Fragmentation in the biopharmaceutical industry.

The large number of biopharmaceutical mergers and acquisitions (M&A) that occurred over the past decade has generated questions about whether the industry is consolidating around too-few players, negatively impacting both the number of medicines developed and overall innovation. However, closer examination of the level of biopharmaceutical consolidation by prescription sales shows that the industry was more fragmented in 2015 than in 2003. The trend towards increasing fragmentation is also observed across noncommercial and independent metrics over the same time period. The number and size of M&A deals has masked an active and competitive marketplace in which market growth and the number of companies entering the market exceeded the apparent reduction in the number of players caused by acquisitions.

Lipid environment modulates the development of acute tolerance to ethanol in Caenorhabditis elegans.

The development of tolerance to a drug at the level of the neuron reflects a homeostatic mechanism by which neurons respond to perturbations of their function by external stimuli. Acute functional tolerance (AFT) to ethanol is a fast compensatory response that develops within a single drug session and normalizes neuronal function despite the continued presence of the drug. We performed a genetic screen to identify genes required for the development of acute functional tolerance to ethanol in the nematode C. elegans. We identified mutations affecting multiple genes in a genetic pathway known to regulate levels of triacylglycerols (TAGs) via the lipase LIPS-7, indicating that there is an important role for TAGs in the development of tolerance. Genetic manipulation of lips-7 expression, up or down, produced opposing effects on ethanol sensitivity and on the rate of development of AFT. Further, decreasing cholesterol levels through environmental manipulation mirrored the effects of decreased TAG levels. Finally, we found that genetic alterations in the levels of the TAG lipase LIPS-7 can modify the phenotype of gain-of-function mutations in the ethanol-inducible ion channel SLO-1, the voltage- and calcium-sensitive BK channel. This study demonstrates that the lipid milieu modulates neuronal responses to ethanol that include initial sensitivity and the development of acute tolerance. These results lend new insight into studies of alcohol dependence, and suggest a model in which TAG levels are important for the development of AFT through alterations of the action of ethanol on membrane proteins.

Developmental control of lateralized neuron size in the nematode Caenorhabditis elegans.

BACKGROUND: Nervous systems are generally bilaterally symmetric on a gross structural and organizational level but are strongly lateralized (left/right asymmetric) on a functional level. It has been previously noted that in vertebrate nervous systems, symmetrically positioned, bilateral groups of neurons in functionally lateralized brain regions differ in the size of their soma. The genetic mechanisms that control these left/right asymmetric soma size differences are unknown. The nematode Caenorhabditis elegans offers the opportunity to study this question with single neuron resolution. A pair of chemosensory neurons (ASEL and ASER), which are bilaterally symmetric on several levels (projections, synaptic connectivity, gene expression patterns), are functionally lateralized in that they express distinct chemoreceptors and sense distinct chemosensory cues. RESULTS: We describe here that ASEL and ASER also differ substantially in size (soma volume, axonal and dendritic diameter), a feature that is predicted to change the voltage conduction properties of the two sensory neurons. This difference in size is not dependent on sensory input or neuronal activity but developmentally programmed by a pathway of gene regulatory factors that also control left/right asymmetric chemoreceptor expression of the two ASE neurons. This regulatory pathway funnels via the DIE-1 Zn finger transcription factor into the left/right asymmetric distribution of nucleoli that contain the rRNA regulator Fibrillarin/FIB-1, a RNA methyltransferase implicated in the non-hereditary immune disease scleroderma, which we find to be essential to establish the size differences between ASEL and ASER. CONCLUSIONS: Taken together, our findings reveal a remarkable conservation of the linkage of functional lateralization with size differences across phylogeny and provide the first insights into the developmentally programmed regulatory mechanisms that control neuron size lateralities.

Lateralized gustatory behavior of C. elegans is controlled by specific receptor-type guanylyl cyclases.

BACKGROUND: Even though functional lateralization is a common feature of many nervous systems, it is poorly understood how lateralized neural function is linked to lateralized gene activity. A bilaterally symmetric pair of C. elegans gustatory neurons, ASEL and ASER, senses a number of chemicals in a left/right asymmetric manner and therefore serves as a model to study the genetic basis of functional lateralization. The extent of functional lateralization of the ASE neurons and genes responsible for the left/right asymmetric activity of ASEL and ASER is unknown. RESULTS: We show here that a substantial number of salt ions are sensed in a left/right asymmetric manner and that lateralized salt responses allow the worm to discriminate between distinct salt cues. To identify molecules that may be involved in sensing salt ions and/or transmitting such sensory information, we examined the chemotaxis behavior of animals harboring mutations in eight different receptor-type, transmembrane guanylyl cyclases (encoded by gcy genes), which are expressed in either ASEL (gcy-6, gcy-7, gcy-14), ASER (gcy-1, gcy-4, gcy-5, gcy-22), or ASEL and ASER (gcy-19). Disruption of a particular ASER-expressed gcy gene, gcy-22, results in a broad chemotaxis defect to nearly all salts sensed by ASER, as well as to a left/right asymmetrically sensed amino acid. In contrast, disruption of other gcy genes resulted in highly salt ion-specific chemosensory defects. CONCLUSIONS: Our findings broaden our understanding of lateralities in neural function, provide insights into how this laterality is molecularly encoded, and reveal an unusual multitude of molecules involved in gustatory signal transduction.

Empirical analysis of transcriptional activity in the Arabidopsis genome.

Functional analysis of a genome requires accurate gene structure information and a complete gene inventory. A dual experimental strategy was used to verify and correct the initial genome sequence annotation of the reference plant Arabidopsis. Sequencing full-length cDNAs and hybridizations using RNA populations from various tissues to a set of high-density oligonucleotide arrays spanning the entire genome allowed the accurate annotation of thousands of gene structures. We identified 5817 novel transcription units, including a substantial amount of antisense gene transcription, and 40 genes within the genetically defined centromeres. This approach resulted in completion of approximately 30% of the Arabidopsis ORFeome as a resource for global functional experimentation of the plant proteome.