Derivatives of vitamin B12 (cobalamin) are essential cofactors for enzymes required in intermediary metabolism. Defects in cobalamin metabolism lead to disorders characterized by the accumulation of methylmalonic acid and/or homocysteine in blood and urine. The most common inborn error of cobalamin metabolism, combined methylmalonic acidemia and hyperhomocysteinemia, cblC type, is caused by mutations in MMACHC. However, several individuals with presumed cblC based on cellular and biochemical analysis do not have mutations in MMACHC. We used exome sequencing to identify the genetic basis of an X-linked form of combined methylmalonic acidemia and hyperhomocysteinemia, designated cblX. A missense mutation in a global transcriptional coregulator, HCFC1, was identified in the index case. Additional male subjects were ascertained through two international diagnostic laboratories, and 13/17 had one of five distinct missense mutations affecting three highly conserved amino acids within the HCFC1 kelch domain. A common phenotype of severe neurological symptoms including intractable epilepsy and profound neurocognitive impairment, along with variable biochemical manifestations, was observed in all affected subjects compared to individuals with early-onset cblC. The severe reduction in MMACHC mRNA and protein within subject fibroblast lines suggested a role for HCFC1 in transcriptional regulation of MMACHC, which was further supported by the identification of consensus HCFC1 binding sites in MMACHC. Furthermore, siRNA-mediated knockdown of HCFC1 expression resulted in the coordinate downregulation of MMACHC mRNA. This X-linked disorder demonstrates a distinct disease mechanism by which transcriptional dysregulation leads to an inborn error of metabolism with a complex clinical phenotype.

As part of our ongoing search for technosignatures, we collected over three terabytes of data in 2017 May with the L-band receiver (1.15–1.73 GHz) of the 100 m diameter Green Bank Telescope. These observations focused primarily on planetary systems in the Kepler field, but also included scans of the recently discovered TRAPPIST-1 and LHS 1140 systems. We present the results of our search for narrowband signals in this data set with techniques that are generally similar to those described by Margot et al. Our improved data processing pipeline classified over 98% of the approximately six million detected signals as anthropogenic radio frequency interference (RFI). Of the remaining candidates, 30 were detected outside of densely populated frequency regions attributable to RFI. These candidates were carefully examined and determined to be of terrestrial origin. We discuss the problems associated with the common practice of ignoring frequency space around candidate detections in radio technosignature detection pipelines. These problems include inaccurate estimates of figures of merit and unreliable upper limits on the prevalence of technosignatures. We present an algorithm that mitigates these problems and improves the efficiency of the search. Specifically, our new algorithm increases the number of candidate detections by a factor of more than four compared to the results of Margot et al.

When a coronal mass ejection (CME) appears in a coronagraph it often exhibits three parts. This "classic" threepart configuration consists of a bright leading edge, a dark circular-or teardrop-shaped cavity, and a bright core within the cavity. It is generally accepted that these are manifestations of coronal plasma pileup, the driving magnetic flux rope, and the associated eruptive filament, respectively. The latter has become accepted by the community since coronagraph CMEs have been commonly associated with eruptive filaments for over 40 years. In this second part of our series challenging views on CMEs, we present the case that the inner core of the three-part coronagraph CME may not be, and in the most common cases is not, a filament. We present our case in the form of four exhibits showing that most of the CMEs in a broad survey are not associated with an eruptive filament at the Sun, and that the cores of those CMEs that are filament-associated do not geometrically resemble or consist of material from the associated filament. We conclude with a discussion on the possible causes of the bright CME core and what happens to the filament material postlaunch. We discuss how the CME core could arise spontaneously from the eruption of a flux rope from the Sun, or could be the result of a mathematical caustic produced by the geometric projection of a twisted flux rope.