Smelling the Dark Proteome : Functional Characterization of PITH Domain-Containing Protein 1 (C1orf128) in Olfactory Metabolism

The Human Proteome Project (HPP) consortium aims to functionally characterize the dark proteome. On the basis of the relevance of olfaction in early neurodegeneration, we have analyzed the dark proteome using data mining in public resources and omics data sets derived from the human olfactory system. Multiple dark proteins localize at synaptic terminals and may be involved in amyloidopathies such as Alzheimer’s disease (AD). We have characterized the dark PITH domain-containing protein 1 (PITHD1) in olfactory metabolism using bioinformatics, proteomics, in vitro and in vivo studies, and neuropathology. PITHD1–/– mice exhibit olfactory bulb (OB) proteome changes related to synaptic transmission, cognition, and memory. OB PITHD1 expression increases with age in wild-type (WT) mice and decreases in Tg2576 AD mice at late stages. The analysis across 6 neurological disorders reveals that olfactory tract (OT) PITHD1 is specifically upregulated in human AD. Stimulation of olfactory neuroepithelial (ON) cells with PITHD1 alters the ON phosphoproteome, modifies the proliferation rate, and induces a pro-inflammatory phenotype. This workflow applied by the Spanish C-HPP and Human Brain Proteome Project (HBPP) teams across the ON-OB-OT axis can be adapted as a guidance to decipher functional features of dark proteins. Data are available via ProteomeXchange with identifiers PXD018784 and PXD021634

Opening a New Gate to Glass Preservative with Long-Lasting Antimicrobial Activity as Replacement of Parabens

In the past few years, the rapid and continuing emergence of antibiotic resistance for microbial pathogens has questioned the future utilization of antibiotics. Thus, the discovery of new antimicrobials is highly desired to fight microorganisms with multidrug-resistant capability. Here, we have used an inorganic UV filter as a model system to investigate the behavior of a new preservative, based on Ag–Zn cations, to replace parabens in sunscreens. The new glass preservative is incorporated into the UV filter composite by using an easy and ecofriendly method based on a dry nanodispersion. The Challenge Test clearly demonstrates a robust toxicity toward microorganisms, both the resistant bacteria and the fungi. This stimulant behavior can be explained by coupling between the antimicrobial activity of the Ag⁺ and the antifungal activity of Zn²⁺. Importantly, leaching assays show that the controlled released of these cations over time results in a long-lasting antimicrobial property, pointing out that this material is a promising paraben-free candidate

Long-lasting memory deficits in mice withdrawn from cocaine are concomitant with neuroadaptations in hippocampal basal activity, GABAergic interneurons and adult neurogenesis

Ladrón de Guevara-Miranda, David et al.Cocaine addiction disorder is notably aggravated by concomitant cognitive and emotional pathology that impedes recovery. We studied whether a persistent cognitive/emotional dysregulation in mice withdrawn from cocaine holds a neurobiological correlate within the hippocampus, a limbic region with a key role in anxiety andmemory but that has been scarcely investigated in cocaine addiction research. Mice were submitted to a chronic cocaine (20 mg/kg/day for 12 days) or vehicle treatment followed by 44 drug-free days. Some mice were then assessed on a battery of emotional (elevated plus-maze, light/dark box, open field, forced swimming) and cognitive (object and place recognition memory, cocaine-induced conditioned place preference, continuous spontaneous alternation) behavioral tests, while othermice remained in their home cage. Relevant hippocampal features [basal c-Fos activity, GABA+, parvalbumin (PV)+ and neuropeptide Y (NPY)+ interneurons and adult neurogenesis (cell proliferation and immature neurons)] were immunohistochemically assessed 73 days after the chronic cocaine or vehicle protocol. The cocaine-withdrawn mice showed no remarkable exploratory or emotional alterations but were consistently impaired in all the cognitive tasks. All the cocainewithdrawn groups, independent of whether they were submitted to behavioral assessment or not, showed enhanced basal c-Fos expression and an increased number of GABA+ cells in the dentate gyrus. Moreover, the cocaine-withdrawn mice previously submitted to behavioral training displayed a blunted experience-dependent regulation of PV+ and NPY+ neurons in the dentate gyrus, and neurogenesis in the hippocampus. Results highlight the importance of hippocampal neuroplasticity for the ingrained cognitive deficits present during chronic cocaine withdrawal.This research was funded by the Spanish Ministerio de Economía y Competitividad and the European Commission Regional Development Fund (UE-ERDF) (PSI2015- 73156-JIN to E.C-O, SAF12-36853 to M.A.-D and PSI2013-44901-P to L.J.S.), Junta de Andalucıa (CTS-2563 to M.A.-D) and Red de Trastornos Adictivos (RD12/ ́ 0028/0001 to F.R.F.). Authors received funds from the National System of Health Instituto de Salud Carlos III (Sara Borrell CD12/00455 to E.C-O; Miguel Servet CP14/00173 to A.S. and CP14/00212 to F.J.P.), from the Spanish Ministerio de Educación, Cultura y Deporte (FPU13/04819 to D.L.d.G.-M.) and from the University of Málaga (Plan Propio grant to C.M. and C.R.-V.).Peer Reviewe

Synthesis and Biological Evaluation of 1α,25-Dihydroxyvitamin D₃ Analogues with a Long Side Chain at C12 and Short C17 Side Chains

Structure-guided optimization was used to design new analogues of 1α,25-dihydroxyvitamin D₃ bearing the main side chain at C12 and a shorter second hydroxylated chain at C17. The new compounds <b>5a</b>–<b>c</b> were efficiently synthesized from ketone <b>9</b> (which is readily accessible from the Inhoffen–Lythgoe diol) with overall yields of 15%, 6%, and 3% for <b>5a</b>, <b>5b</b>, and <b>5c</b>, respectively. The triene system was introduced by the Pd-catalyzed tandem cyclization–Suzuki coupling method. The new analogues were assayed against human colon and breast cancer cell lines and in mice. All new vitamin D₃ analogues bound less strongly to the VDR than 1α,25-dihydroxyvitamin D₃ but had similar antiproliferative, pro-differentiating, and transcriptional activity as the native hormone. In vivo, the three analogues had markedly low calcemic effects

Branimycins B and C, Antibiotics Produced by the Abyssal Actinobacterium <i>Pseudonocardia carboxydivorans</i> M‑227

Two new antibiotics, branimycins B (<b>2</b>) and C (<b>3</b>), were produced by fermentation of the abyssal actinobacterium <i>Pseudonocardia carboxydivorans</i> M-227, isolated from deep seawater of the Avilés submarine Canyon. Their structures were elucidated by HRMS and NMR analyses. These compounds exhibit antibacterial activities against a panel of Gram-positive bacteria, including <i>Corynebacterium urealyticum</i>, <i>Clostridium perfringens</i>, and <i>Micrococcus luteus</i>, and against the Gram-negative bacterium <i>Neisseria meningitidis.</i> Additionally, branimycin B displayed moderate antibacterial activity against other Gram-negative bacteria such as <i>Bacteroides fragilis</i>, <i>Haemophilus influenzae</i>, and <i>Escherichia coli</i>, and branimycin C against the Gram-positive <i>Enterococcus faecalis</i> and methicillin-sensitive and methicillin-resistant <i>Staphylococcus aureus.</i

Synthesis and Structure–Activity Relationships of the Novel Antimalarials 5‑Pyridinyl-4(1<i>H</i>)‑Pyridones

Malaria is still one of the most prevalent parasitic infections in the world, with half of the world’s population at risk for malaria. The effectiveness of current antimalarial therapies, even that of the most recent class of antimalarial drugs (artemisinin-combination therapies, ACTs), is under continuous threat by the spread of resistant <i>Plasmodium</i> strains. As a consequence, there is still an urgent requirement for new antimalarial drugs. We previously reported the identification of 4­(1<i>H</i>)-pyridones as a novel series with potent antimalarial activities. The low solubility was identified as an issue to address. In this paper, we describe the synthesis and biological evaluation of 4­(1<i>H</i>)-pyridones with potent antimalarial activities in vitro and in vivo and improved pharmacokinetic profiles. Their main structural novelties are the presence of polar moieties, such as hydroxyl groups, and the replacement of the lipophilic phenyl rings with pyridines on their lipophilic side chains

Surgeons’ practice and preferences for the anal fissure treatment: results from an international survey

The best nonoperative or operative anal fissure (AF) treatment is not yet established, and several options have been proposed. Aim is to report the surgeons' practice for the AF treatment. Thirty-four multiple-choice questions were developed. Seven questions were about to participants' demographics and, 27 questions about their clinical practice. Based on the specialty (general surgeon and colorectal surgeon), obtained data were divided and compared between two groups. Five-hundred surgeons were included (321 general and 179 colorectal surgeons). For both groups, duration of symptoms for at least 6 weeks is the most important factor for AF diagnosis (30.6%). Type of AF (acute vs chronic) is the most important factor which guide the therapeutic plan (44.4%). The first treatment of choice for acute AF is ointment application for both groups (59.6%). For the treatment of chronic AF, this data is confirmed by colorectal surgeons (57%), but not by the general surgeons who prefer the lateral internal sphincterotomy (LIS) (31.8%) (p = 0.0001). Botulin toxin injection is most performed by colorectal surgeons (58.7%) in comparison to general surgeons (20.9%) (p = 0.0001). Anal flap is mostly performed by colorectal surgeons (37.4%) in comparison to general surgeons (28.3%) (p = 0.0001). Fissurectomy alone is statistically significantly most performed by general surgeons in comparison to colorectal surgeons (57.9% and 43.6%, respectively) (p = 0.0020). This analysis provides useful information about the clinical practice for the management of a debated topic such as AF treatment. Shared guidelines and consensus especially focused on operative management are required to standardize the treatment and to improve postoperative results