Multiple sclerosis is characterized by inflammatory activity that results in destruction of the myelin sheaths that enwrap axons. The currently available medications for multiple sclerosis are predominantly immune-modulating and do not directly promote repair. White matter regeneration, or remyelination, is a new and exciting potential approach to treating multiple sclerosis, as remyelination repairs the damaged regions of the central nervous system. A wealth of new strategies in animal models that promote remyelination, including the repopulation of oligodendrocytes that produce myelin, has led to several clinical trials to test new reparative therapies. In this Review, we highlight the biology of, and obstacles to, remyelination. We address new strategies to improve remyelination in preclinical models, highlight the therapies that are currently undergoing clinical trials and discuss the challenges of objectively measuring remyelination in trials of repair in multiple sclerosis.

BackgroundAlthough over 1400 Salmonella serovars cause usually self-limited gastroenteritis in humans, a few, e.g., Salmonella typhi and S. paratyphi C, cause typhoid, a potentially fatal systemic infection. It is not known whether the typhoid agents have evolved from a common ancestor (by divergent processes) or acquired similar pathogenic traits independently (by convergent processes). Comparison of different typhoid agents with non-typhoidal Salmonella lineages will provide excellent models for studies on how similar pathogens might have evolved.Methodologies/Principal FindingsWe sequenced a strain of S. paratyphi C, RKS4594, and compared it with previously sequenced Salmonella strains. RKS4594 contains a chromosome of 4,833,080 bp and a plasmid of 55,414 bp. We predicted 4,640 intact coding sequences (4,578 in the chromosome and 62 in the plasmid) and 152 pseudogenes (149 in the chromosome and 3 in the plasmid). RKS4594 shares as many as 4346 of the 4,640 genes with a strain of S. choleraesuis, which is primarily a swine pathogen, but only 4008 genes with another human-adapted typhoid agent, S. typhi. Comparison of 3691 genes shared by all six sequenced Salmonella strains placed S. paratyphi C and S. choleraesuis together at one end, and S. typhi at the opposite end, of the phylogenetic tree, demonstrating separate ancestries of the human-adapted typhoid agents. S. paratyphi C seemed to have suffered enormous selection pressures during its adaptation to man as suggested by the differential nucleotide substitutions and different sets of pseudogenes, between S. paratyphi C and S. choleraesuis.Conclusions S. paratyphi C does not share a common ancestor with other human-adapted typhoid agents, supporting the convergent evolution model of the typhoid agents. S. paratyphi C has diverged from a common ancestor with S. choleraesuis by accumulating genomic novelty during adaptation to man.

Regeneration of peripheral nerves involves complex and intimate interactions between axons and Schwann cells. Here we show that local axon synthesis and action of the neuropeptide calcitonin gene-related peptide (CGRP) is critical for this collaboration. Following peripheral sural sensory axon injury in rats, we observed an unexpectedly large proportion of axons that newly expressed CGRP during regeneration. Intense peptide expression accompanied local rises in αCGRP mRNA in the nerve trunk and there was evidence of transport of αCGRP mRNA into regenerating axons, indicating intra-axonal peptide synthesis. CGRP receptor (CRLR) and its receptor modifying protein (RAMP-1) were expressed on adjacent Schwann cells where they were available for signaling. Moreover, exogenous CGRP induced proliferation in isolated adult Schwann cells. New axon outgrowth and CGRP expression depended on local peptide synthesis and was inhibited by exposure to local translation inhibitors. Local delivery of siRNAs to either αCGRP or RAMP-1 to sites of nerve transection was associated with severe disruption of axon outgrowth. These findings indicate that robust localized intra-axonal translation of the CGRP neuropeptide during regeneration signals Schwann cell proliferation; behavior that is critical for partnering during adult peripheral nerve regrowth.

In this paper, a new conception of linguistic q‐rung orthopair fuzzy number (Lq‐ROFN) is proposed where the membership and nonmembership of the q‐rung orthopair fuzzy numbers ( q‐ROFNs) are represented as linguistic variables. Compared with linguistic intuitionistic fuzzy numbers and linguistic Pythagorean fuzzy numbers, the Lq‐ROFNs can more fully describe the linguistic assessment information by considering the parameter q to adjust the range of fuzzy information. To deal with the multiple‐attribute group decision‐making (MAGDM) problems with Lq‐ROFNs, we proposed the linguistic score and accuracy functions of the Lq‐ROFNs. Further, we introduce and prove the operational rules and the related properties characters of Lq‐ROFNs. For aggregating the Lq‐ROFN assessment information, some aggregation operators are developed, involving the linguistic q‐rung orthopair fuzzy power Bonferroni mean (BM) operator, linguistic q‐rung orthopair fuzzy weighted power BM operator, linguistic q‐rung orthopair fuzzy power geometric BM (GBM) operator, and linguistic q‐rung orthopair fuzzy weighted power GBM operator, and then presents their rational properties and particular cases, which cannot only reduce the influences of some unreasonable data caused by the biased decision‐makers, but also can take the interrelationship between any two different attributes into account. Finally, we propose a method to handle the MAGDM under the environment of Lq‐ROFNs by using the new proposed operators. Further, several examples are given to show the validity and superiority of the proposed method by comparing with other existing MAGDM methods.

Salmonella enterica serovar Pullorum is a fowl-adapted bacterial pathogen that causes dysentery (pullorum disease). Host adaptation and special pathogenesis make S. enterica serovar Pullorum an exceptionally good system for studies of bacterial evolution and speciation, especially regarding pathogen-host interactions and the acquisition of pathogenicity. We constructed a genome map of S. enterica serovar Pullorum RKS5078, using I-CeuI, XbaI, AvrII, and SpeI and Tn10 insertions. Pulsed-field gel electrophoresis was employed to separate the large DNA fragments generated by the endonucleases. The genome is 4,930 kb, which is similar to most salmonellas . However, the genome of S. enterica serovar Pullorum RKS5078 is organized very differently from the majority of salmonellas, with three major inversions and one translocation. This extraordinary genome structure was seen in most S. enterica serovar Pullorum strains examined, with different structures in a minority of S. enterica serovar Pullorum strains. We describe the coexistence of different genome structures among the same bacteria as genomic plasticity. Through comparisons with S. enterica serovar Typhimurium, we resolved seven putative insertions and eight deletions ranging in size from 12 to 157 kb. The genomic plasticity seen among S. enterica serovar Pullorum strains supported our hypothesis about its association with bacterial evolution: a large genomic insertion (157 kb in this case) disrupted the genomic balance, and rebalancing by independent recombination events in individual lineages resulted in diverse genome structures. As far as the structural plasticity exists, the S. enterica serovar Pullorum genome will continue evolving to reach a further streamlined and balanced structure.

Genome plasticity resulting from frequent rearrangement of the bacterial genome is a fascinating but poorly understood phenomenon. First reported in Salmonella typhi, it has been observed only in a small number of Salmonella serovars, although the over 2,500 known Salmonella serovars are all very closely related. To gain insights into this phenomenon and elucidate its roles in bacterial evolution, especially those involved in the formation of particular pathogens, we systematically analyzed the genomes of 127 wild-type S. typhi strains isolated from many places of the world and compared them with the two sequenced strains, Ty2 and CT18, attempting to find possible associations between genome rearrangement and other significant genomic features. Like other host-adapted Salmonella serovars, S. typhi contained large genome insertions, including the 134 kb Salmonella pathogenicity island, SPI7. Our analyses showed that SPI7 disrupted the physical balance of the bacterial genome between the replication origin (ori) and terminus (ter) when this DNA segment was inserted into the genome, and rearrangement in individual strains further changed the genome balance status, with a general tendency toward a better balanced genome structure. In a given S. typhi strain, genome diversification occurred and resulted in different structures among cells in the culture. Under a stressed condition, bacterial cells with better balanced genome structures were selected to greatly increase in proportion; in such cases, bacteria with better balanced genomes formed larger colonies and grew with shorter generation times. Our results support the hypothesis that genome plasticity as a result of frequent rearrangement provides the opportunity for the bacterial genome to adopt a better balanced structure and thus eventually stabilizes the genome during evolution.

BackgroundBecause human diets are composed of a wide variety of nutrients that may work synergistically to prevent or promote disease, assessing dietary nutrient intake status may be informative. The purpose of this study was to assess the dietary nutrient intake status of Chinese adults with metabolic syndrome (MetS) and to evaluate its possible role in MetS.MethodsThis case–control study was conducted from March 2010 to January 2011. A total of 123 patients with MetS and 135 controls participated in this study at the Health Examination Center of Heping District in Tianjin, China. Dietary intake was estimated by 24-h dietary recalls. We used principal component factor analysis to derive nutrient groups from 17 major nutrients. We examined the odds ratios and 95% confidence intervals using logistic regression models to test the relationship between tertiles of dietary nutrient pattern and MetS.ResultsThere were 4 major dietary nutrient patterns in this study: “vitamin B group”, “protein and lipids”, “vitamin E and minerals”, and “antioxidant vitamins”. After adjustment for potential confounders, the highest tertile of the nutrient pattern factor score for the “vitamin B group” (odds ratio: 0.16; 95% confidence interval: 0.05–0.47) was negatively associated with MetS compared with the lowest tertiles. No relationships were found between other dietary nutrient patterns and MetS.ConclusionsThe “vitamin B group” pattern was inversely associated with MetS in Chinese adults. This finding supports the hypothesis that the “vitamin B group” pattern may have a potentially beneficial effect on the prevention of MetS.

Background: Recent evidence suggests a role for the gut–brain axis in the pathophysiology of multiple sclerosis (MS). Materials and methods: We studied biomarkers of intestinal permeability in 126 people with MS (57 relapsing-remitting multiple sclerosis (RRMS) and 69 progressive MS) and in a group of healthy controls for comparison. Serum/plasma concentrations of zonulin (a regulator of enterocyte tight junctions), tight junction proteins (ZO-1 and occludin), intestinal fatty acid binding protein (IFABP)/ileal bile acid binding protein (IBABP), D-lactate, and lipopolysaccharide (LPS) binding protein were measured. Results: Zonulin concentrations were significantly higher when a concurrent magnetic resonance imaging (MRI) confirmed the presence of blood–brain barrier (BBB) disruption (Gad+ RRMS) and were correlated with tight junction proteins. IBABP and D-lactate were elevated in people with RRMS compared to controls, but did not discriminate between Gad+ and Gad– subgroups. Baseline zonulin concentrations were associated with 1-year disease progression in progressive MS. Conclusions: People with MS have altered biomarkers of intestinal barrier integrity. Zonulin concentrations are associated with 1-year disease progression in progressive MS and closely mirror BBB breakdown in RRMS. Zonulin may mediate breakdown of both the intestinal barrier and the BBB in gut dysbiosis through the regulation of tight junctions. This could explain how the gut–brain axis modulates neuroinflammation in MS.