Identification of novel prognostic alternative splicing signature in papillary renal cell carcinoma

Papillary renal cell carcinoma (pRCC) is a heterogeneous disease containing multifocal or solitary tumors with an aggressive phenotype. Increasing evidence has indicated the involvement of aberrant splicing variants in renal cell cancer, while systematic profiling of aberrant alternative splicing (AS) in pRCC was lacking and largely unknown. In the current study, comprehensive profiling of AS events were performed based on the integration of pRCC cohort from the Cancer Genome Atlas database and SpliceSeq software. With rigorous screening and univariate Cox analysis, a total of 2077 prognoses AS events from 1642 parent genes were identified. Then, stepwise least absolute shrinkage and selection operator method-penalized Cox regression analyses with 10-fold cross-validation followed by multivariate Cox regression were used to construct the prognostic AS signatures within each AS type. And a final 21 AS event-based signature was proposed which showed potent prognostic capability in stratifying patients into low- and high-risk subgroups (P < .0001). Furthermore, time-dependent receiver operating characteristics curves confirmed that the final AS signature was effective and robust in predicting overall survival for pRCC patients with the area under the curve above 0.9 from 1 to 5 years. In addition, splicing correlation network was built to uncover the potential regulatory pattern among prognostic splicing factors and candidate AS events. Besides, gene set enrichment analysis revealed the involvement of these candidates AS events in tumor-related pathways including extracellular matrix organization, oxidative phosphorylation, and P53 signaling pathways. Taken together, our results could contribute to elucidating the underlying mechanism of AS in the oncogenesis process and broaden the novel field of prognostic and clinical application of molecule-targeted approaches in pRCC.     

Linear skin markings in common bottlenose dolphins (Tursiops truncatus) from the Indian River Lagoon,Florida

A previously undescribed skin abnormality, referred to as “linear skin markings” (LSM), has been identified in free-ranging common bottlenose dolphins (Tursiops truncatus) in the Indian River Lagoon, Florida (IRL). The lesions were identified during photo-identification surveys conducted from 2002 and 2015. LSM presented as distinct, parallel lines running dorso-ventrally on the torso and varied in length and width. The goals of this study were to determine (1) prevalence of the condition in IRL dolphins, (2) age and sex distribution of affected animals, (3) spatial and temporal distribution patterns, (4) duration of the condition, and (5) development of hypotheses regarding the etiology of the condition. Among 1,357 individual dolphins identified during the study period, 96 (7.0%) showed evidence of LSM. Nearly all (98.8%) cases with an established home range occurred in the northern and central regions of the IRL. The majority of cases of known sex were female (85%), of which 100% had given birth to one or more calves. The mean age of animals with LSM when first observed was 7.3 with a range of 1–20 years. The maximum observed duration of LSM was 15 years. Once observed, the condition persisted indefinitely. The etiology of LSM has not been established.     

Skin in the game: Epidermal molt as a driver of long-distance migration in whales

Long-distance migration in whales has historically been described as an annual, round-trip movement between high-latitude, summer feeding grounds, and low-latitude, winter breeding areas, but there is no consensus about why whales travel to the tropics to breed. Between January 2009 and February 2016, we satellite-tagged 62 antarctic killer whales (Orcinus orca) of four different ecotypes, of which at least three made short-term (6–8 weeks), long-distance (maximum 11,000 km, round trip), essentially nonstop, migrations to warm waters (SST 20°C–24°C), and back. We previously suggested that antarctic killer whales could conserve body heat in subfreezing (to −1.9°C) waters by reducing blood flow to their skin, but that this might preclude normal (i.e., continuous) epidermal molt, and necessitate periodic trips to warm waters for routine skin maintenance (“skin molt migration,” SMM). In contrast to the century-old “feeding/breeding” migration paradigm, but consistent with a “feeding/molting” hypothesis, the current study provides additional evidence that deferred skin molt could be the main driver of long-distance migration for antarctic killer whales. Furthermore, we argue that for all whales that forage in polar latitudes and migrate to tropical waters, SMM might also allow them to exploit rich prey resources in a physiologically challenging environment and maintain healthy skin.     

Discussion on Spatial and Time Averaging Restrictions Within the Electromagnetic Exposure Safety Framework in the Frequency Range Above 6 GHz for Pulsed and Localized Exposures

Both the current and newly proposed safety guidelines for local human exposure to millimeter-wave frequencies aim at restricting the maximum local temperature increase in the skin to prevent tissue damage. In this study, we show that the application of the current and proposed limits for pulsed fields can lead to a temperature increase of 10°C for short pulses and frequencies between 6 and 30 GHz. We also show that the proposed averaging area of 4 cm², that is greatly reduced compared with the current limits, does not prevent high-temperature increases in the case of narrow beams. A realistic Gaussian beam profile with a 1 mm radius can result in a temperature increase about 10 times higher than the 0.4°C increase the same averaged power density would produce for a plane wave. In the case of pulsed narrow beams, the values for the time and spatial-averaged power density allowed by the proposed new guidelines could result in extreme temperature increases. Bioelectromagnetics. 2020;41:164–168. © 2019 Bioelectromagnetics Society.     

Arginine vasopressin does not mediate heat loss in the tail of the rat

It has been reported that hypothermia induced by arginine vasopressin (AVP) is brought about by a coordinated response of reduced thermogenesis in brown adipose tissue (BAT) and increased heat loss through the tail of rats. However, it is well known that AVP is one of the strongest peripheral vasoconstrictors. Whether the AVP-induced hypothermia is associated with an increase in heat loss through the tail is questionable. Therefore, the present study assessed the relationship between the effects of AVP on tail skin temperature and the induced hypothermic response, and to determine if peripheral AVP administration increases heat loss from the tail. Core, BAT and tail skin temperature were monitored by telemetry in male Sprague–Dawley rats before and after intraperitoneal administration of AVP or vasopressin receptor antagonist. We also analyzed simultaneously of the time-course of AVP-induced hypothermic response and its relationship with changes in BAT temperature, and effect of AVP on grooming behavior. The key observations in this study were: (1) rats dosed with AVP induced a decrease in heat production (i.e., a reduction of BAT thermogenesis) and an increase of saliva spreading for evaporative heat loss (i.e., grooming behavior); (2) AVP caused a marked decrease in tail skin temperature and this effect was prevented by the peripheral administration of the vasopressin V1a receptor antagonist, suggesting that exogenous AVP does not increase heat loss in the tail of rats; (3) the vasopressin V1a receptor antagonist could elevate core temperature without affecting tail skin temperature, suggesting that endogenous AVP is involved in suppression of thermogenesis, but not mediates heat loss in the tail of rats. Overall, the present study does not support the conclusion of previous reports that AVP increased tail heat loss in rats, because AVP-induced hypothermia in the rat is accompanied by a decrease in tail skin temperature. The data indicate that exogenous AVP-induced hypothermia attributed to the suppression of thermoregulatory heat production and the increase of saliva spreading for evaporative heat loss.     

Seasonal acclimatization to the hot summer over 60 days in the Republic of Korea suppresses sweating sensitivity during passive heating

The main objective of this study was to determine the central mechanisms involved in suppression of thermal sweating after seasonal acclimatization (SA) during passive heating (immersing the legs in 43 °C hot water for 30 min). Testing was performed in July (before-SA) and August (after-SA) [25.2±2.2 °C, 73.9±10.3% relative humidity (RH), Cheonan (Chungnam,126° 52′N, 33.38′E), in the Republic of Korea. All experiments were carried out in an automated climatic chamber (25.0±0.5 °C and RH 60.0±3.00%). Twelve healthy men (height, 174.6±5.40 cm; weight, 65.4±5.71 kg; age, 22.7±2.90 yr) participated. The local sweat onset time was delayed in the after-SA compared to that in the before-SA (p<0.001). The local sweat rate and whole body sweat loss volume decreased in the after-SA compared to those in the before-SA (p<0.001). In addition, evaporative loss volume decreased significantly in the after-SA compared to that in the before-SA [chest, upper-back, thigh and forearm (p<0.001)]. Changes in tympanic temperature and mean body temperature were significantly lower (p<0.05) and the basal metabolic rate decreased significantly in the after-SA compared to those in the before-SA (p<0.001). These results suggest that maintenance of a lower body temperature and basal metabolic rate can occur and blunt the central sudomotor mechanisms following seasonal acclimatization, which suppresses sweating sensitivity.     

In vitro evaluation of archaeosome vehicles for transdermal vaccine delivery

Abstract

Archaeosomes composed of archaeal total polar lipids (TPL) or semi-synthetic analog vesicles have been used as vaccine adjuvants and delivery systems in animal models for many years. Typically administered by intramuscular or subcutaneous injections, archaeosomes can induce robust, long-lasting humoral and cell-mediated immune responses against entrapped antigens and provide protection in murine models of infectious disease and cancer. Herein, we evaluated various archaeosomes for transdermal delivery, since this route may help eliminate needle-stick injuries and needle re-use, and therefore increase patient compliance. Archaeosomes composed of TPL from different archaea (Halobacterium salinarum, Methanobrevibacter smithii, Haloferax volcanii) and various semi-synthetic glycolipid combinations were evaluated for their ability to diffuse across the skin barrier using an ex vivo pig skin model and the results were compared to conventional synthetic ester liposomes. Physicochemical characteristics were determined for selected formulations including vesicle size, size distribution, zeta potential, fluidity, antigen (ovalbumin) incorporation efficiency and release. Archaeosomes, in particular those composed of M. smithii TPL or the synthetic glycolipid sulfated S-lactosylarchaeol (SLA) mixed with uncharged glycolipid lactosyl archaeol (LA), appeared to be effective carriers for ovalbumin, achieving much better antigen distribution and vesicle accumulation in the skin epidermis than conventional liposomes. The enhanced skin permeation of archaeosomes may be attributed to their chemical structure and physicochemical properties such as particle size, surface charge, stability, and fluidity of their lipid bilayer.     

THERMOREGULATORY EFFECT IN HUMANS OF SUPPRESSED ENDOGENOUS MELATONIN BY PRE-SLEEP BRIGHT-LIGHT EXPOSURE IN A COLD ENVIRONMENT

This study investigated the physiological function of suppressed melatonin through thermoregulation in a cold environment. Interactions between thermoregulation directly affected by exposure to a cold environment and indirectly affected by endogenous melatonin suppression by bright-light exposure were examined. Ten male subjects were exposed to two different illumination intensities (30 and 5000 lux) for 4.5?h, and two different ambient temperatures (15 and 27°C) for 2?h before sleep under dark and thermoneutral conditions. Salivary melatonin level was suppressed by bright light (p?<?0.001), although the ambient temperature condition had no significant effect on melatonin. During sleep, significant effects of pre-sleep exposure to a cold ambient temperature (p?<?0.001) and bright light (p?<?0.01) on rectal temperature (T_re) were observed. Pre-sleep, bright-light exposure led to an attenuated fall in T_re during sleep. Moreover, T_re dropped more precipitously after cold exposure than thermoneutral conditions (cold: ?0.54?±?0.07°C/h; thermoneutral: ?0.16?±?0.03°C/h; p?<?0.001). Pre-sleep, bright-light exposure delayed the nadir time of T_re under thermoneutral conditions (p?<?0.05), while cold exposure masked the circadian rhythm with a precipitous decrease in T_re. A significant correlation between the T_re nadir and melatonin level (r?=??0.774, p?<?0.05) indicated that inter-individual differences with higher melatonin levels lead to a reduction in T_re after cold exposure. These results suggest that suppressed endogenous melatonin inhibits the downregulation of the body temperature set-point during sleep. (Author correspondence: ishibasi@design.kyushu-u.ac.jp)     

Nonoverlapping Thalamocortical Connections to Normal and Deprived Primary Somatosensory Cortex for Similar Forelimb Receptive Fields in Chronic Spinal Cats

The fluorescent dye retrograde tracing technique, using fast blue in combination with fluorogold, was used to examine thalamocortical projections from the ventrobasal complex to primary somatosensory cortex in chronic spinal cats that sustained T12 cord transection at 2 weeks of age. Following cord transection at this age, it has been shown that forelimb afferents can excite the deprived hindlimb projection zone, in addition to the region of somatosensory cortex that they normally occupy (McKinley et al, 1987). These two regions of cortex are separated by over 10 mm, thus facilitating the determination of whether the forelimb representation in “hindlimb cortex” is derived from the sector of the ventrobasal complex of the thalamus representing the forelimb, hindlimb, or both. Injections of the two dyes into separate regions of the cortex that were excited by the same peripheral forelimb receptive fields produced single labeling of two nonoverlapping clusters of thalamic neurons. This finding suggests that the projections for these two areas are independent and distinct, and indicates that altered thalamocortical projections do not contribute the critical component underlying reorganizational changes observed at the cortical level after spinal cord transection. It is hypothesized that the degree of reorganization required to achieve the magnitude of change observed in the cortex must occur below the level of the thalamocortical relay.