Simultaneous electrophysiology and fiber photometry in freely behaving mice

In vivo electrophysiology is the gold standard technique used to investigate sub-second neural dynamics in freely behaving animals. However, monitoring cell-type-specific population activity is not a trivial task. Over the last decade, fiber photometry based on genetically encoded calcium indicators (GECIs) has been widely adopted as a versatile tool to monitor cell-type-specific population activity in vivo. However, this approach suffers from low temporal resolution. Here, we combine these two approaches to monitor both sub-second field potentials and cell-type-specific population activity in freely behaving mice. By developing an economical custom-made system and constructing a hybrid implant of an electrode and a fiber optic cannula, we simultaneously monitor artifact-free mesopontine field potentials and calcium transients in cholinergic neurons across the sleep-wake cycle. We find that mesopontine cholinergic activity co-occurs with sub-second pontine waves, called P-waves, during rapid eye movement sleep. Given the simplicity of our approach, simultaneous electrophysiological recording and cell-type-specific imaging provides a novel and valuable tool for interrogating state-dependent neural circuit dynamics in vivo

Depth-specific optogenetic control in vivo with a scalable, high density µLED neural probe

Controlling neural circuits is a powerful approach to uncover a causal link between neural activity and behaviour. Optogenetics has been widely adopted by the neuroscience community as it offers cell-type-specific perturbation with millisecond precision. However, these studies require light delivery in complex patterns with cellular-scale resolution, while covering a large volume of tissue at depth in vivo. Here we describe a novel high-density silicon-based microscale light-emitting diode (µLED) array, consisting of up to ninety-six 25 µm-diameter µLEDs emitting at a wavelength of 450 nm with a peak irradiance of 400 mW/mm2. A width of 100 µm, tapering to a 1 µm point, and a 40 µm thickness help minimise tissue damage during insertion. Thermal properties permit a set of optogenetic operating regimes, with ~0.5°C average temperature increase. We demonstrate depth-dependent activation of mouse neocortical neurons in vivo, offering an inexpensive novel tool for the precise manipulation of neural activity

Thermal and optical characterization of micro-LED probes for in vivo optogenetic neural stimulation

Within optogenetics there is a need for compact light sources that are capable of delivering light with excellent spatial, temporal, and spectral resolution to deep brain structures. Here, we demonstrate a custom GaN-based LED probe for such applications and the electrical, optical, and thermal properties are analyzed. The output power density and emission spectrum were found to be suitable for stimulating channelrhodopsin-2, one of the most common light-sensitive proteins currently used in optogenetics. The LED device produced high light intensities, far in excess of those required to stimulate the light-sensitive proteins within the neurons. Thermal performance was also investigated, illustrating that a broad range of operating regimes in pulsed mode are accessible while keeping a minimum increase in temperature for the brain (0.5°C). This type of custom device represents a significant step forward for the optogenetics community, allowing multiple bright excitation sites along the length of a minimally invasive neural probe

The intranuclear PEX domain of MMP involves proliferation, migration, and metastasis of aggressive adenocarcinoma cells

Members of matrix metalloproteinase (MMP) family promote cancer cell migration, invasion, and metastasis through alteration of the tumor milieu, intracellular signaling pathways, and transcription. We examined gene expression signatures of colon adenocarcinoma cell lines with different metastatic potentials and found that rapidly metastatic cells powerfully expressed genes encoding MMP3 and MMP9. The non-proteolytic PEX isoform and proteolytic isoforms of MMPs were significantly expressed in the metastatic cells in vitro. Knockdown of MMP3 attenuated cancer cell migration and invasion in vitro and lung metastasis in vivo. Profound nuclear localization of MMP3/PEX was found in tumor-stroma marginal area. In contrast, MMP9 was localized in central area of subcutaneous tumors. Overexpression of the PEX isoform of MMP3 promoted proliferation and migration of the rapidly metastatic cells in vitro. Taken together, the non-proteolytic PEX isoform of MMPs locating in cell nuclei involves proliferation, migration, and subsequent metastasis of aggressive adenocarcinoma cells

Mutation of neuron-specific chromatin remodeling subunit BAF53b:rescue of plasticity and memory by manipulating actin remodeling

Recent human exome-sequencing studies have implicated polymorphic Brg1-associated factor (BAF) complexes (mammalian SWI/SNF chromatin remodeling complexes) in several intellectual disabilities and cognitive disorders, including autism. However, it remains unclear how mutations in BAF complexes result in impaired cognitive function. Post-mitotic neurons express a neuron-specific assembly, nBAF, characterized by the neuron-specific subunit BAF53b. Subdomain 2 of BAF53b is essential for the differentiation of neuronal precursor cells into neurons. We generated transgenic mice lacking subdomain 2 of Baf53b (BAF53b Delta SB2). Long-term synaptic potentiation (LTP) and long-term memory, both of which are associated with phosphorylation of the actin severing protein cofilin, were assessed in these animals. A phosphorylation mimic of cofilin was stereotaxically delivered into the hippocampus of BAF53b Delta SB2 mice in an effort to rescue LTP and memory. BAF53b Delta SB2 mutant mice show impairments in phosphorylation of synaptic cofilin, LTP, and memory. Both the synaptic plasticity and memory deficits are rescued by overexpression of a phosphorylation mimetic of cofilin. Baseline physiology and behavior were not affected by the mutation or the experimental treatment. This study suggests a potential link between nBAF function, actin cytoskeletal remodeling at the dendritic spine, and memory formation. This work shows that a targeted manipulation of synaptic function can rescue adult plasticity and memory deficits caused by manipulations of nBAF, and thereby provides potential novel avenues for therapeutic development for multiple intellectual disability disorders

Bioavailability of iodine in the UK-Peak District environment and its human bioaccessibility: an assessment of the causes of historical goitre in this area

Iodine is an essential micronutrient for human health. Its deficiency causes a number of functional and developmental abnormalities such as goitre. The limestone region of Derbyshire, UK was goitre-endemic until it declined from the 1930s and the reason for this has escaped a conclusive explanation. The present study investigates the cause(s) of goitre in the UK-Peak District area through an assessment of iodine in terms of its environmental mobility, bioavailability, uptake into the food chain and human bioaccessibility. The goitre-endemic limestone area is compared with the background millstone grit area of the UK-Peak District. The findings of this study show that ‘total’ environmental iodine is not linked to goitre in the limestone area, but the governing factors include iodine mobility, bioavailability and bioaccessibility. Compared with the millstone grit area, higher soil pH and calcium content of the limestone area restrict iodine mobility in this area, also soil organic carbon in the limestone area is influential in binding the iodine to the soil. Higher calcium content in the limestone area is an important factor in terms of strongly fixing the iodine to the soil. Higher iodine bioaccessibility in the millstone grit than the limestone area suggests that its oral bioaccessibility is restricted in the limestone area. Iodine taken up by plant roots is transported freely into the aerial plant parts in the millstone grit area unlike the limestone area, thus providing higher iodine into the human food chain in the millstone grit area through grazing animals unlike the goitre-prevalent limestone area

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Land Misuse and Hydrologic Response: Kaho'olawe, Hawai'i

DEDICATION: This paper is dedicated to "Ka'imipono" Rendell D. Tong (13 September 1959-4 January 1995). In his lifetime Rendell supported many environmental efforts in Hawai'i, especially the work reported in this paper, with a passion that was contagious. About Kaho'olawe he once wrote: "I'm looking forward to our continued work to restore Hakioawa ahupua'a [watershed] and to gain a comprehensive scientific observation and understanding of the hydrologic cycle on Kaho'olawe. We are invigorated and proud to be practicing that foundation of Hawaiian cultural values, miilama 'iiina [take care of the land]. So we keep working for the land, physically, spiritually ... for the people of the earth-e kupono e ka po'e honua." The spirit of Ka'imipono lives on in Hawai'i, especially on the island of Kaho'olawe, forever! ABSTRACT: This paper is concerned with the characterization of near-surface hydrologic response for the Hawaiian island of Kaho'olawe, where erosion caused, in part, by surface runoff is the major factor in landscape denudation. New sets of saturated hydraulic conductivity and sorptivity data from 110 sites across Kaho'olawe are presented and analyzed for spatial structure using statistical methods and land cover classification. At a regional scale there was no statistically characterizable spatial structure in either of the new data sets; we characterized the spatial distribution of saturated hydraulic conductivity and sorptivity based upon land cover. Also presented is a suite of runoff simulations for the entire island of Kaho'olawe, based upon the near-surface soil hydraulic property interpretations reported, for 10 separate rainfall events. The hydrologic response simulator used provides a relatively realistic representation of Hortonian overland flow. This study consisted of 700 deterministic-conceptual rainfall-runoff simulations, based upon the 10 rainfall events applied to 70 catchments that were divided into 1529 overland flow planes. Our simulations suggest, for the large events selected for this study, that the maximum island average surface runoff by the Horton mechanism is ca. 20% of rainfall