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<jats:sec> <jats:title>INTRODUCTION</jats:title> <jats:p>Condensed-matter systems have recently become a fertile ground for the discovery of fermionic particles and phenomena predicted in high-energy physics; examples include Majorana fermions, as well as Dirac and Weyl semimetals. However, fermions in condensed-matter systems are not constrained by Poincare symmetry. Instead, they must only respect the crystal symmetry of one of the 230 space groups. Hence, there is the potential to find and classify free fermionic excitations in solid-state systems that have no high-energy counterparts.</jats:p> </jats:sec> <jats:sec> <jats:title>RATIONALE</jats:title> <jats:p> The guiding principle of our classification is to find irreducible representations of the little group of lattice symmetries at high-symmetry points in the Brillouin zone (BZ) for each of the 230 space groups (SGs), the dimension of which corresponds to the number of bands that meet at the high-symmetry point. Because we are interested in systems with spin-orbit coupling, we considered only the double-valued representations, where a 2π rotation gives a minus sign. Furthermore, we considered systems with time-reversal symmetry that squares to –1. For each unconventional representation, we computed the low-energy <jats:bold>k</jats:bold> · <jats:bold>p</jats:bold> Hamiltonian near the band crossings by writing down all terms allowed by the crystal symmetry. This allows us to further differentiate the band crossings by the degeneracy along lines and planes that emanate from the high-symmetry point, and also to compute topological invariants. For point degeneracies, we computed the monopole charge of the band-crossing; for line nodes, we computed the Berry phase of loops encircling the nodes. </jats:p> </jats:sec> <jats:sec> <jats:title>RESULTS</jats:title> <jats:p>We found that three space groups exhibit symmetry-protected three-band crossings. In two cases, this results in a threefold degenerate point node, whereas the third case results in a line node away from the high-symmetry point. These crossings are required to have a nonzero Chern number and hence display surface Fermi arcs. However, upon applying a magnetic field, they have an unusual Landau level structure, which distinguishes them from single and double Weyl points. Under the action of spatial symmetries, these fermions transform as spin-1 particles, as a consequence of the interplay between nonsymmorphic space group symmetries and spin. Additionally, we found that six space groups can host sixfold degeneracies. Two of these consist of two threefold degeneracies with opposite chirality, forced to be degenerate by the combination of time reversal and inversion symmetry, and can be described as “sixfold Dirac points.” The other four are distinct. Furthermore, seven space groups can host eightfold degeneracies. In two cases, the eightfold degeneracies are required; all bands come in groups of eight that cross at a particular point in the BZ. These two cases also exhibit fourfold degenerate line nodes, from which other semimetals can be derived: By adding strain or a magnetic field, these line nodes split into Weyl, Dirac, or line node semimetals. For all the three-, six- and eight-band crossings, nonsymmorphic symmetries play a crucial role in protecting the band crossing.</jats:p> <jats:p>Last, we found that seven space groups may host fourfold degenerate “spin-3/2” fermions at high symmetry points. Like their spin-1 counterparts, these quasiparticles host Fermi surfaces with nonzero Chern number. Unlike the other cases we considered, however, these fermions can be stabilized by both symmorphic and nonsymmorphic symmetries. Three space groups that host these excitations also host unconventional fermions at other points in the BZ.</jats:p> <jats:p>We propose nearly 40 candidate materials that realize each type of fermion near the Fermi level, as verified with ab initio calculations. Seventeen of these have been previously synthesized in single-crystal form, whereas others have been reported in powder form.</jats:p> </jats:sec> <jats:sec> <jats:title>CONCLUSION</jats:title> <jats:p> We have analyzed all types of fermions that can occur in spin-orbit coupled crystals with time-reversal symmetry and explored their topological properties. We found that there are several distinct types of such unconventional excitations, which are differentiated by their degeneracies at and along high-symmetry points, lines, and surfaces. We found natural generalizations of Weyl points: three- and four-band crossings described by a simple <jats:bold>k</jats:bold> · <jats:bold>S</jats:bold> Hamiltonian, where <jats:italic> S <jats:sub>i</jats:sub> </jats:italic> is the set of spin generators in either the spin-1 or spin-3/2 representations. These points carry a Chern number and, consequently, can exhibit Fermi arc surface states. We also found excitations with six- and eightfold degeneracies. These higher-band crossings create a tunable platform to realize topological semimetals by applying an external magnetic field or strain to the fourfold degenerate line nodes. Last, we propose realizations for each species of fermion in known materials, many of which are known to exist in single-crystal form. </jats:p> <jats:fig fig-type="figure" orientation="portrait" position="float"> <jats:caption> <jats:title>Fermi arcs from a threefold degeneracy.</jats:title> <jats:p>Shown is the surface density of states as a function of momentum for a crystal in SG 214 with bulk threefold degeneracies that project to (0.25, 0.25) and (–0.25, –0.25). Two Fermi arcs emanate from these points, indicating that their monopole charge is 2. The arcs then merge with the surface projection of bulk states near the origin.</jats:p> </jats:caption> <jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" orientation="portrait" position="float" xlink:href="353_aaf5037_fa.jpeg" /> </jats:fig> </jats:sec>

<jats:sec> <jats:title>BACKGROUND</jats:title> <jats:p>Prokaryotes have evolved multiple systems to combat invaders such as viruses and plasmids. Examples of such defense systems include receptor masking, restriction-modification (R-M) systems, DNA interference (Argonaute), bacteriophage exclusion (BREX or PGL), and abortive infection, all of which act in an innate, nonspecific manner. In addition, prokaryotes have evolved adaptive, heritable immune systems: clustered regularly interspaced palindromic repeats (CRISPR) and the CRISPR-associated proteins (CRISPR-Cas). Adaptive immunity is conferred by the integration of DNA sequences from an invading element into the CRISPR array (adaptation), which is transcribed into long pre-CRISPR RNAs (pre-crRNAs) and processed into short crRNAs (expression), which guide Cas proteins to specifically degrade the cognate DNA on subsequent exposures (interference).</jats:p> </jats:sec> <jats:sec> <jats:title>ADVANCES</jats:title> <jats:p>A plethora of distinct CRISPR-Cas systems are represented in genomes of most archaea and almost half of the bacteria. The latest CRISPR-Cas classification scheme delineates two classes that are each subdivided into three types. Integration of biochemistry and molecular genetics has contributed substantially to revealing many of the unique features of the variant CRISPR-Cas types. Additionally, structural analysis and single-molecule studies have further advanced our understanding of the molecular basis of CRISPR-Cas functionality. Recent progress includes relevant steps in the adaptation stage, when fragments of foreign DNA are processed and incorporated as new spacers into the CRISPR array. In addition, three novel CRISPR-Cas types (IV, V, and VI) have been identified, and in particular, the type V interference complexes have been experimentally characterized. Moreover, the ability to easily program sequence-specific DNA targeting and cleavage by CRISPR-Cas components, as demonstrated for Cas9 and Cpf1, allows for the application of CRISPR-Cas components as highly effective tools for genetic engineering and gene regulation in a wide range of eukaryotes and prokaryotes. The pressing issue of off-target cleavage by the Cas9 nuclease is being actively addressed using structure-guided engineering.</jats:p> </jats:sec> <jats:sec> <jats:title>OUTLOOK</jats:title> <jats:p>Although our understanding of the CRISPR-Cas system has increased tremendously over the past few years, much remains to be revealed. The continuing discovery of CRISPR-Cas variants will provide direct tests of the recently proposed modular scenario for the evolution of CRISPR-Cas systems. The recent discovery and characterization of new CRISPR-Cas types with previously unknown features implies that our current knowledge has relatively limited power for predicting the functional details of distantly related CRISPR-Cas variants. Hence, newly discovered CRISPR-Cas systems need to be dissected thoroughly to gain insight into their biological roles, to unravel their molecular mechanisms, and to harness their potential for biotechnology. Key outstanding questions regarding CRISPR-Cas biology include the ecological roles of microbial adaptive immunity, the high rates of CRISPR-Cas horizontal transfer, and the coevolution of CRISPR-Cas and phage-encoded anti-CRISPR proteins. Relatively little is known about the regulation of CRISPR-Cas expression, and about the roles of CRISPR-Cas in processes other than defense. With respect to the CRISPR-Cas mechanism, details illuminating the connection between the adaptation stage and the interference stage in primed spacer acquisition remain elusive. A key aspect of CRISPR-Cas that is poorly understood at present is self/nonself discrimination. The discrimination mechanisms seem to differ substantially among CRISPR variants. Recent comparison of class 2 type effector complexes (Cas9/Cpf1) has revealed overall architectural similarities as well as structural and mechanistic differences, as had previously been found for the distinct types of class 1 effector complexes (Cascade/Cmr). These variations may translate into complementary biotechnological applications. As well as innovative tools for basic research, CRISPR-associated effector complexes will be instrumental for developing the next generation of antiviral prophylactics and therapeutics. For applications in human gene therapy, improved methods for efficient and safe delivery of Cas9/Cpf1 and their guide RNAs to cells and tissues are still needed. Further insight into the basic details of CRISPR-Cas structure, functions, and biology—and characterization of new Cas effector proteins in particular—is crucial for optimizing and further expanding the diverse applications of CRISPR-Cas systems.</jats:p> <jats:fig fig-type="figure" orientation="portrait" position="float"> <jats:caption> <jats:title>Evolution of CRISPR-Cas systems resulted in incredible structural and functional diversity.</jats:title> <jats:p>Class 1 CRISPR-Cas systems are considered to be the evolutionary ancestral systems. The class 2 systems have evolved from class 1 systems via the insertion of transposable elements encoding various nucleases, and are now being used as tools for genome editing.</jats:p> </jats:caption> <jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" orientation="portrait" position="float" xlink:href="353_aad5147_fa.jpeg" /> </jats:fig> </jats:sec>

<jats:sec> <jats:title>INTRODUCTION</jats:title> <jats:p>Almost all archaea and about half of bacteria possess clustered regularly interspaced short palindromic repeat (CRISPR)–CRISPR-associated genes (Cas) adaptive immune systems, which protect microbes against viruses and other foreign DNA. All functionally characterized CRISPR systems have been reported to target DNA, with some multicomponent type III systems also targeting RNA. The putative class 2 type VI system, which has not been functionally characterized, encompasses the single-effector protein C2c2, which contains two Higher Eukaryotes and Prokaryotes Nucleotide-binding (HEPN) domains commonly associated with ribonucleases (RNases), suggesting RNA-guided RNA-targeting function.</jats:p> </jats:sec> <jats:sec> <jats:title>RATIONALE</jats:title> <jats:p> Existing studies have only established a role for RNA interference, in addition to DNA interference, in the multicomponent type III-A and III-B systems. We investigated the possibility of C2c2-mediated RNA inference by heterologously expressing C2c2 locus from <jats:italic>Leptotrichia shahii</jats:italic> (LshC2c2) in the model system <jats:italic>Escherichia coli.</jats:italic> The ability of LshC2c2 to protect against MS2 single-stranded RNA (ssRNA) phage infection was assessed by using every possible spacer sequence against the phage genome. We next developed protocols to reconstitute purified recombinant LshC2c2 protein and test its biochemical activity when incubated with its mature CRISPR RNA (crRNA) and target ssRNA. We systematically evaluated the parameters necessary for cleavage. Last, to demonstrate the potential utility of the LshC2c2 complex for RNA targeting in living bacterial cells, we guided it to knockdown red fluorescent protein (RFP) mRNA in vivo. </jats:p> </jats:sec> <jats:sec> <jats:title>RESULTS</jats:title> <jats:p> This work demonstrates the RNA-guided RNase activity of the putative type VI CRISPR-effector LshC2c2. Heterologously expressed C2c2 can protect <jats:italic>E. coli</jats:italic> from MS2 phage, and by screening against the MS2 genome, we identified a H (non-G) protospacer flanking site (PFS) following the RNA target site, which was confirmed by targeting a complementary sequence in the β-lactamase transcript followed by a degenerate nucleotide sequence. Using purified LshC2c2 protein, we demonstrate that C2c2 and crRNA are sufficient in vitro to achieve RNA-guided, PFS-dependent RNA cleavage. This cleavage preferentially occurs at uracil residues in ssRNA regions and depends on conserved catalytic residues in the two HEPN domains. Mutation of these residues yields a catalytically inactive RNA-binding protein. The secondary structure of the crRNA direct repeat (DR) stem is required for LshC2c2 activity, and mutations in the 3′ region of the DR eliminate cleavage activity. Targeting is also sensitive to multiple or consecutive mismatches in the spacer:protospacer duplex. C2c2 targeting of RFP mRNA in vivo results in reduced fluorescence. The knockdown of the RFP mRNA by C2c2 slowed <jats:italic>E. coli</jats:italic> growth, and in agreement with this finding, in vitro cleavage of the target RNA results in “collateral,” nonspecific cleavage of other RNAs present in the reaction mix. </jats:p> </jats:sec> <jats:sec> <jats:title>CONCLUSION</jats:title> <jats:p>LshC2c2 is a RNA-guided RNase which requires the activity of its two HEPN domains, suggesting previously unidentified mechanisms of RNA targeting and degradation by CRISPR systems. Promiscuous RNase activity of C2c2 after activation by the target slows bacterial growth and suggests that C2c2 could protect bacteria from virus spread via programmed cell death and dormancy induction. A single-effector RNA targeting system has the potential to serve as a general chassis for molecular tools for visualizing, degrading, or binding RNA in a programmable, multiplexed fashion.</jats:p> <jats:fig fig-type="figure" orientation="portrait" position="float"> <jats:caption> <jats:title>C2c2 is an RNA-guided RNase that provides protection against RNA phage.</jats:title> <jats:p> CRISPR-C2c2 from <jats:italic>L. shahii</jats:italic> can be reconstituted in <jats:italic>E. coli</jats:italic> to mediate RNA-guided interference of the RNA phage MS2. Biochemical characterization of C2c2 reveals crRNA-guided RNA cleavage facilitated by the two HEPN nuclease domains. Binding of the target RNA by C2c2-crRNA also activates a nonspecific RNase activity, which may lead to promiscuous cleavage of RNAs without complementarity to the crRNA guide sequence. </jats:p> </jats:caption> <jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" orientation="portrait" position="float" xlink:href="353_aaf5573_fa.jpeg" /> </jats:fig> </jats:sec>

<jats:p>Tools for judging the impact of publications are critical for scientific leaders, librarians, and individual investigators. An important, but certainly imperfect, measure of impact is the number of times that a paper is cited over time. Citation numbers for individual papers can be aggregated to develop indices that are used to evaluate the content of journals or productivity over the course of a career. Although these indices are convenient, it is important to examine them critically to avoid their misuse.</jats:p>

<jats:p>A roundup of weekly science policy and related news.</jats:p>

<jats:p>Only the most daring researchers now risk a trip to premier site in the American tropics.</jats:p>

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<jats:p>Brief preliminary proposals can't do justice to innovative research, scientists complain.</jats:p>