislabeling rates themselves (≤ 11%, except mahi mahi with 39% mislabeling). The other half of the samples revealed nearly 100 species targeted by small-scale fishers in Mexico and sold under 42 distinct commercial names. Popular local commercial names ( dorado , marlin , mero , robalo , mojarra , huachinango , pargo , sierra ) showed the highest mislabeling rates (36.3% to 94.4%) and served to sell many of the 53 species identified as substitutes in our study. We discuss the observed patterns in relation to landing and import data showing differences in availability of commercial species and the links to explain observed mislabeling rates and the use of a species as a substitute for other species. We also outline some of the implications of establishing a labeling and traceability standard as an alternative to improve transparency in the trade of seafood products in Mexico.

Background The COVID-19 pandemic has been recognized as a trigger for redefining supply chains at the global level, and has created an intense debate within the academic community and among policy-makers and practitioners. Among other industries, health care has been dramatically hit by the scarcity of “medical products,” specifically for personal protective equipment (PPE-like), due to supply chain disruptions coupled with dramatically increased demand. We aimed to analyze how the scarcity of PPE-like during the COVID-19 pandemic has modified the behavior of decision-makers in the PPE-like supply chain at the hospital level, and to explore what changes could be implemented to cope with future PPE-like shortages. Methods We used an explorative approach based on semi-structured interviews with key informants in the Spanish health care industry. More specifically, we held interviews to industry experts at three hospitals in three Spanish regions to map the consequences of the COVID-19 pandemic onto the buying decision-making process. Results Different strategies were developed by decision-makers at hospitals before, during, and after the first wave of the COVID-19 pandemic in Spain. Our paper offers two main findings: a) decision-makers changed their purchasing behavior from a cost main driver to guaranteeing the availability of supplies; b) they supported the idea of giving more “strategic autonomy” to Spain or Europe through back and nearshoring decisions. Conclusions This paper could be of interest to health care management at the national, regional, and hospital levels, as well as for policy-makers, since it could help to establish and configure policies to support the sourcing of medical products (specifically PPE-like) to anticipate potential supply disruptions. Our paper contributes to the limited existing literature on how purchasing strategies at the decision-maker level and supply vary in the health care industry when a public health crisis appears, and what potential solutions might be for policy-makers and practitioners involved in the health care industry.

HIV-1 is internalized into mature dendritic cells (mDCs) via an as yet undefined mechanism with subsequent transfer of stored, infectious virus to CD4+ T lymphocytes. Thus, HIV-1 subverts a DC antigen capture mechanism to promote viral spread. Here, we show that gangliosides in the HIV-1 membrane are the key molecules for mDC uptake. HIV-1 virus-like particles and liposomes mimicking the HIV-1 lipid composition were shown to use a common internalization pathway and the same trafficking route within mDCs. Hence, these results demonstrate that gangliosides can act as viral attachment factors, in addition to their well known function as cellular receptors for certain viruses. Furthermore, the sialyllactose molecule present in specific gangliosides was identified as the determinant moiety for mDC HIV-1 uptake. Thus, sialyllactose represents a novel molecular recognition pattern for mDC capture, and may be crucial both for antigen presentation leading to immunity against pathogens and for succumbing to subversion by HIV-1.

Calcium- and voltage-activated potassium channels (BK) are regulated by a multiplicity of signals. The prevailing view is that different BK gating mechanisms converge to determine channel opening and that these gating mechanisms are allosterically coupled. In most instances the pore forming α subunit of BK is associated with one of four alternative β subunits that appear to target specific gating mechanisms to regulate the channel activity. In particular, β1 stabilizes the active configuration of the BK voltage sensor having a large effect on BK Ca ²⁺ sensitivity. To determine the extent to which β subunits regulate the BK voltage sensor, we measured gating currents induced by the pore-forming BK α subunit alone and with the different β subunits expressed in Xenopus oocytes (β1, β2IR, β3b, and β4). We found that β1, β2, and β4 stabilize the BK voltage sensor in the active conformation. β3 has no effect on voltage sensor equilibrium. In addition, β4 decreases the apparent number of charges per voltage sensor. The decrease in the charge associated with the voltage sensor in α β4 channels explains most of their biophysical properties. For channels composed of the α subunit alone, gating charge increases slowly with pulse duration as expected if a significant fraction of this charge develops with a time course comparable to that of K ⁺ current activation. In the presence of β1, β2, and β4 this slow component develops in advance of and much more rapidly than ion current activation, suggesting that BK channel opening proceeds in two steps.

Schiff bases are imine derivatives widely recognized for their structural versatility and ability to coordinate transition metals, giving rise to compounds with remarkable physicochemical and biological properties. Over the last decade, numerous studies have reported their diverse applications, ranging from antimicrobial, antioxidant, and anticancer activities to roles as catalysts, fluorescent sensors, and photovoltaic materials. While previous reviews have focused on specific aspects—such as biomedical activity, catalytic transformations, or luminescent sensing—there is still a lack of an integrative perspective that connects these different areas. In this review, we provide a comprehensive analysis of recent advances in Schiff bases and their metal complexes, emphasizing their multifunctionality at the interface of bioinorganic chemistry and materials science. We highlight how metal coordination enhances biological activity, how structural design expands the scope of asymmetric catalysis, how Schiff‐based fluorophores are emerging as versatile luminescent sensors, and how aromatic and metal‐Schiff derivatives contribute to the development of next‐generation photovoltaic devices. By offering this transversal vision, the article aims to bridge fragmented knowledge and outline future research directions to fully exploit the potential of Schiff bases in medicine, catalysis, sensing, and sustainable energy.

Few sclerophyllous plants from the central coast of Chile have been systematically studied. This work describes the phytochemical composition and antimicrobial properties of Baccharis concava Pers. (sin. B. macraei), a shrub found in the first line and near the Pacific coast. B. concava has been traditionally used by indigenous inhabitants of today’s central Chile for its medicinal properties. Few reports exist regarding the phytochemistry characterization and biological activities of B. concava. A hydroalcoholic extract of B. concava was prepared from leaves and small branches. Qualitative phytochemical characterization indicated the presence of alkaloids, steroids, terpenoids, flavonoids, phenolic, and tannin compounds. The antimicrobial activity of this extract was assessed in a panel of microorganisms including Gram-positive bacteria, Gram-negative bacteria, and pathogenic yeasts. The extract displayed an important antimicrobial effect against Gram-positive bacteria, Candida albicans, and Cryptococcus neoformans but not against Gram-negatives, for which an intact Lipopolysaccharide is apparently the determinant of resistance to B. concava extracts. The hydroalcoholic extract was then fractionated through a Sephadex LH-20/methanol–ethyl acetate column. Afterward, the fractions were pooled according to a similar pattern visualized by TLC/UV analysis. Fractions obtained by this criterion were assessed for their antimicrobial activity against Staphylococcus aureus. The fraction presenting the most antimicrobial activity was HPLC-ESI-MS/MS, obtaining molecules related to caffeoylquinic acid, dicaffeoylquinic acid, and quercetin, among others. In conclusion, the extracts of B. concava showed strong antimicrobial activity, probably due to the presence of metabolites derived from phenolic acids, such as caffeoylquinic acid, and flavonoids, such as quercetin, which in turn could be responsible for helping with wound healing. In addition, the development of antimicrobial therapies based on the molecules found in B. concava could help to combat infection caused by pathogenic yeasts and Gram-positive bacteria, without affecting the Gram-negative microbiota.