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Significance The new species Homo naledi was discovered in 2013 in a remote cave chamber of the Rising Star cave system, South Africa. This species survived until between 226,000 and 335,000 y ago, placing it in continental Africa at the same time as the early ancestors of modern humans were arising. Yet, H. naledi was strikingly primitive in many aspects of its anatomy, including the small size of its brain. Here, we have provided a description of endocast anatomy of this primitive species. Despite its small brain size, H. naledi shared some aspects of human brain organization, suggesting that innovations in brain structure were ancestral within the genus Homo .

Hominin cranial remains from the Dinaledi Chamber, South Africa, represent multiple individuals of the species

Purpose The purpose of this paper is to discuss the implementation of a skills development project aimed at increasing the technology competencies of participating librarians in Columbia University’s Science & Engineering Libraries, in response to changing instructional needs. Design/methodology/approach Adopting a DIY or Maker learning model gave librarians a perfect opportunity to experience learning new technology skills just as their users encounter them. Findings The authors conclude that this collaborative project methodology could potentially fit a large variety of different library environments, providing other institutions with an excellent opportunity to reassess and revamp staff skills, no matter their instructional focus. Originality/value The literature notes that previous library staff training models were largely devised for newly matriculated Library and Information Science graduates preparing to enter the workforce. Burgeoning technology developments require libraries to explore novel methods to expose staff to new technology skills; this case study applies the programmatic lens of the Maker Movement to a collaborative staff learning model.

Introductory materials science and engineering courses universally include the study of crystal structure and unit cells, which are by their nature highly visual 3D concepts. Traditionally, such topics are explored with 2D drawings or perhaps a limited set of difficult-to-construct 3D models. The rise of 3D printing, coupled with the wealth of freely available crystallographic data online, offers an elegant solution to materials science visualization problems. Here, we report a concise and up-to-date method to easily and rapidly transform actual crystallography files to 3D models of diverse unit cells for use as instructional aids.

G-protein-coupled receptors (GPCRs) are important mediators of signal transduction, and mutations in GPCR-encoding genes can lead to disease states. Here we describe a null mutation in an orphan GPCR-encoding gene that is predicted to inactivate completely the encoded receptor. The TA 3 receptor is a putative member of the recently described mammalian trace amine receptor family, and it is expressed in the pituitary gland and skeletal muscle. We tested for the presence of the mutant form of TA 3 (named TA 3 -TR ) in a normal population, as well as in two disease groups (ADHD and bipolar affective disorder). We found TA 3 -TR to be commonly expressed in all groups, with ∼20% allele frequency. We did not find any statistically significant correlation between either disease and the presence of TA 3 -TR .

G-protein-coupled receptors (GPCRs) are important mediators of signal transduction and targets for pharmacological therapeutics. Novel receptor-ligand systems have been discovered through the identification and analysis of orphan GPCRs (oGPCRs). Here we describe the discovery of seven novel human genes encoding oGPCRs. Each novel oGPCR gene was discovered using customized searches of the GenBank genomic databases with previously known GPCR-encoding sequences. The expressed genes can now be used in assays to determine endogenous and pharmacological ligands. GPR133, GPR134, GPR135, GPR136, and GPR137 share identities with a prostate-specific odorant-like GPCR-encoding gene (PSGR). GPR138 and GPR139 share identities with an odorant-like gene derived from human erythroid cells. Transcripts encoding GPR133, GPR134, GPR135, GPR136, and GPR137 were detected in various CNS tissues. The expression of odorant-like genes in non-olfactory tissues requires further clarification, which may be achieved through the search for endogenous cognate ligands for these and other oGPCRs.

(Cell 146, 359–371; August 5, 2011)In this paper, we described the directed conversion of skin fibroblasts from unaffected individuals or familial Alzheimer’s disease patients into human induced neuronal cells. We also presented molecular analyses of Alzheimer’s-associated markers in these cells. Dr. Ryousuke Fujita, who was specifically and only responsible for the molecular analyses of Alzheimer’s-associated pathology, has acknowledged inappropriately manipulating image panels and data points, as well as misrepresenting the number of repeats performed, in the experiments presented in Figures 6 and 7 of the paper (and corresponding Figures S5 and S6). We are in the process of repeating these analyses. Given these issues, we believe that the most appropriate course of action is to retract the paper. We deeply regret this circumstance and apologize to the community.

A paradigm shift has occurred in the post-genomic age where genes are rapidly identified using homology based experimental and computational approaches. The intellectual property (IP) rights to these genes as research tools has changed the nature of what is being patented, by whom and for what purpose. The traditional idea of an invention's commercial value has been altered from having an intrinsic value to having potential value in biomedical research as a therapeutic target. Companies and universities alike are filing patents on discovered genes in order to license them for scientific research or simply to ensure freedom to operate for internal investigation without threat of infringement. The IP of one protein family in particular is the focus of this review. G-protein-coupled receptors are proven to be important drug targets and therefore, the number of patent filings on the genes, proteins and uses of these receptors currently exceeds the number of receptors themselves. A profile of the current paten...

The terminal half of the 5′ untranslated region (UTR) in the (+)-strand RNA genome of tomato bushy stunt virus was analyzed for possible roles in viral RNA replication. Computer-aided thermodynamic analysis of secondary structure, phylogenetic comparisons for base-pair covariation, and chemical and enzymatic solution structure probing were used to analyze the 78 nucleotide long 5′-terminal sequence. The results indicate that this sequence adopts a branched secondary structure containing a three-helix junction core. The T-shaped domain (TSD) formed by this terminal sequence is closed by a prominent ten base-pair long helix, termed stem 1 (S1). Deletion of either the 5′ or 3′ segment forming S1 (coordinates 1–10 or 69–78, respectively) in a model subviral RNA replicon, i.e. a prototypical defective interfering (DI) RNA, reduced in vivo accumulation levels of this molecule approximately 20-fold. Compensatory-type mutational analysis of S1 within this replicon revealed a strong correlation between formation of the predicted S1 structure and efficient DI RNA accumulation. RNA decay studiesin vivodid not reveal any notable changes in the physical stabilities of DI RNAs containing disrupted S1s, thus implicating RNA replication as the affected process. Further investigation revealed that destabilization of S1 in the (+)-strand was significantly more detrimental to DI RNA accumulation than (−)-strand destabilization, therefore S1-mediated activity likely functions primarily via the (+)-strand. The essential role of S1 in DI RNA accumulation prompted us to examine the 5′-proximal secondary structure of a previously identified mutant DI RNA, RNA B, that lacks the 5′ UTR but is still capable of low levels of replication. Mutational analysis of a predicted S1-like element present within a cryptic 5′-terminal TSD confirmed the importance of the former in RNA B accumulation. Collectively, these data support a fundamental role for the TSD, and in particular its S1 subelement, in tombusvirus RNA replication.

α-Synuclein is implicated both in physiological functions at neuronal synaptic terminals as well as in pathological processes in the context of Parkinson's disease. However, the molecular mechanisms for these apparently diverse roles are unclear. Here we show that specific RNA transcript isoforms of α-synuclein with an extended 3' untranslated region, termed aSynL, appear selectively linked to pathological processes, relative to shorter α-synuclein transcripts. Common variants in the aSynL 3' untranslated region associated with Parkinson's disease risk promote the accumulation and translation of aSynL transcripts. The presence of intracellular dopamine can further enhance the relative abundance of aSynL transcripts through alternative polyadenylation site selection. We demonstrate that the presence of the extended aSynL transcript 3' untranslated region impacts accumulation of α-synuclein protein, which appears redirected away from synaptic terminals and towards mitochondria, reminiscent of Parkinson's disease pathology. Taken together, these findings identify a novel mechanism for aSyn regulation in the context of Parkinson's disease-associated genetic and environmental variations.

Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by using the pluripotency factors Oct4, Sox2, Klf4 and c-Myc (together referred to as OSKM)1. iPSC reprogramming erases somatic epigenetic signatures—as typified by DNA methylation or histone modification at silent pluripotency loci—and establishes alternative epigenetic marks of embryonic stem cells (ESCs)2. Here we describe an early and essential stage of somatic cell reprogramming, preceding the induction of transcription at endogenous pluripotency loci such as Nanog and Esrrb. By day 4 after transduction with OSKM, two epigenetic modification factors necessary for iPSC generation, namely poly(ADP-ribose) polymerase-1 (Parp1) and ten-eleven translocation-2 (Tet2), are recruited to the Nanog and Esrrb loci. These epigenetic modification factors seem to have complementary roles in the establishment of early epigenetic marks during somatic cell reprogramming: Parp1 functions in the regulation of 5-methylcytosine (5mC) modification, whereas Tet2 is essential for the early generation of 5-hydroxymethylcytosine (5hmC) by the oxidation of 5mC (refs 3,4). Although 5hmC has been proposed to serve primarily as an intermediate in 5mC demethylation to cytosine in certain contexts5–7, our data, and also studies of Tet2-mutant human tumour cells8, argue in favour of a role for 5hmC as an epigenetic mark distinct from 5mC. Consistent with this, Parp1 and Tet2 are each needed for the early establishment of histone modifications that typify an activated chromatin state at pluripotency loci, whereas Parp1 induction further promotes accessibility to the Oct4 reprogramming factor. These findings suggest that Parp1 and Tet2 contribute to an epigenetic program that directs subsequent transcriptional induction at pluripotency loci during somatic cell reprogramming.

MicroRNAs (miRNAs) are evolutionarily conserved, 18- to 25-nucleotide, non–protein coding transcripts that posttranscriptionally regulate gene expression during development. miRNAs also occur in postmitotic cells, such as neurons in the mammalian central nervous system, but their function is less well characterized. We investigated the role of miRNAs in mammalian midbrain dopaminergic neurons (DNs). We identified a miRNA, miR-133b, that is specifically expressed in midbrain DNs and is deficient in midbrain tissue from patients with Parkinson's disease. miR-133b regulates the maturation and function of midbrain DNs within a negative feedback circuit that includes the paired-like homeodomain transcription factor Pitx3. We propose a role for this feedback circuit in the fine-tuning of dopaminergic behaviors such as locomotion.

Midbrain dopamine (DA) neurons play a central role in the regulation of voluntary movement, and their degeneration is associated with Parkinson’s disease. Cell replacement therapies, and in particular embryonic stem (ES) cell-derived DA neurons, offer a potential therapeutic venue for Parkinson’s disease. We sought to identify genes that can potentiate maturation of ES cell cultures to the midbrain DA neuron phenotype. A number of transcription factors have been implicated in the development of midbrain DA neurons by expression analyses and loss-of-function knockout mouse studies, including Nurr1, Pitx3, Lmx1b, Engrailed-1, and Engrailed-2. However, none of these factors appear sufficient alone to induce the mature midbrain DA neuron phenotype in ES cell cultures in vitro , suggesting a more complex regulatory network. Here we show that Nurr1 and Pitx3 cooperatively promote terminal maturation to the midbrain DA neuron phenotype in murine and human ES cell cultures.

We report the identification, cloning and tissue distributions of ten novel human genes encoding G protein-coupled receptors (GPCRs) GPR78, GPR80, GPR81, GPR82, GPR93, GPR94, GPR95, GPR101, GPR102, GPR103 and a pseudogene, psi GPR79. Each novel orphan GPCR (oGPCR) gene was discovered using customized searches of the GenBank high-throughput genomic sequences database with previously known GPCR-encoding sequences. The expressed genes can now be used in assays to determine endogenous and pharmacological ligands. GPR78 shared highest identity with the oGPCR gene GPR26 (56% identity in the transmembrane (TM) regions). psi GPR79 shared highest sequence identity with the P2Y(2) gene and contained a frame-shift truncating the encoded receptor in TM5, demonstrating a pseudogene. GPR80 shared highest identity with the P2Y(1) gene (45% in the TM regions), while GPR81, GPR82 and GPR93 shared TM identities with the oGPCR genes HM74 (70%), GPR17 (30%) and P2Y(5) (40%), respectively. Two other novel GPCR genes, GPR94 and GPR95, encoded a subfamily with the genes encoding the UDP-glucose and P2Y(12) receptors (sharing >50% identities in the TM regions). GPR101 demonstrated only distant identities with other GPCR genes and GPR102 shared identities with GPR57, GPR58 and PNR (35-42% in the TM regions). GPR103 shared identities with the neuropeptide FF 2, neuropeptide Y2 and galanin GalR1 receptors (34-38% in the TM regions). Northern analyses revealed GPR78 mRNA expression in the pituitary and placenta and GPR81 expression in the pituitary. A search of the GenBank databases with the GPR82 sequence retrieved an identical sequence in an expressed sequence tag (EST) partially encoding GPR82 from human colonic tissue. The GPR93 sequence retrieved an identical, human EST sequence from human primary tonsil B-cells and an EST partially encoding mouse GPR93 from small intestinal tissue. GPR94 was expressed in the frontal cortex, caudate putamen and thalamus of brain while GPR95 was expressed in the human prostate and rat stomach and fetal tissues. GPR101 revealed mRNA transcripts in caudate putamen and hypothalamus. GPR103 mRNA signals were detected in the cortex, pituitary, thalamus, hypothalamus, basal forebrain, midbrain and pons.

Directed conversion of mature human cells, as from fibroblasts to neurons, is of potential clinical utility for neurological disease modeling as well as cell therapeutics. Here, we describe the efficient generation of human-induced neuronal (hiN) cells from adult skin fibroblasts of unaffected individuals and Alzheimer's patients, using virally transduced transcription regulators and extrinsic support factors. hiN cells from unaffected individuals display morphological, electrophysiological, and gene expression profiles that typify glutamatergic forebrain neurons and are competent to integrate functionally into the rodent CNS. hiN cells from familial Alzheimer disease (FAD) patients with presenilin-1 or -2 mutations exhibit altered processing and localization of amyloid precursor protein (APP) and increased production of Aβ, relative to the source patient fibroblasts or hiN cells from unaffected individuals. Together, our findings demonstrate directed conversion of human fibroblasts to a neuronal phenotype and reveal cell type-selective pathology in hiN cells derived from FAD patients.