KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia.

Variants in the KIF1A gene can cause autosomal recessive spastic paraplegia 30, autosomal recessive hereditary sensory neuropathy, or autosomal (de novo) dominant mental retardation type 9. More recently, variants in KIF1A have also been described in a few cases with autosomal dominant spastic paraplegia. Here, we describe 20 KIF1A variants in 24 patients from a clinical exome sequencing cohort of 347 individuals with a mostly 'pure' spastic paraplegia. In these patients, spastic paraplegia was slowly progressive and mostly pure, but with a highly variable disease onset (0-57 years). Segregation analyses showed a de novo occurrence in seven cases, and a dominant inheritance pattern in 11 families. The motor domain of KIF1A is a hotspot for disease causing variants in autosomal dominant spastic paraplegia, similar to mental retardation type 9 and recessive spastic paraplegia type 30. However, unlike these allelic disorders, dominant spastic paraplegia was also caused by loss-of-function variants outside this domain in six families. Finally, three missense variants were outside the motor domain and need further characterization. In conclusion, KIF1A variants are a frequent cause of autosomal dominant spastic paraplegia in our cohort (6-7%). The identification of KIF1A loss-of-function variants suggests haploinsufficiency as a possible mechanism in autosomal dominant spastic paraplegia.

Safety Concerns About an Epidural Blood Patch in a Patient with Extensive Epidural Fluid Accumulation.

We present a case of postdural puncture headache in a patient with extensive epidural fluid accumulation. An initial epidural blood patch was aborted because of concern about increased risk of complications. After magnetic resonance imaging, we proceeded with epidural blood patch with a good therapeutic result. We discuss the imaging results and safety concerns we considered when assessing the benefits and risks of epidural blood patch in this patient.

Loss of vision as a presenting sign of cobalamin deficiency: An eye-opener.

We describe a patient who presented with loss of vision that turned out to be caused by cobalamin deficiency. Both her vision and her visual field improved upon supplementation of cobalamin. It is, therefore, important to consider cobalamin deficiency as a treatable cause of loss of vision.

Membrane depolarization mediates phosphorylation and nuclear translocation of CREB in vascular smooth muscle cells.

Diverse signals have the potential to modulate gene transcription through the Ca2+ and cAMP response element binding protein (CREB) in vascular smooth muscle cells (VSMCs). A key step in the transmission of these signals is import into the nucleus. Here, we provide evidence that the Ran GTPase, which regulates nuclear import, exerts different regulation over PDGF-BB, Ca2+, and cAMP signaling to CREB in VSMCs. PDGF-BB, membrane depolarization, and forskolin increased levels of activated CREB (P-CREB) and c-fos in VSMCs and intact aorta. The calcium channel antagonist nimodipine reduced the level of P-CREB stimulated by membrane depolarization, but not by PDGF-BB or forskolin. Block of Ran-mediated nuclear import, by wheat germ agglutinin or an inactivating Ran mutant (T24N Ran), significantly reduced nuclear P-CREB in response to PDGF-BB or membrane depolarization, but enhanced levels of P-CREB in response to forskolin. Contrary to expectation, block of nuclear import led to the appearance of P-CREB in the cytoplasm after depolarization. Furthermore, blocking nuclear export with leptomycin B reduced P-CREB stimulation by both depolarization and PDGF-BB. These results suggest that translocation of CREB between the nucleus and the cytoplasm provides an important role in CREB activating pathways in VSMCs.

Overgrowth competition between clades: implications for interpretation of the fossil record and overgrowth indices.

Overgrowth interactions (2693 in total) were observed among three major groups (arguably clades) of bryozoans--cheilostomatids (57 species), ctenostomatids (3 species), and cyclostomatids (14 species). The bryozoans studied here occur in shallow water at high-temperate polar latitudes where they encrust hard substrata such as rock piles. The main study site was the intertidal and infralittoral zones of Kodiak Island, Alaska, but observations were also made in similar zones of South Georgia Island and the Falkland Islands in the South Atlantic Ocean. Cheilostomatids dominated the number of species, individuals, and interactions at all depths. Intraclade interactions formed 73.7% of the encounters for cheilostomatids, 1.6% for ctenostomatids, and 5.7% for cyclostomatids. The competitive ranking of the three clades was broadly ctenostomatids > cyclostomatids > cheilostomatids. Significantly, these results contradict all previous quantitative studies of bryozoan overgrowth, in which cheilostomatids are reported to overgrow cyclostomatids at a higher rate. From these studies and the literature, we calculated win indices to vary from 0 to 0.42 for living cyclostomatids, from 0.08 to 0.9 for living cheilostomatids, and from 0.25 to 0.75 for living ctenostomatids. The win indices of cyclostomatid and cheilostomatid clades show significantly more variation in living assemblages than in fossil assemblages. This disparity may be due to differential preservation (polar and subpolar assemblages last less than 4 years). The diversity was very high in terms of both species richness and interaction types (outcomes between competitor pairs). Comparison with the literature suggests the possibility that nearshore diversity of bryozoans may be bimodal (have two peaks) between high arctic and antarctic latitudes. Indices of success in overgrowth competition have been constructed in various ways. For cheilostomatids, the method of calculation had little influence on the ranking of representatives. In contrast, the apparent success of ctenostomatids and cyclostomatids varied hugely with how the index was calculated. This inconsistency is due to the use of very different strategies in overgrowth competition; among the two latter groups, many interactions involve tied outcomes.

Over one-half billion years of head conservation? Expression of an ems class gene in Hydractinia symbiolongicarpus (Cnidaria: Hydrozoa).

We report the isolation of an empty spiracles class homeodomain-containing gene, Cn-ems, from the hydrozoan Hydractinia symbiolongicarpus, the first gene of this class characterized in a lower metazoan. Cn-ems was found to be expressed in the head of gastrozooids, specifically in endodermal epithelial cells of the taeniolae of the hypostome. Cn-ems is not expressed in gonozooids, which lack taeniolae. Experimental conversion of the posterior region of the planula larva into head structures up-regulates expression of the gene. These findings establish that the association of ems-class genes with head structures preceded the evolution of bilateral symmetry.

A new species of microporella (bryozoa, cheilostomata) from alaska.

Microporella speciosa sp. nov. is described from Alaska, USA. The new species is characterized by the following combination of features: 1) semicircular orifice with slightly curved and faintly denticu-late proximal edge having a straight, shallow groove, 2) two distal oral spines, 3) laterally directed avicularian rostrum with a broad, channeled tip, 4) open frontal pores, and 5) completely calcified basal walls. Opercula, avicularian mandibles, the ancestrula, and early ontogeny are also described.

A PCR-based survey of homeobox genes in Ctenodrilus serratus (Annelida: Polychaeta).

The polychaete worm Ctenodrilus serratus was surveyed for the presence of HOM/HOX and engrailed-type homeobox genes using PCR with degenerate primers. Sixteen unique homeobox fragments were found in surveys of genomic and cDNA with three different primer sets. For three fragments, RACE was employed to obtain additional homeobox sequence and the 3' flanking region. Nine HOM/HOX-type fragments were identified, including putative representatives of the Hox1/lab, Hox2/pb, Hox3, Hox4/Dfd, and Antp/Lox5 cognate groups. Two additional Antp-like fragments could not be assigned specific orthology. Presence of an ortholog of leech Lox2 in addition to a Ubx/abdA-like gene suggests that independent duplications of a single precursor occurred in the annelid and arthropod lineages. No representative of the Hox9/AbdB group was identified. Our results are consistent with a hypothesis of a single HOM/HOX cluster in Ctenodrilus as extensive as that seen in strongly tagmatized arthropods, suggesting that the primitive role of these genes even in overtly metameric animals was something other than specification of overt segmental differentiation. The primers used also detected representatives of six other homeobox classes or families: Xlox (XlHbox8/HTr-A2), Ovx (Chox7), caudal, Prh (proline-rich homeobox), NEC (ceh-9/Tghbox5), and engrailed.