Carbon catabolite repression is a regulatory mechanism to ensure sequential utilization of carbohydrates and is usually accomplished by repression of genes for the transport and metabolism of less preferred carbon compounds by a more preferred one. Although glucose and mannitol share the general components, enzyme I and HPr, of the phosphoenolpyruvate-dependent phosphotransferase system (PTS) for their transport, glucose represses the transport and metabolism of mannitol in a manner dependent on the mannitol operon repressor MtlR in Escherichia coli. In a recent study, we identified the dephosphorylated form of HPr as a regulator determining the glucose preference over mannitol by interacting with and augmenting the repressor activity of MtlR in E. coli. Here, we determined the X-ray structure of the MtlR-HPr complex at 3.5 Å resolution to understand how phosphorylation of HPr impedes its interaction with MtlR. The phosphorylation site (His15) of HPr is located close to Glu108 and Glu140 of MtlR and phosphorylation at His15 causes electrostatic repulsion between the two proteins. Based on this structural insight and comparative sequence analyses, we suggest that the determination of the glucose preference over mannitol solely by the MtlR-HPr interaction is conserved within  the Enterobacteriaceae family.

Methylxanthines, purine alkaloids found in plants, are found in beverages (coffee, tea, cocoa) and foods (chocolate and other cocoa-containing foods) commonly consumed worldwide. Members of this family include caffeine, theophylline and theobromine. Methylxanthines have a variety of pharmacological effects, and caffeine and theophylline are used as pharmaceuticals. Methylxanthines are metabolized in the liver predominantly by the enzyme CYP1A2. Their co-administration with CYP1A2 inhibitors may lead to pharmacokinetic interactions. Little is known about the possible drug interactions between caffeine and substrates of other CYP450 enzymes. In our study, methylxanthine fractions inhibited CYP3A4 in a concentration-dependent manner. Concomitant consumption of green tea with CYP3A4 substrates could increase the possibility of interactions, and this requires further clarification. The inhibition of CYP3A4 is not only due to the presence of catechin derivatives but methylxanthines may also contribute to this effect.

The shikimate pathway, a metabolic pathway absent in humans, is responsible for the production of chorismate, a branch point metabolite. In the malaria parasite, chorismate is postulated to be a direct precursor in the synthesis of p-aminobenzoic acid (folate biosynthesis), p-hydroxybenzoic acid (ubiquinone biosynthesis), menaquinone, and aromatic amino acids. While the potential value of the shikimate pathway as a drug target is debatable, the metabolic dependency of chorismate in P. falciparum remains unclear. Current evidence suggests that the main role of chorismate is folate biosynthesis despite ubiquinone biosynthesis being active and essential in the malaria parasite. Our goal in the present work was to expand our knowledge of the ubiquinone head group biosynthesis and its potential metabolic dependency on chorismate in P. falciparum. We systematically assessed the development of both asexual and sexual stages of P. falciparum in a defined medium in the absence of an exogenous supply of chorismate end-products and present biochemical evidence suggesting that the benzoquinone ring of ubiquinones in this parasite may be synthesized through a yet unidentified route.

Cpf1 is an RNA-guided endonuclease that can be programmed to cleave DNA targets. Specific features, such as containing a short crRNA, creating a staggered cleavage pattern and having a low off-target rate, render Cpf1 a promising gene-editing tool. Here, we present a new Cpf1 ortholog, EeCpf1, as a genome-editing tool; this ortholog is derived from the gut bacterial species Eubacterium eligens. EeCpf1 exhibits a higher cleavage activity with the Mn2+ metal cofactor and efficiently cuts the target DNA with an engineered, nucleotide extended crRNA at the 5' target site. When mouse blastocysts were injected with multitargeting crRNAs against the IL2R-γ gene, an essential gene for immunodeficient mouse model production, EeCpf1 efficiently generated IL2R-γ knockout mice. For the first time, these results demonstrate that EeCpf1 can be used as an in vivo gene-editing tool for the production of knockout mice. The utilization of engineered crRNA with multiple target sites will help to explore the in vivo DNA cleavage activities of Cpf1 orthologs from other species that have not been demonstrated.

Primary carnitine deficiency (PCD) not treated with L-Carnitine can lead to sudden cardiac death. To our knowledge, it is unknown if asymptomatic patients treated with L-Carnitine suffer from myocardial scarring and thus be at greater risk of potentially serious arrhythmia. Cardiac evaluation of function and myocardial scarring is non-invasively best supported by cardiac magnetic resonance imaging (CMR) with late gadolinium enhancement (LGE). The study included 36 PCD patients, 17 carriers and 17 healthy subjects. A CMR cine stack in the short-axis plane were acquired to evaluate left ventricle (LV) systolic and diastolic function and a similar LGE stack to evaluate myocardial scarring and replacement fibrosis. LV volumes and ejection fraction were not different between PCD patients, carriers and healthy subjects. However, LV mass was higher in PCD patients with the severe homozygous mutation, c.95 A > G (p = 0.037; n = 17). Among homozygous PCD patients there were two cases of unexplained myocardial scarring and this is in contrast to no myocardial scarring in any of the other study participants (p = 0.10). LV mass was increased in PCD patients. L-carnitine supplementation is essential in order to prevent potentially lethal cardiac arrhythmia and serious adverse cardiac remodeling.

These updated EBMT guidelines review the clinical evidence, registry activity and mechanisms of action of haematopoietic stem cell transplantation (HSCT) in multiple sclerosis (MS) and other immune-mediated neurological diseases and provide recommendations for patient selection, transplant technique, follow-up and future development. The major focus is on autologous HSCT (aHSCT), used in MS for over two decades and currently the fastest growing indication for this treatment in Europe, with increasing evidence to support its use in highly active relapsing remitting MS failing to respond to disease modifying therapies. aHSCT may have a potential role in the treatment of the progressive forms of MS with a significant inflammatory component and other immune-mediated neurological diseases, including chronic inflammatory demyelinating polyneuropathy, neuromyelitis optica, myasthenia gravis and stiff person syndrome. Allogeneic HSCT should only be considered where potential risks are justified. Compared with other immunomodulatory treatments, HSCT is associated with greater short-term risks and requires close interspeciality collaboration between transplant physicians and neurologists with a special interest in these neurological conditions before, during and after treatment in accredited HSCT centres. Other experimental cell therapies are developmental for these diseases and patients should only be treated on clinical trials.

Retinoid X Receptor Gamma (RXRG) is a member of the nuclear receptor superfamily and plays a role in tumour suppression. This study aims to explore the prognostic significance of RXRG in breast cancer.

Ixazomib-revlimid-dexamethason showed significant activity in relapsed/refractory multiple myeloma (RRMM). Here, we evaluate ixazomib in combination with thalidomide and dexamethasone for induction treatment followed by ixazomib maintenance therapy in RRMM patients.

Vertebrates have highly methylated genomes at CpG positions, whereas invertebrates have sparsely methylated genomes. This increase in methylation content is considered a major regulatory innovation of vertebrate genomes. However, here we report that a sponge, proposed as the potential sister group to the rest of animals, has a highly methylated genome. Despite major differences in genome size and architecture, we find similarities between the independent acquisitions of the hypermethylated state. Both lineages show genome-wide CpG depletion, conserved strong transcription factor methyl-sensitivity and developmental methylation dynamics at 5-hydroxymethylcytosine enriched regions. Together, our findings trace back patterns associated with DNA methylation in vertebrates to the early steps of animal evolution. Thus, the sponge methylome challenges previous hypotheses concerning the uniqueness of vertebrate genome hypermethylation and its implications for regulatory complexity.

Treatment of tumor cells with cold atmospheric plasma (CAP) or with plasma-activated medium (PAM) leads to a biochemical imprint on these cells. This imprint is mediated by primary singlet oxygen, which is mainly generated through the interaction between CAP-derived H2O2 and NO2-. This imprint is induced with a low efficiency as local inactivation of a few membrane-associated catalase molecules. As sustained generation of secondary singlet oxygen by the tumor cells is activated at the site of the imprint, a rapid bystander effect-like spreading of secondary singlet oxygen generation and catalase inactivation within the cell population is thus induced. This highly dynamic process is essentially driven by NOX1 and NOS of the tumor cells, and finally leads to intercellular RONS-driven apoptosis induction. This dynamic process can be studied by kinetic analysis, combined with the use of specific inhibitors at defined time intervals. Alternatively, it can be demonstrated and quantified by transfer experiments, where pretreated cells are mixed with untreated cells and bystander signaling is determined. These studies allow to conclude that the specific response of tumor cells to generate secondary singlet oxygen is the essential motor for their self-destruction, after a singlet oxygen-mediated triggering process by CAP or PAM.

Long non-coding RNAs (lncRNAs) are members of the non-protein coding RNA family longer than 200 nucleotides. They participate in the regulation of gene and protein expression influencing apoptosis, cell proliferation and immune responses, thereby playing a critical role in the development and progression of various cancers, including colorectal cancer (CRC). As CRC is one of the most frequently diagnosed malignancies worldwide with high mortality, its screening and early detection are crucial, so the identification of disease-specific biomarkers is necessary. LncRNAs are promising candidates as they are involved in carcinogenesis, and certain lncRNAs (e.g., CCAT1, CRNDE, CRCAL1-4) show altered expression in adenomas, making them potential early diagnostic markers. In addition to being useful as tissue-specific markers, analysis of circulating lncRNAs (e.g., CCAT1, CCAT2, BLACAT1, CRNDE, NEAT1, UCA1) in peripheral blood offers the possibility to establish minimally invasive, liquid biopsy-based diagnostic tests. This review article aims to describe the origin, structure, and functions of lncRNAs and to discuss their contribution to CRC development. Moreover, our purpose is to summarise lncRNAs showing altered expression levels during tumor formation in both colon tissue and plasma/serum samples and to demonstrate their clinical implications as diagnostic or prognostic biomarkers for CRC.

Highly upregulated in liver cancer (HULC) is a long non-coding RNA (lncRNA) which has recently been identified as a key regulator in hepatocellular carcinoma (HCC) progression. However, its role in the secretion of exosomes from HCC cells remains unknown.

To date, the histopathological parameters predicting the risk of lymph node (LN) metastases and local recurrence, associated mortality and appropriateness of endoscopic or surgical resection in patients with gastric neuroendocrine neoplasms type 1 (GNENs1) have not been fully elucidated.

We aimed to determine the predictive value of several hematological markers of inflammation on the presence/absence of cervical cancer and also to determine their ability in discriminating precancerous cervical pathologies from cervical cancer.

Cuscutae Semen mainly includes salt-processed product (SPP) and wine-processed product (WPP), which are most commonly used in traditional Chinese medicine. However, the differences between SPP and WPP have not been reported. In this paper, comparative studies between SPP and WPP on chemical contents and effect in kidney-yang deficiency rats have been investigated. UPLC-MS/MS was used to study the differences in chemical components. Kidney-yang deficiency was induced by hydrocortisone in rats. Rats were orally administrated with different doses of Jinkui Shenqi Pills, SPP, and WPP for 28 days. The average organ coefficients, renal function indexes, sex hormone levels, and testicular morphology were detected. As a result, the contents of flavonoids and chlorogenic acids were higher in SPP than in WPP, which may be caused by different processing methods. The improvement on reproduction of SPP was reflected in organ coefficients, renal function indexes, and biochemical properties of seminal plasma; furthermore, WPP was in sex hormone levels and morphology of testis. As a conclusion, these results indicated that both SPP and WPP can improve the reproductive function of kidney-yang deficiency rats with different mechanisms, which may be due to the differences in chemical contents between WPP and SPP as well as different processing methods. It is the first time that the differences between SPP and WPP have been studied in reproductive function in rats with kidney-yang deficiency.

Xiyanping injection (XYP) is a well-known Chinese medicinal preparation reputed as a most effective alternative to antibiotics. XYP has been widely used in combination therapies to treat various infectious diseases, among which XYP plus azithromycin (AZM) chemotherapy is often used for the treatment of Mycoplasma pneumoniae pneumonia in pediatric patients (p-MPP) in China.

Cannabidiol (CBD) is a major chemical compound present in Cannabis sativa. CBD is a nonpsychotomimetic substance, and it is considered one of the most promising candidates for the treatment of psychiatric disorders.

The molecular mechanisms involved in microRNAs (miRNAs) have been extensively investigated in gastric cancer (GC). However, how miR-331 regulates GC pathogenesis remains unknown.

Elderly patients aged at least 75 years old (Elderly_75), represent 45% of colorectal cancer (CRC) incidence. As others, the French Colorectal Cancer Screening Program (CRCSP) does not include Elderly_75. To date, there is little evidence to justify stopping screening at 74 years of age.

Gastrointestinal schwannomas are slow-growing benign mesenchymal neoplasms that originate from Schwann cells of the nerve sheath of Auerbach´s plexus or less frequently from Meissner´s plexus. The main differential diagnosis of gastric schwannomas are the gastrointestinal stromal tumors (GISTs), which are classified by their immunohistochemistry. The treatment of choice for gastric schwannomas is surgery where laparoscopy plays an important role. Wedge resection, subtotal or total gastrectomy can be done. In its counterpart, esophageal schwannomas are benign tumors of the esophagus that are very uncommon since they comprise less than 2% of all esophageal tumors. The main differential diagnosis is the leiomyoma which corresponds to the most common benign esophageal tumor, followed by GIST. The treatment consists on tumoral enucleation or esophagectomy.