Inositol pyrophosphate profiling reveals regulatory roles of IP6K2-dependent enhanced IP7 metabolism in the enteric nervous system

Inositol pyrophosphates regulate diverse physiological processes; to better understand their functional roles, assessing their tissue-specific distribution is important. Here, we profiled inositol pyrophosphate levels in mammalian organs using an originally designed liquid chromatography-mass spectrometry (LC-MS) protocol and discovered that the gastrointestinal tract (GIT) contained the highest levels of diphosphoinositol pentakisphosphate (IP7) and its precursor inositol hexakisphosphate (IP6). Although their absolute levels in the GIT are diet dependent, elevated IP7 metabolism still exists under dietary regimens devoid of exogenous IP7. Of the major GIT cells, enteric neurons selectively express the IP7-synthesizing enzyme IP6K2. We found that IP6K2-knockout mice exhibited significantly impaired IP7 metabolism in the various organs including the proximal GIT. In addition, our LC-MS analysis displayed that genetic ablation of IP6K2 significantly impaired IP7 metabolism in the gut and duodenal muscularis externa containing myenteric plexus. Whole transcriptome analysis of duodenal muscularis externa further suggested that IP6K2 inhibition significantly altered expression levels of the gene sets associated with mature neurons, neural progenitor/stem cells, and glial cells, as well as of certain genes modulating neuronal differentiation and functioning, implying critical roles of the IP6K2-IP7 axis in developmental and functional regulation of the enteric nervous system. These results collectively reveal an unexpected role of mammalian IP7-a highly active IP6K2-IP7 pathway is conducive to the enteric nervous system

Shallow non-inversion tillage in organic farming maintains crop yields and increases soil C stocks: a meta-analysis

Reduced tillage is increasingly promoted to improve sustainability and productivity of agricultural systems. Nonetheless, adoption of reduced tillage by organic farmers has been slow due to concerns about nutrient supply, soil structure, and weeds that may limit yields. Here, we compiled the results from both published and unpublished research comparing deep or shallow inversion tillage, with various categories of reduced tillage under organic management. Shallow refers to less than 25 cm. We found that (1) division of reduced tillage practices into different classes with varying degrees of intensity allowed us to assess the trade-offs between reductions in tillage intensity, crop yields, weed incidence, and soil C stocks. (2) Reducing tillage intensity in organic systems reduced crop yields by an average of 7.6 % relative to deep inversion tillage with no significant reduction in yield relative to shallow inversion tillage. (3) Among the different classes of reduced tillage practice, shallow non-inversion tillage resulted in non-significant reductions in yield relative to deep inversion; whereas deep non-inversion tillage resulted in the largest yield reduction, of 11.6 %. (4) Using inversion tillage to only a shallow depth resulted in minimal reductions in yield, of 5.5 %, but significantly higher soil C stocks and better weed control. This finding suggests that this is a good option for organic farmers wanting to improve soil quality while minimizing impacts on yields. (5) Weeds were consistently higher, by about 50 %, when tillage intensity was reduced, although this did not always result in reduced yields

Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

This work was supported by a restricted research grant of Bayer AG

Stereoselective Heck Reactions with Vinyl Sulfoxides, Sulfides and Sulfones

We report the Heck cross-coupling of notoriously unreactive, but synthetically valuable olefins: vinyl sulfoxides, vinyl sulfones, and vinyl sulfides. Key findings include the importance of the sterically hindered (tri-tert-butyl)phosphine ligand and the unique effectiveness of triethylamine as the base. The method is general, E-selective, and can be used to synthesize disubstituted or trisubstituted olefins through simple adjustments of stoichiometry

Monolithically integrated femtosecond optical parametric oscillators

Synchronously pumped optical parametric oscillators (OPOs) are highly efficient sources of long-wavelength pulses and nonclassical light, making them invaluable for applications in spectroscopy, metrology, multi-photon microscopy, and quantum computation. Typical systems based on free-space cavities either operate non-degenerately, which limits their efficiency, or use active feedback control to achieve degenerate operation, which limits these systems to dedicated low-noise environments. In this work, we demonstrate a femtosecond monolithically integrated OPO. In contrast with bulk OPOs, our monolithic 10 GHz cavity, based on reverse-proton-exchanged lithium niobate, operates stably without active locking. By detuning the repetition rate of the free-running pump laser from the cavity free spectral range, we control the intracavity pulse dynamics and observe many of the operating regimes previously encountered in free-space degenerate OPOs, such as box-pulsing and quadratic bright-dark solitons (simultons), in addition to non-degenerate operation. When operated in the simulton regime and pumped with 125 fs pulses at 1 µm, this monolithic OPO chip outputs broadband sech² pulses (63 nm, 3 dB) with tens of milliwatts of average power.ISSN:2334-253

Considerations and recommendations for assessment of plasma protein binding and drug-drug interactions for siRNA therapeutics

At the time of writing, although four siRNA therapeutics have been approved for human use, no official regulatory guidance specific to this modality is available. In the absence of guidance, preclinical development for siRNA followed a hybrid of the small molecule (ICH M3(R2)) and biologics (ICH S6(R1)) guidance documents. However, siRNA differs significantly from small molecules and protein-based biologics in both its physicochemical and absorption, distribution, metabolism and excretion (ADME) properties, and its mechanism of action. Consequently, certain reports typically included in filing packages for small molecule or biologics may benefit from adaption, or even omission, from an siRNA filing. In this white paper, members of the ‘siRNA plasma protein binding and drug-drug interaction working group’ in the IQ consortium discuss the relevance of two such reports---the plasma protein binding (PPB) evaluation and the drug-drug interaction (DDI) risk assessment---to support siRNA regulatory filings. Publicly available siRNA approval packages and the literature were systematically reviewed to examine the role of siRNA PPB and DDIs in ADME, safety and translation. This information has been summarized into two decision trees to help guide industry to decide when siRNA PPB and DDI studies are warranted