The epidermal circadian clock integrates and subverts brain signals to guarantee skin homeostasis.

In mammals, the circadian clock network drives daily rhythms of tissue-specific homeostasis. To dissect daily inter-tissue communication, we constructed a mouse minimal clock network comprising only two nodes: the peripheral epidermal clock and the central brain clock. By transcriptomic and functional characterization of this isolated connection, we identified a gatekeeping function of the peripheral tissue clock with respect to systemic inputs.

Brain-muscle communication prevents muscle aging by maintaining daily physiology.

A molecular clock network is crucial for daily physiology and maintaining organismal health. We examined the interactions and importance of intratissue clock networks in muscle tissue maintenance. In arrhythmic mice showing premature aging, we created a basic clock module involving a central and a peripheral (muscle) clock.

2,6-Bis(pyrazol-1-yl)pyridine (1-bpp) as a General Ligand for the Negishi Alkylation of Alkylpyridinium Salts.

A Ni/1-bpp catalyst was demonstrated to be effective in the Negishi alkylation with multiple classes of alkylpyridinium salts, including α-primary and α-secondary. These conditions are also effective for benzylic pyridinium salts, demonstrating the successful Negishi alkylation of benzylic pyridinium salts for the first time. Further, 14 derivatives of 1-bpp were prepared with a variety of steric and electronic properties to study how these changes impact the success of the Negishi alkylation.

Liver and muscle circadian clocks cooperate to support glucose tolerance in mice.

Physiology is regulated by interconnected cell and tissue circadian clocks. Disruption of the rhythms generated by the concerted activity of these clocks is associated with metabolic disease. Here we tested the interactions between clocks in two critical components of organismal metabolism, liver and skeletal muscle, by rescuing clock function either in each organ separately or in both organs simultaneously in otherwise clock-less mice.

Getting the clock back on its feet: targeting the circadian clock to treat osteoarthritis.

Growing evidence suggests that circadian clock dysfunction may contribute to the pathology of osteoarthritis. In this issue, He et al. use in vivo and human-derived osteoarthritis models to demonstrate the therapeutic potential of pharmacologically manipulating components of the cartilage circadian clock.

The central clock suffices to drive the majority of circulatory metabolic rhythms.

Life on Earth anticipates recurring 24-hour environmental cycles via genetically encoded molecular clocks active in all mammalian organs. Communication between these clocks controls circadian homeostasis. Intertissue communication is mediated, in part, by temporal coordination of metabolism.

Integration of feeding behavior by the liver circadian clock reveals network dependency of metabolic rhythms.

The mammalian circadian clock, expressed throughout the brain and body, controls daily metabolic homeostasis. Clock function in peripheral tissues is required, but not sufficient, for this task. Because of the lack of specialized animal models, it is unclear how tissue clocks interact with extrinsic signals to drive molecular oscillations.

Deaminative Reductive Methylation of Alkylpyridinium Salts.

Methyl groups can imbue valuable properties in organic molecules, often leading to enhanced bioactivity. To enable efficient installation of methyl groups on simple building blocks and in late-stage functionalization, a nickel-catalyzed reductive coupling of secondary Katritzky alkylpyridinium salts with methyl iodide was developed. When coupled with formation of the pyridinium salt from an alkyl amine, this method allows amino groups to be readily transformed to methyl groups with broad functional group and heterocycle tolerance.

Collecting mouse livers for transcriptome analysis of daily rhythms.

Molecular daily rhythms can be captured by precisely timed tissue harvests from groups of animals. This protocol will allow the investigator to identify transcriptional rhythms in the mouse liver while also providing a template for similar analyses in other whole metabolic organs. We describe steps for mouse entrainment, liver dissection, and rhythmicity analysis from total RNA sequencing data.

Redistribution of EZH2 promotes malignant phenotypes by rewiring developmental programmes.

Epigenetic regulators are often hijacked by cancer cells to sustain malignant phenotypes. How cells repurpose key regulators of cell identity as tumour-promoting factors is unclear. The antithetic role of the Polycomb component EZH2 in normal brain and glioma provides a paradigm to dissect how wild-type chromatin modifiers gain a pathological function in cancer.

Electron transfer processes occurring on platinum neural stimulating electrodes: pulsing experiments for cathodic-first, charge-imbalanced, biphasic pulses for 0.566 ⩽ k ⩽ 2.3 in rat subcutaneous tissues.

Objective: Charge injection through platinum neural stimulation electrodes is often constrained by the Shannon limit (Shannon 1992 IEEE Trans. Biomed. Eng.

Electron transfer processes occurring on platinum neural stimulating electrodes: pulsing experiments for cathodic-first, charge-balanced, biphasic pulses for 0.566 ⩽ k ⩽ 2.3 in rat subcutaneous tissues.

Objective: Our mission is twofold: (1) find a way to safely inject more charge through platinum electrodes than the Shannon limit (k  =  1.75) permits and (2) nurture an interest in the neural stimulation community to understand the electron transfer process occurring on neural stimulating electrodes.

Approach: We report here on measurements of the electrode potential, performed on platinum neural stimulating electrodes in the subcutaneous space of an anesthetized rat under neural stimulation conditions.

A dynamic and adaptive network of cytosolic interactions governs protein export by the T3SS injectisome.

Many bacteria use a type III secretion system (T3SS) to inject effector proteins into host cells. Selection and export of the effectors is controlled by a set of soluble proteins at the cytosolic interface of the membrane spanning type III secretion 'injectisome'. Combining fluorescence microscopy, biochemical interaction studies and fluorescence correlation spectroscopy, we show that in live Yersinia enterocolitica bacteria these soluble proteins form complexes both at the injectisome and in the cytosol.

Electron transfer processes occurring on platinum neural stimulating electrodes: calculated charge-storage capacities are inaccessible during applied stimulation.

Objective: Neural prostheses employing platinum electrodes are often constrained by a charge/charge-density parameter known as the Shannon limit. In examining the relationship between charge injection and observed tissue damage, the electrochemistry at the electrode-tissue interface should be considered. The charge-storage capacity (CSC) is often used as a predictor of how much charge an electrode can inject during stimulation, but calculating charge from a steady-state i-E curve (cyclic voltammogram) over the water window misrepresents how electrodes operate during stimulation.

Electron transfer processes occurring on platinum neural stimulating electrodes: a tutorial on the i(V e) profile.

The aim of this tutorial is to encourage members of the neuroprosthesis community to incorporate electron transfer processes into their thinking and provide them with the tools to do so when they design and work with neurostimulating devices. The focus of this article is on platinum because it is the most used electrode metal for devices in commercial use. The i(V e) profile or cyclic voltammogram contains information about electron transfer processes that can occur when the electrode-electrolyte interface, V e, is at a specific potential, and assumed to be near steady-state conditions.

Electron transfer processes occurring on platinum neural stimulating electrodes: pulsing experiments for cathodic-first/charge-balanced/biphasic pulses for 0.566 ≤ k ≤ 2.3 in oxygenated and deoxygenated sulfuric acid.

The application of a train of cathodic-first/charge-balanced/biphasic pulses applied to a platinum electrode resulted in a positive creep of the anodic phase potential that increases with increasing charge injection but reaches a steady-state value before 1000 pulses have been delivered. The increase follows from the fact that charge going into irreversible reactions occurring during the anodic phase must equal the charge going into irreversible reactions during the cathodic phase for charge-balanced pulses. In an oxygenated electrolyte the drift of the measured positive potential moved into the platinum oxidation region of the i(V e) profile when the charge injection level exceeds k = 1.

Linear summation of torque produced by selective activation of two motor fascicles.

Linear summation of torque was observed while applying selective activation to two different motor fascicles in the cat sciatic nerve. The excitatory stimulus was applied to two or more contacts housed in a four contact self-sizing spiral cuff electrode. To achieve a linear summation of torque, a delay between the two stimuli that was longer than the length of the facilitatory period but less than the length of the refractory period was used.

Selective activation of the sacral anterior roots for induction of bladder voiding.

Aim: We investigated the efficacy of selective activation of the smaller diameter axons in the sacral anterior roots for electrically induced bladder voiding.

Materials And Methods: Acute experiments were conducted in five adult dogs. The anterior sacral roots S2 and S3 were implanted bilaterally with tripolar electrodes.

A preliminary feasibility study of different implantable pulse generators technologies for diaphragm pacing system.

Diaphragm pacing stimulation (DPS) for ventilator-dependent patients provides several advantages over conventional techniques such as phrenic nerve pacing or mechanical ventilator support. To date, the only existing system for DPS uses lead electrodes, percutaneously attached to an external pulse generator (PG). However, for a widespread use of this technique it would be more appropriate to eliminate the need for percutaneous wire and use a totally implantable system.

Phrenic nerve pacing via intramuscular diaphragm electrodes in tetraplegic subjects.

Context: Diaphragm pacing in ventilator-dependent tetraplegic subjects is usually achieved by the placement of phrenic nerve electrodes via thoracotomy. However, this technique may be accomplished less invasively via laparoscopic placement of IM electrodes, at a lower cost and with less risk of injury to the phrenic nerve.

Objective: To assess the feasibility of laparascopic placement of IM diaphragm electrodes to achieve long-term ventilatory support in ventilator-dependent tetraplegic subjects.

Mapping the phrenic nerve motor point: the key to a successful laparoscopic diaphragm pacing system in the first human series.

Background: For patients with high spinal cord injury and chronic respiratory insufficiency, electrically induced diaphragm pacing is an alternative to long-term positive pressure ventilation. The goal of this study was to laparoscopically assess the phrenic nerve motor point of the diaphragm and then implant electrodes to produce chronic negative pressure ventilation.

Methods: Patients undergoing elective laparoscopic procedures (volunteer patient group) underwent a series of electrical stimuli (2 to 24 mA at 100-microsecond pulse widths) with a mapping probe to identify the motor point through qualitative visualization of diaphragm motion and quantitative measurement of the abdominal pressure to assess the strength of the contraction.

Selective and independent activation of four motor fascicles using a four contact nerve-cuff electrode.

Any one of the four motor nerves in the cat sciatic nerve could be activated selectively and independently, from threshold to saturation, using a self-sizing spiral cuff electrode containing four radially placed monopolar contacts. These studies were carried out in nine adult cats with acute implants. Of the 36 possible fascicles, 23 fascicles could be activated selectively with current stimuli applied to a single contact and ten of the remaining fascicles could be activated selectively with current stimuli applied to two contacts, "field steering.

Characterization of the human diaphragm muscle with respect to the phrenic nerve motor points for diaphragmatic pacing.

Diaphragm pacing from laparoscopically placed electrodes is an alternative to conventional phrenic pacers that use electrodes placed in direct contact with the nerve in the neck or chest. The challenge with the laparoscopic approach is determining where to implant the electrodes, as the phrenic nerves are not visible from the abdomen. The objective of this study was to locate the phrenic nerve "motor points" in the human diaphragm muscle from an abdominal perspective.

Comparison of joint torque evoked with monopolar and tripolar-cuff electrodes.

Using a self-sizing spiral-cuff electrode placed on the sciatic nerve of the cat, the joint torque evoked with stimulation applied to contacts in a monopolar configuration was judged to be the same as the torque evoked by stimulation applied to contacts in a tripolar configuration. Experiments were carried out in six acute cat preparations. In each experiment, a 12-contact electrode was placed on the sciatic nerve and used to effect both the monopolar and tripolar electrode configurations.