Ethanol reversal of tolerance to the respiratory depressant effects of morphine

Opioids are the most common drugs associated with unintentional drug overdose. Death results from respiratory depression. Prolonged use of opioids results in the development of tolerance but the degree of tolerance is thought to vary between different effects of the drugs. Many opioid addicts regularly consume alcohol (ethanol), and post-mortem analyses of opioid overdose deaths have revealed an inverse correlation between blood morphine and ethanol levels. In the present study, we determined whether ethanol reduced tolerance to the respiratory depressant effects of opioids. Mice were treated with opioids (morphine, methadone, or buprenorphine) for up to 6 days. Respiration was measured in freely moving animals breathing 5% CO(2) in air in plethysmograph chambers. Antinociception (analgesia) was measured as the latency to remove the tail from a thermal stimulus. Opioid tolerance was assessed by measuring the response to a challenge dose of morphine (10 mg/kg i.p.). Tolerance developed to the respiratory depressant effect of morphine but at a slower rate than tolerance to its antinociceptive effect. A low dose of ethanol (0.3 mg/kg) alone did not depress respiration but in prolonged morphine-treated animals respiratory depression was observed when ethanol was co-administered with the morphine challenge. Ethanol did not alter the brain levels of morphine. In contrast, in methadone- or buprenorphine-treated animals no respiratory depression was observed when ethanol was co-administered along with the morphine challenge. As heroin is converted to morphine in man, selective reversal of morphine tolerance by ethanol may be a contributory factor in heroin overdose deaths

Sediment-laden sea ice in southern Hudson Bay: Entrainment, transport, and biogeochemical implications

During a research expedition in Hudson Bay in June 2018, vast areas of thick (>10 m), deformed sediment-laden sea ice were encountered unexpectedly in southern Hudson Bay and presented difficult navigation conditions for the Canadian Coast Guard Ship Amundsen. An aerial survey of one of these floes revealed a maximum ridge height of 4.6 m and an average freeboard of 2.2 m, which corresponds to an estimated total thickness of 18 m, far greater than expected within a seasonal ice cover. Samples of the upper portion of the ice floe revealed that it was isothermal and fresh in areas with sediment present on the surface. Fine-grained sediment and larger rocks were visible on the ice surface, while a pronounced sediment band was observed in an ice core. Initial speculation was that this ice had formed in the highly dynamic Nelson River estuary from freshwater, but δ^{18}O isotopic analysis revealed a marine origin. In southern Hudson Bay, significant tidal forcing promotes both sediment resuspension and new ice formation within a flaw lead, which we speculate promotes the formation of this sediment-laden sea ice. Historic satellite imagery shows that sediment-laden sea ice is typical of southern Hudson Bay, varying in areal extent from 47 to 118 km2 during June. Based on an average sediment particle concentration of 0.1 mg mL^{–1} in sea ice, an areal extent of 51,924 km2 in June 2018, and an estimated regional end-of-winter ice thickness of 1.5 m, we conservatively estimated that a total sediment load of 7.8 × 106 t, or 150 t km^{–2}, was entrained within sea ice in southern Hudson Bay during winter 2018. As sediments can alter carbon concentrations and light transmission within sea ice, these first observations of this ice type in Hudson Bay imply biogeochemical impacts for the marine system

Contrasting effects of long term versus short-term nitrogen addition on photosynthesis and respiration in the Arctic

We examined the effects of short (<1–4 years) and long-term (22 years) nitrogen (N) and/or phosphorus (P) addition on the foliar CO2 exchange parameters of the Arctic species Betula nana and Eriophorum vaginatum in northern Alaska. Measured variables included: the carboxylation efficiency of Rubisco (Vcmax), electron transport capacity (Jmax), dark respiration (Rd), chlorophyll a and b content (Chl), and total foliar N (N). For both B. nana and E. vaginatum, foliar N increased by 20–50 % as a consequence of 1–22 years of fertilisation, respectively, and for B. nana foliar N increase was consistent throughout the whole canopy. However, despite this large increase in foliar N, no significant changes in Vcmax and Jmax were observed. In contrast, Rd was significantly higher (>25 %) in both species after 22 years of N addition, but not in the shorter-term treatments. Surprisingly, Chl only increased in both species the first year of fertilisation (i.e. the first season of nutrients applied), but not in the longer-term treatments. These results imply that: (1) under current (low) N availability, these Arctic species either already optimize their photosynthetic capacity per leaf area, or are limited by other nutrients; (2) observed increases in Arctic NEE and GPP with increased nutrient availability are caused by structural changes like increased leaf area index, rather than increased foliar photosynthetic capacity and (3) short-term effects (1–4 years) of nutrient addition cannot always be extrapolated to a larger time scale, which emphasizes the importance of long-term ecological experiments

Bryostatin Modulates Latent HIV-1 Infection via PKC and AMPK Signaling but Inhibits Acute Infection in a Receptor Independent Manner

HIV's ability to establish long-lived latent infection is mainly due to transcriptional silencing in resting memory T lymphocytes and other non dividing cells including monocytes. Despite an undetectable viral load in patients treated with potent antiretrovirals, current therapy is unable to purge the virus from these latent reservoirs. In order to broaden the inhibitory range and effectiveness of current antiretrovirals, the potential of bryostatin was investigated as an HIV inhibitor and latent activator. Bryostatin revealed antiviral activity against R5- and X4-tropic viruses in receptor independent and partly via transient decrease in CD4/CXCR4 expression. Further, bryostatin at low nanomolar concentrations robustly reactivated latent viral infection in monocytic and lymphocytic cells via activation of Protein Kinase C (PKC) -α and -δ, because PKC inhibitors rottlerin and GF109203X abrogated the bryostatin effect. Bryostatin specifically modulated novel PKC (nPKC) involving stress induced AMP Kinase (AMPK) inasmuch as an inhibitor of AMPK, compound C partially ablated the viral reactivation effect. Above all, bryostatin was non-toxic in vitro and was unable to provoke T-cell activation. The dual role of bryostatin on HIV life cycle may be a beneficial adjunct to the treatment of HIV especially by purging latent virus from different cellular reservoirs such as brain and lymphoid organs