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More than half of the >5000 approved mineral species are known from five or fewer localities and thus are rare. Mineralogical rarity arises from different circumstances, but all rare mineral species conform to one or more of four criteria: (1) P-T-Xrange: minerals that form only under highly restricted conditions in pressure-temperature-composition space; (2) Planetary constraints: minerals that incorporate essential elements that are rare or that form at extreme conditions that seldom occur in Earth's near-surface environment; (3) Ephemeral phases: minerals that rapidly break down under ambient conditions; and (4) Collection biases: phases that are difficult to recognize because they lack crystal faces or are microscopic, or minerals that arise in lithological contexts that are difficult to access. Minerals that conform to criterion 1, 2, or 3 are inherently rare, whereas those matching criterion 4 may be much more common than represented by reported occurrences. Rare minerals, though playing minimal roles in Earth's bulk properties and dynamics, are nevertheless of significance for varied reasons. Uncommon minerals are key to understanding the diversity and disparity of Earth's mineralogical environments, for example in the prediction of as yet undescribed minerals. Novel minerals often point to extreme compositional regimes that can arise in Earth's shallow crust and they are thus critical to understanding Earth as a complex evolving system. Many rare minerals have unique crystal structures or reveal the crystal chemical plasticity of well-known structures, as dramatically illustrated by the minerals of boron. Uncommon minerals may have played essential roles in life's origins; conversely, many rare minerals arise only as a consequence, whether direct or indirect, of biological processes. The distribution of rare minerals may thus be a robust biosignature, while these phases individually and collectively exemplify the co-evolution of the geosphere and biosphere. Finally, mineralogical rarities, as with novelty in other natural domains, are inherently fascinating.

Diversity in cytoskeleton organization and function may be achieved through variations in primary sequence of tubulin isotypes. Recently, isotype functional diversity has been linked to a "tubulin code" in which the C-terminal tail, a region of substantial sequence divergence between isotypes, specifies interactions with microtubule-associated proteins. However, it is not known whether residue changes in this region alter microtubule dynamic instability. Here, we examine recombinant tubulin with human beta isotype IIB and characterize polymerization dynamics. Microtubules with beta IIB have catastrophe frequencies approximately threefold lower than those with isotype beta III, a suppression similar to that achieved by regulatory proteins. Further, we generate chimeric beta tubulins with native tail sequences swapped between isotypes. These chimeras have catastrophe frequencies similar to that of the corresponding full-length construct with the same core sequence. Together, our data indicate that residue changes within the conserved beta tubulin core are largely responsible for the observed isotype-specific changes in dynamic instability parameters and tune tubulin's polymerization properties across a wide range.

Acinetobacter baumannii is a Gram-negative bacterial pathogen responsible for a range of nosocomial infections. The recent rise and spread of multidrug-resistant A. baumannii clones has fueled a search for alternative therapies, including bacteriophage endolysins with potent antibacterial activities. A common feature of these lysins is the presence of a highly positively charged C-terminal domain with a likely role in promoting outer membrane penetration. In the present study, we show that the C-terminal amino acids 108 to 138 of phage lysin PlyF307, named P307, alone were sufficient to kill A. baumannii (> 3 logs). Furthermore, P307 could be engineered for improved activity, the most active derivative being P307(SQ-8C) (> 5-log kill). Both P307 and P307(SQ-8C) showed high in vitro activity against A. baumannii in biofilms. Moreover, P307(SQ-8C) exhibited MICs comparable to those of levofloxacin and ceftazidime and acted synergistically with polymyxin B. Although the peptides were shown to kill by disrupting the bacterial cytoplasmic membrane, they did not lyse human red blood cells or B cells; however, serum was found to be inhibitory to lytic activity. In a murine model of A. baumannii skin infection, P307(SQ-8C) reduced the bacterial burden by similar to 2 logs in 2 h. This study demonstrates the prospect of using peptide derivatives from bacteriophage lysins to treat topical infections and remove biofilms caused by Gram-negative pathogens.

Multidirectional interactions between the nervous and immune systems have been documented in homeostasis and pathologies ranging from multiple sclerosis to autism, and from leukemia to acute and chronic inflammation. Recent studies have addressed this crosstalk using cell-specific targeting, novel sequencing, imaging, and analytical tools, shedding light on unappreciated mechanisms of neuro-immune regulation. This Review focuses on neuro-immune interactions at barrier surfaces-mostly the gut, but also including the skin and the airways, areas densely populated by neurons and immune cells that constantly sense and adapt to tissue-specific environmental challenges.

Lysine to methionine (K-to-M) mutations in genes encoding histone H3 are thought to drive a subset of pediatric brain and bone cancers. These high-frequency K-to-M mutations occur at sites of methylation on histone H3, and tumors containing the mutant histones exhibit a global loss of specific histone methylation marks. Previous studies showed that K-to-M mutant histones, also known as oncohistones, are potent orthosteric inhibitors of specific Su(var)3-9, Enhancer-of-zeste, Trithorax (SET) domain methyltransferases. However, the biochemical and biophysical details of the interaction between K-to-M mutant histones and the respective SET domain methyltransferases are currently unknown. Here, we use the histone H3K9-directed methyltransferase G9a as a model to explore the mechanism of inhibition by K-to-M oncohistones. X-ray cocrystal structures revealed that the K9M residue of histone H3 occupies the active site cavity of G9a, and kinetic analysis indicates competitive inhibition of G9a by histone H3K9M. Additionally, we find that the cofactor S-adenosyl methionine (SAM) is necessary for stable interaction between G9a and H3K9M histone. Consistent with the formation of a ternary complex, we find that the inhibitory peptide is uncompetitive with regard to SAM. These data and others indicate that K-to-M oncohistones promote global loss of specific lysine methylation through sequestration and inhibition of SAM-bound SET domain methyltransferases.

Clinical disease caused by weakly pathogenic mycobacterial species, which is known as Mendelian susceptibility to mycobacterial disease (MSMD), is a rare entity. IFN-gamma and IL-17 production are defective due to insufficient response to IL-2 and IL-23 in IL-12R beta 1 deficiency; so this also causes tendency to intracellular microorganisms and candidal diseases. Here, we present a patient who suffers IL-12R beta 1 deficiency caused by a novel bi-allelic mutation with recurrent salmonellosis, mycobacterial, fungal infections and remained asymptomatic during 13 months of follow-up after hIFN-gamma treatment. In addition she had hemolytic anemia and midline defects like cleft lip and palate which have not been reported in a patient with MSMD in the literature prior to this case report. In conclusion, diagnosis of MSMD should be kept in mind in patients with recurrent salmonellosis, mycobacterial and fungal infections especially in countries with a high consanguinity rate.

Despite the success of potent anti-retroviral drugs in controlling human immunodeficiency virus type 1 (HIV-1) infection, little progress has been made in generating an effective HIV-1 vaccine. Although passive transfer of anti-HIV-1 broadly neutralizing antibodies can protect mice or macaques against a single high-dose challenge with HIV or simian/human (SIV/HIV) chimaeric viruses (SHIVs) respectively(1-8), the long-term efficacy of a passive antibody transfer approach for HIV-1 has not been examined. Here we show, on the basis of the relatively long-term protection conferred by hepatitis A immune globulin, the efficacy of a single injection (20 mg kg(-1)) of four anti-HIV-1-neutralizing monoclonal antibodies (VRC01, VRC01-LS, 3BNC117, and 10-1074 (refs 9-12)) in blocking repeated weekly low-dose virus challenges of the clade B SHIVAD8. Compared with control animals, which required two to six challenges (median = 3) for infection, a single broadly neutralizing antibody infusion prevented virus acquisition for up to 23 weekly challenges. This effect depended on antibody potency and half-life. The highest levels of plasma-neutralizing activity and, correspondingly, the longest protection were found in monkeys administered the more potent antibodies 3BNC117 and 10-1074 (median = 13 and 12.5 weeks, respectively). VRC01, which showed lower plasma-neutralizing activity, protected for a shorter time (median = 8 weeks). The introduction of a mutation that extends antibody half-life into the crystallizable fragment (Fc) domain of VRC01 increased median protection from 8 to 14.5 weeks. If administered to populations at high risk of HIV-1 transmission, such an immunoprophylaxis regimen could have a major impact on virus transmission.

Individual cells within a tumour can exhibit distinct genetic and molecular features. The impact of such diversification on metastatic potential is unknown. Here we identify clonal human breast cancer subpopulations that display different levels of morphological and molecular diversity. Highly variable subpopulations are more proficient at metastatic colonization and chemotherapeutic survival. Through single-cell RNA-sequencing, inter-cell transcript expression variability is identified as a defining feature of the highly variable subpopulations that leads to protein-level variation. Furthermore, we identify high variability in the spliceosomal machinery gene set. Engineered variable expression of the spliceosomal gene SNRNP40 promotes metastasis, attributable to cells with low expression. Clinically, low SNRNP40 expression is associated with metastatic relapse. Our findings reveal transcriptomic variability generation as a mechanism by which cancer subpopulations can diversify gene expression states, which may allow for enhanced fitness under changing environmental pressures encountered during cancer progression.

Background: Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis. Objectives:We sought to report longer-term tofacitinib efficacy and safety in patients with moderate to severe psoriasis. Methods: Data from 2 identical phase-III studies, Oral-treatment Psoriasis Trial Pivotal 1 and 2, were pooled with data from these patients in an ongoing open-label long-term extension study. Patients (n = 1861) were randomized 2:2:1 to tofacitinib 5 mg, 10 mg, or placebo twice daily (BID). At week 16, placebo patients were rerandomized to tofacitinib. Pivotal study participants could enroll into the long-term extension where they received tofacitinib at 10 mg BID for 3 months, after which dosing could be 5 or 10 mg BID. Results: At week 28, the proportions of patients randomized to tofacitinib 5 and 10 mg BID achieving 75% or greater reduction in Psoriasis Area and Severity Index score from baseline were 55.6% and 68.8%, and achieving Physician Global Assessment of clear or almost clear were 54.7% and 65.9%. Efficacy was maintained in most patients through 24 months. Serious adverse events and discontinuations because of adverse events were reported in less than 11% of patients over 33 months of tofacitinib exposure. Limitations: There was no dose comparison beyond week 52. Conclusions: Oral tofacitinib demonstrated sustained efficacy in patients with psoriasis through 2 years, with 10 mg BID providing greater efficacy than 5 mg BID. No unexpected safety findings were observed.

Certain components and functions of the immune system, most notably cytokine production and immune cell migration, are under circadian regulation. Such regulation suggests that circadian rhythms may have an effect on disease onset, progression, and resolution. In the vesicular stomatitis virus (VSV)-induced encephalitis model, the replication, caudal penetration, and survivability of intranasally applied VSV depends on both innate and adaptive immune mechanisms. In the current study, we investigated the effect of circadian time of infection on the progression and outcome of VSV-induced encephalitis and demonstrated a significant decrease in the survival rate in mice infected at the start of the rest cycle, zeitgeber time 0 (ZT0). The lower survival rate in these mice was associated with higher levels of circulating chemokine (C-C motif) ligand 2 (CCL2), a greater number of peripherally derived immune cells accumulating in the olfactory bulb (OB), and increased production of proinflammatory cytokines, indicating an immune-mediated pathology. We also found that the acrophase of molecular circadian clock component REV-ERB alpha mRNA expression in the OB coincides with the start of the active cycle, ZT12, when VSV infection results in a more favorable outcome. This result led us to hypothesize that REV-ERB alpha may mediate the circadian effect on survival following VSV infection. Blocking REV-ERB alpha activity before VSV administration resulted in a significant increase in the expression of CCL2 and decreased survival in mice infected at the start of the active cycle. These data demonstrate that REV-ERB alpha-mediated inhibition of CCL2 expression during viral- induced encephalitis may have a protective effect.