Effects of rapid temperature fluctuations prior to breeding on reproductive efficiency in replacement gilts

Rapidly cooling pigs after heat stress (HS) results in a pathophysiological condition, and because rapid temperature fluctuations may be associated with reduced reproductive success in sows, it lends itself to the hypothesis that these conditions may be linked. Objectives were to determine the effects of rapid cooling on thermal response and future reproductive success in pigs. Thirty-six replacement gilts (137.8±0.9 kg BW) were estrus synchronized and then 14.1±0.4 d after estrus confirmation, pigs were exposed to thermoneutral conditions (TN; n=12; 19.7±0.9°C) for 6 h, or HS (36.3±0.5°C) for 3 h, followed by 3 h of rapid cooling (HSRC; n=12; immediate TN exposure and water dousing) or gradual cooling (HSGC; n=12; gradual decrease to TN conditions) repeated over 2 d. Vaginal (T_V) and gastrointestinal tract temperatures (T_GI) were obtained every 15 min, and blood was collected on d 1 and d 2 during the HS and recovery periods at 180 and 60 min, respectively. Pigs were bred 8.3±0.8 d after thermal treatments over 2 d. Reproductive tracts were collected and total fetus number and viability were recorded 28.0±0.8 d after insemination. HS increased T_V and T_GI (P=0.01; 0.98 °C) in HSRC and HSGC compared to TN pigs. During recovery, T_V was reduced from 15 to 105 min (P=0.01; 0.33 °C) in HSRC compared to HSGC pigs, but no overall differences in T_GI were detected (P<0.05; 39.67 °C). Rapid cooling increased (P<0.05) TNFα compared to HSGC and TN pigs during recovery-d 1 (55.2%), HS-d 2 (35.1%), and recovery-d 2 (64.9%). Viable fetuses tended to be reduced (P=0.08; 10.5%) and moribund fetuses tended to be increased (P=0.09; 159.3%) in HSRC compared to HSGC and TN pigs. In summary, rapid cooling prior to breeding may contribute to reduced fetal viability and reproductive success in pigs.     

Nonlinear analysis of heart rate variability for evaluating the growing pig stress response to an acute heat episode

Heart rate variability (HRV) is a proxy measure of autonomic function and can be used as an indicator of swine stress. While traditional linear measures are used to distinguish between stressed and unstressed treatments, inclusion of nonlinear HRV measures that evaluate data structure and organization shows promise for improving HRV interpretation. The objective of this study was to evaluate the inclusion of nonlinear HRV measures in response to an acute heat episode. Twenty 12- to 14-week-old growing pigs were individually housed for 7 days and acclimated to thermoneutral conditions (20.35°C ± 0.01°C; 67.6% ± 0.2% RH) before undergoing one of the two treatments: (1) thermoneutral control (TN; n = 10 pigs) or (2) acute heat stress (HS; n = 10 pigs; 32.6°C ± 0.1°C; 26.2% ± 0.1% RH). In Phase 1 of the experimental procedure (P1; 60 min), pigs underwent a baseline HRV measurement period in thermoneutral conditions before treatment [Phase 2; P2; 60 min once gastrointestinal temperature (T_g) reached 40.6°C], where HS pigs were exposed to heated conditions and TN pigs remained in thermoneutral conditions. After P2, all pigs were moved back to thermoneutral conditions (Phase 3; P3; 60 min). During each phase, T_g data were collected every 5 min and behavioural data were collected to evaluate the amount of time each pig spent in an active posture. Additionally, linear (time and frequency domain) and nonlinear [sample entropy (SampEn), de-trended fluctuation analysis, percentage recurrence, percentage determinism (%DET), mean diagonal line length in a recurrence plot] HRV measures were quantified. Heat stressed pigs exhibited greater T_g (P = 0.002) and spent less time in an active posture compared to TN pigs during P2 (P = 0.0003). Additionally, low frequency to high frequency ratio was greater in HS pigs during P3 compared to TN pigs (P = 0.02). SampEn was reduced in HS pigs during P2 (P = 0.01) and P3 (P = 0.03) compared to TN pigs. Heat stressed pigs exhibited greater %DET during P3 (P = 0.03) and tended to have greater %DET (P = 0.09) during P2 than TN pigs. No differences between treatments were detected for the remaining HRV measures. In conclusion, linear HRV measures were largely unchanged during P2. However, changes to SampEn and %DET suggest increased heat stress as a result of the acute heat episode. Future work should continue to evaluate the benefits of including nonlinear HRV measures in HRV analysis of swine heat stress.     

Bat thermoregulation in the heat: Limits to evaporative cooling capacity in three southern African bats

High environmental temperatures pose significant physiological challenges related to energy and water balance for small endotherms. Although there is a growing literature on the effect of high temperatures on birds, comparable data are scarcer for bats. Those data that do exist suggest that roost microsite may predict tolerance of high air temperatures. To examine this possibility further, we quantified the upper limits to heat tolerance and evaporative cooling capacity in three southern African bat species inhabiting the same hot environment but using different roost types (crevice, foliage or cave). We used flow-through respirometry and compared heat tolerance limits (highest air temperature (T_a) tolerated before the onset of severe hyperthermia), body temperature (T_b), evaporative water loss, metabolic rate, and maximum cooling capacity (i.e., evaporative heat loss/metabolic heat production). Heat tolerance limits for the two bats roosting in more exposed sites, Taphozous mauritianus (foliage-roosting) and Eptesicus hottentotus (crevice-roosting), were T_a = ~44 °C and those individuals defended maximum T_b between 41 °C and 43 °C. The heat tolerance limit for the bat roosting in a more buffered site, Rousettus aegyptiacus (cave-roosting), was T_a = ~38 °C with a corresponding T_b of ~38 °C. These interspecific differences, together with a similar trend for higher evaporative cooling efficiency in species occupying warmer roost microsites, add further support to the notion that ecological factors like roost choice may have profound influences on physiological traits related to thermoregulation.     

Responses of intestinal morphology and function in offspring to heat stress in primiparous sows during late gestation

Late gestation is a key period for intestinal development. Maternal heat exposure may induce intestinal dysfunction of offspring. To investigate the responses of intestinal morphology and function of offspring to the maternal heat stress (HS), twelve first-parity Landrace × Large White sows were assigned to thermoneutral (TN) (18-22 °C; n = 6) or HS (28-32 °C; n = 6) treatment groups at 85 d of gestation until natural farrowing. Twenty-four newborn piglets (two piglets at medium body weight from each litter) were randomly selected and divided into in utero thermoneutral (IUTN, n = 12) and heat-stressed (IUHS, n = 12) groups according to the sow’s treatment. Blood and intestinal samples were harvested to evaluate stress hormone levels, intestinal morphology, integrity and barrier function in the newborn piglets. Our results showed that maternal HS piglets exhibited increased serum adrenocorticotropic hormone (ACTH) concentration compared with that observed in the IUTN group. IUHS piglets showed lower lactase activities in the jejunum and ileum, whereas no significant differences were found between the two groups in the length of intestine, villus length or crypt depth. Serum diamine oxidase (DAO) activity was increased in IUHS piglets. IUHS piglets also exhibited decreased ZO-1, ZO-2 and MUC2 mRNA expression in the jejunum, while the protein levels were not affected. Additionally, IUHS piglets had a lower apoptotic percentage and FAS mRNA expression in the jejunum than those in the IUTN group. Taken together, these results demonstrate that high ambient temperature during late gestation of primiparous sows causes stress response in neonatal piglets, compromising intestinal permeability and mucosal barrier function, which may be partly mediated by inducing intestinal apoptosis.     

Heat stress of gilts around farrowing causes oxygen insufficiency in the umbilical cord and reduces piglet survival

Late gestating sows are susceptible to high ambient temperatures, possibly causing farrowing complications and reducing piglet survival. This experiment aimed to quantify in the days leading up to farrowing the impact of sow heat stress (HS) on farrowing physiology and survival of the piglets. Pregnant primiparous sows (gilts) were allocated to either thermoneutral control (CON, n = 8; constant 20 °C) or cyclical HS conditions (n = 8; 0900 h to 1700 h, 30 °C; 1700 h to 0900 h, 28 °C) from d 110 of gestation until farrowing completion. Gilt respiration rate, skin temperature and rectal temperature were recorded daily, and farrowing duration was quantified by video analyses. Blood samples were collected from the piglet umbilical vein at birth. At 48 h of age, piglet growth was quantified by morphometric analyses. The thermal exposure model induced HS and respiratory alkalosis in the gilts, as indicated by increased respiration rate, rectal temperature, skin temperature (all P < 0.001), plasma cortisol (P = 0.01) and blood pH (P < 0.001). Heat-stressed gilts took longer to start expelling placentae (P = 0.003), although the active farrowing duration was not significantly different between treatments. Stillbirth rates were higher in the HS group (P < 0.001), with surviving piglets at birth having lower umbilical vein partial pressure of oxygen (P = 0.04), oxygen saturation rate (P = 0.03) and tending to have increased lactate concentrations (P = 0.07). At birth, piglet skin meconium staining scores were greater in the HS group (P = 0.022). At 48 h of age, piglets from the HS group had reduced small intestinal length (P = 0.02), reduced jejunal crypt depth (P = 0.02) and lighter absolute brain weight (P = 0.001). In contrast, piglet BW, growth rate, relative organ weight and small intestinal mucosal barrier function did not change between treatments. Collectively, these findings demonstrated gilt HS during late gestation caused farrowing complications and reduced the umbilical oxygen supply to the piglets at parturition, leading to increased risks of piglet stillbirth with implications on impaired neonatal survivability and development.     

Bovine colostrum promoted ileal health in newborn lambs at 24 h after birth: insight from intestinal morphology and innate immunity

The contribution of colostrum to passive immunity transfer and intestinal protection in newborn ruminants is well known; however, it is currently unclear how colostrum intake affects intestinal innate immunity. We investigated the effects of bovine colostrum intake on ileal morphology, expression of genes involved in intestinal innate immunity, and serum concentrations of inflammatory cytokines in newborn lambs. Twenty-seven newborn male Hu lambs were used, of which 18 were bottle-fed either bovine colostrum (C24h; n = 9) or bovine mature milk (M24h; n = 9) within the first 2 h after birth at an intake of approximately 8% of BW; the remaining nine lambs did not receive any feeding (N24h). Blood and ileal tissue samples were collected after the lambs were slaughtered at 24 h after birth. Ileal villus height and villus height-to-crypt depth ratio were significantly higher in C24h than those in N24h and M24h lambs (P < 0.01). Messenger RNA (mRNA) abundance of toll-like receptor (TLR)-2, TLR3, TLR4, TLR6, TLR7, TLR8 and tumour necrosis factor alpha in the ileum was lower in C24h than that in N24h lambs (P < 0.05). Moreover, C24h lambs had a lower TLR3 mRNA abundance (P < 0.01) and a trend of lower TLR6 (P = 0.06) and interleukin 1 beta (P = 0.08) expression compared with those in M24h lambs. We also observed strong positive correlations of tumour necrosis factor alpha expression with that of TLR2 (r = 0.71; P < 0.001), TLR4 (r = 0.88; P < 0.001) and TLR8 (r = 0.83; P < 0.001). Interestingly, the expression of barrier-related molecules, including mucin-13, lysozyme, claudin (CLDN)-1, CLDN2, CLDN4, CLDN7, CLDN12, occludin, zonula occluden-1 and junctional adhesion molecule-1, was consistently lower in C24h lambs than that in N24h and M24h lambs (P < 0.05). These results indicated that the beneficial roles of colostrum intake on intestinal protection in newborn lambs were associated with low TLR expression, which was reflected by improved intestinal development and reduced inflammatory response. Further studies using fluorescence in situ hybridisation and immunohistochemical methods are needed to further explore the mechanisms underlying the lower expression of intestinal barrier-related molecules due to colostrum feeding.     

Effect of cooling strategies on overall performance of a hybrid personal cooling system incorporated with phase change materials (PCMs) and electric fans

The effect of four cooling strategies on cooling performance of a hybrid personal cooling system (HPCS) incorporated with phase change materials (PCMs) and electric fans in a hot environment (i.e., T_air = 36 ± 0.5 °C, RH = 59 ± 5%) was investigated. Twelve healthy young male participants underwent four 90-min trials comprising 70 min walking and 20 min resting periods. Cooling strategies adopted in this work were CON (control), PCM-control (PCMs were removed at the end of exercise), Fan-control (fans were switched OFF during the initial 20 min) and PCM&Fan-control (fans were turned ON after 20 min exercising and PCMs were removed after the 70-min exercise). Results demonstrated that the control of electric fans could suppress the mean skin temperature rise to 34.0 °C by over 15 min and also cut down the energy consumption of the HPCS from 15.6 W h to 12.1 W h over the entire 90-min trials. Thus, it is recommended that fans should be turned off at the beginning of hot exposure and switched on once participants felt warm. Our findings also showed that the removal of fully melted PCM packs from the HPCS could enhance the evaporative cooling effect brought about by air circulation. The removal of melted PCMs significantly reduced the physical load by 37.3% and ratings of perceived exertion (RPE) were decreased by 3.5–4.2 RPE units. This could also help quickly restore the PCM energy for future usage. In summary, cooling strategies demonstrated in this work could improve HPCS's overall cooling performance on workers while working in the studied hot environment.     

The Added and Interpretative Value of CGM-Derived Parameters in Type 1 Diabetes Depends on the Level of Glycemic Control

ObjectiveIn type 1 diabetes mellitus (T1DM) management, continuous glucose monitoring (CGM)-derived parameters can provide additional insights, with time in range (TIR) and other parameters reflecting glycemic control and variability being put forward. This study aimed to examine the added and interpretative value of the CGM-derived indices TIR and coefficient of variation (CV%) in T1DM patients stratified according to their level of glycemic control by means of HbA1C.MethodsT1DM patients with a minimum disease duration of 10 years and without known macrovascular disease were enrolled. Patients were equipped with a blinded CGM device for 7 days. TIR and time spent in hypoglycemia and hyperglycemia were determined, and CV% was used as a parameter for glycemic variability. Pearson (r) and Spearman correlations (r_s) and a regression analysis were used to examine associations.ResultsNinety-five patients (age: 45 ± 10 years; HbA1C level: 7.7% ± 0.8% [61 ± 7 mmol/mol]) were included (mean blood glucose [MBG]: 159 ± 31 mg/dL; TIR: 55.8% ± 14.9%; CV%: 43.5% ± 7.8%) and labeled as having good (HbA1C level ≤7% [≤53 mmol/mol]; n = 20), moderate (7%-8%; n = 44), or poor (>8% [>64 mmol/mol]; n = 31) glycemic control. HbA1C was significantly associated with MBG (r_s = 0.48, P < .001) and time spent in hyperglycemia (total: r_s = 0.52; level 2: r = 0.46; P < .001) but not with time spent in hypoglycemia and CV%, even after an analysis of the HbA1C subgroups. Similarly, TIR was negatively associated with HbA1C (r = −0.53; P < .001), MBG (r_s = −0.81; P < .001), and time spent in hyperglycemia (total: r_s = −0.90; level 2: r_s = −0.84; P < .001) but not with time in hypoglycemia. The subgroup analyses, however, showed that TIR was associated with shorter time spent in level-2 hypoglycemia in patients with good (r_s = −0.60; P = .007) and moderate (r_s = −0.25; P = .047) glycemic control. In contrast, CV% was strongly positively associated with time in hypoglycemia (total: r_s = 0.78; level 2: r_s = 0.76; P < .001) but not with TIR or time in hyperglycemia in the entire cohort, although the subgroup analyses showed that TIR was negatively associated with CV% in patients with good glycemic control (r = −0.81, P < .001) and positively associated in patients with poor glycemic control (r = +0.47; P < .01).ConclusionThe CGM-derived metrics TIR and CV% are related to clinically important situations, TIR being strongly dependent on hyperglycemia and CV% being reflective of hypoglycemic risk. However, the interpretation and applicability of TIR and CV% and their relationship depends on the level of glycemic control of the individual patient, with CV% generally adding less clinically relevant information in those with poor control. This illustrates the need for further research and evaluation of composite measures of glycemic control in T1DM.     

Heat acclimation does not modify autonomic responses to core cooling and the skin thermal comfort zone

Exercise heat acclimation (HA) is known to magnify the sweating response by virtue of a lower threshold as well as increased gain and maximal capacity of sweating. However, HA has been shown to potentiate the shivering response in a cold-air environment. We investigated whether HA would alter heat loss and heat production responses during water immersion. Twelve healthy male participants underwent a 10-day HA protocol comprising daily 90-min controlled-hyperthermia (target rectal temperature, T_re 38.5 °C) exercise sessions. Preceding and following HA, the participants performed a maximal exercise test in thermoneutral conditions (ambient temperature 23 °C, relative humidity 50%) and were, following exercise, immersed in 28 °C water for 60 min. Thermal comfort zone (TCZ) was also assessed with participants regulating the temperature of a water-perfused suit during heating and cooling. Baseline pre-immersion T_re was similar pre- and post-HA (pre: 38.33 ± 0.33 °C vs post: 38.12 ± 0.36 °C, p = 0.092). The T_re cooling rate was identical pre-to post-HA (−0.03 ± 0.01 °C·min⁻¹, p = 0.31), as was the vasomotor response reflected in the forearm-fingertip temperature difference. Shivering thresholds (p = 0.43) and gains (p = 0.61) were not affected by HA. TCZ was established at similar temperatures, with the magnitude in regulated water temperature being 7.6 (16.3) °C pre-HA and 5.1 (24.7) °C post-HA (p = 0.65). The present findings suggest that heat production and heat loss responses during whole body cooling as well as the skin thermal comfort zone remained unaltered by a controlled-hyperthermia HA protocol.     

The magnitude of physical exercise-induced hyperthermia is associated with changes in the intestinal permeability and expression of tight junction genes in rats

We investigated whether the magnitude of exercise-induced hyperthermia influences intestinal permeability and tight junction gene expression. Twenty-nine male Wistar rats were divided into four groups: rest at 24 °C and exercise at 13 °C, 24 °C or 31 °C. The exercise consisted of a 90-min treadmill run at 15 m/min, and different ambient temperatures were used to produce distinct levels of exercise-induced hyperthermia. Before the experimental trials, the rats were treated by gavage with diethylenetriaminepentaacetic acid labeled with technetium-99 metastable as a radioactive probe. The rats' core body temperature (T_CORE) was measured by telemetry. Immediately after the trials, the rats were euthanized, and the intestinal permeability was assessed by measuring the radioactivity of blood samples. The mRNA levels of occludin and zonula occludens-1 (ZO-1) genes were determined in duodenum samples. Exercise at 24 °C increased T_CORE to values close to 39 °C, without changing permeability compared with the resting trial at the same environment. Meanwhile, rats’ T_CORE exceeded 40 °C during exercise at 31 °C, leading to greater permeability relative to those observed after exercise in the other ambient temperatures (e.g., 0.0037%/g at 31 °C vs. 0.0005%/g at 13 °C; data expressed as medians; p < 0.05). Likewise, the rats exercised at 31 °C exhibited higher mRNA levels of ZO-1 and occludin genes than the rats exercised at 24 °C or 13 °C. The changes in permeability and gene expression were positively and significantly associated with the magnitude of hyperthermia. We conclude that marked hyperthermia caused by exercise in the warmer environment increases intestinal permeability and mRNA levels of tight junction genes.     

Hibernation patterns of Turkish hamsters: influence of sex and ambient temperature

Turkish hamsters (Mesocricetus brandti) are a model organism for studies of hibernation, yet a detailed account of their torpor characteristics has not been undertaken. This study employed continuous telemetric monitoring of body temperature (T _b) in hibernating male and female Turkish hamsters at ambient temperatures (T _as) of 5 and 13 °C to precisely characterize torpor bout depth, duration, and frequency, as well as rates of entry into and arousal from torpor. Hamsters generated brief intervals of short (<12 h), shallow test bouts (T _b > 20 °C), followed by deep torpor bouts lasting 4–6 days at T _a = 5 °C and 2–3 days at T _a = 13 °C. Females at T _a = 5 °C had longer bouts than males, but maintained higher torpor T _b; there were no sex differences at T _a = 13 °C. Neither body mass loss nor food intake differed between the two T _as. Hamsters entered torpor primarily during the scotophase (subjective night), but timing of arousals was highly variable. Hamsters at both T _as generated short, shallow torpor bouts between deep bouts, suggesting that this species may be capable of both hibernation and daily torpor.     

Effects of soybean isoflavones on the growth performance,intestinal morphology and antioxidative properties in pigs

Soybean meal is rich in soybean isoflavones, which exhibit antioxidant, anti-inflammatory, antiviral and anticancer functions in humans and animals. This study was conducted to investigate the effects of soybean isoflavones on the growth performance, intestinal morphology and antioxidative properties in pigs. A total of 72 weaned piglets (7.45 ± 0.13 kg; 36 males and 36 females) were allocated into three treatments and fed corn-soybean meal (C-SBM), corn-soy protein concentrate (C-SPC) or C-SPC supplemented with equal levels of the isoflavones found in the C-SBM diet (C-SPC + ISF) for a 72-day trial. Each treatment had six replicates and four piglets per replicate, half male and half female. On day 42, one male pig from each replicate was selected and euthanized to collect intestinal samples. The results showed that compared to pigs fed the C-SPC diet, pigs fed the C-SBM and C-SPC + ISF diets had higher BW on day 72 (P < 0.05); pigs fed the C-SBM diet had significantly higher average daily gain (ADG) during days 14 to 28 (P < 0.05), with C-SPC + ISF being intermediate; pigs fed the C-SBM diet tended to have higher ADG during days 42 to 72 (P = 0.063), while pigs fed the C-SPC + ISF diet had significantly higher ADG during days 42 to 72 (P < 0.05). Moreover, compared to pigs fed the C-SPC diet, pigs fed the C-SBM diet tended to have greater villus height (P = 0.092), while pigs fed the C-SPC + ISF diet had significantly greater villus height (P < 0.05); pigs fed the C-SBM and C-SPC + ISF diets had significantly increased villus height-to-crypt depth ratio (P < 0.05). Compared with the C-SPC diet, dietary C-SPC + ISF tended to increase plasma superoxide dismutase activity on days 28 (P = 0.085) and 42 (P = 0.075) and reduce plasma malondialdehyde (MDA) content on day 42 (P = 0.089), as well as significantly decreased jejunal mucosa MDA content on day 42 (P < 0.05). However, no significant difference in the expression of tight junction genes among the three groups was found (P > 0.05). In conclusion, our results suggest that a long-term exposure to soybean isoflavones enhances the growth performance, protects the intestinal morphology and improves the antioxidative properties in pigs.     

Evolution of viscera and muscle fractional protein synthesis rate in lean meat selected hybrids and castrated Duroc pigs fed under moderate crude protein restriction

Differences in producing performance and organoleptic meat characteristics among pig genotypes and/or producing types are widely known. These parameters are also subjected to the animal’s development, feeding and management. Detailed knowledge of the effects of production phase (PP), pig producing type (PT), dietary protein availability and their interactions on nutrient digestibility, nitrogen balance and protein metabolism is essential information to improve precision feeding techniques. The experiment was a 2 (PP) × 2 (PT) × 2 (diet) factorial design conducted with 32 male pigs, 16 entire F2 pigs progeny of Pietrain sires and Duroc × Landrace dams, and 16 castrated purebred Durocs belonging to two production phases (growing: 29.5 ± 3.19 v. fattening: 88.6 ± 6.26 kg BW), and assigned to one of two dietary CP levels, either standard (SP: 17% in growing and 15% in fattening) or low (LP: 15% in growing and 13% in fattening). Viscera and muscle fractional protein synthesis rates (FSRs; %/day) were conducted through a single infusion of 15% L-[ring-²H₅]-phenylalanine, with subsequent blood sampling from 12 to 40 min, and sample collection of liver, duodenum, biceps femoris and longissimus dorsi skeletal muscles after sacrifice. Fattening animals acquired a greater feed ingestion capacity, average daily gain (P < 0.01) and apparent ileal digestibility, whereas growing pigs showed higher FSRs in both viscera (duodenum and liver) and in longissimus dorsi. F2 pigs showed higher average daily gain, nitrogen retention rates and FSR in liver and longissimus dorsi (P < 0.01). Nevertheless, apparent ileal digestibility in all essential amino acids was lower in F2 compared with Duroc pigs (P < 0.05). Protein metabolism was barely influenced by dietary CP content, although animals fed LP registered the lowest apparent ileal digestibility for CP and also for most of the essential amino acids compared with SP-fed pigs. This information may reveal differences in amino acid requirements between both PTs, with Duroc pigs receiving excess of dietary amino acids.     

Amphipathic short helix-stabilized peptides with cell-membrane penetrating ability

We synthesized four types of arginine-based amphipathic nonapeptides, including two homochiral peptides, R-(l-Arg-l-Arg-Aib)₃-NH₂ (R = 6-FAM-β-Ala: FAM-1; R = Ac: Ac-1) and R-(d-Arg-d-Arg-Aib)₃-NH₂ (R = 6-FAM-β-Ala: ent-FAM-1; R = Ac: ent-Ac-1); a heterochiral peptide, R-(l-Arg-d-Arg-Aib)₃-NH₂ (R = 6-FAM-β-Ala: FAM-2; R = Ac: Ac-2); and a racemic mixture of diastereomeric peptides, R-(rac-Arg-rac-Arg-Aib)₃-NH₂ (R = 6-FAM-β-Ala: FAM-3; R = Ac: Ac-3), and then investigated the relationship between their secondary structures and their ability to pass through cell membranes. Peptides 1 and ent-1 formed stable one-handed α-helical structures and were more effective at penetrating HeLa cells than the non-helical peptides 2 and 3.     

Heat Stress Reduces Intestinal Barrier Integrity and Favors Intestinal Glucose Transport in Growing Pigs

Excessive heat exposure reduces intestinal integrity and post-absorptive energetics that can inhibit wellbeing and be fatal. Therefore, our objectives were to examine how acute heat stress (HS) alters intestinal integrity and metabolism in growing pigs. Animals were exposed to either thermal neutral (TN, 21°C; 35–50% humidity; n = 8) or HS conditions (35°C; 24–43% humidity; n = 8) for 24 h. Compared to TN, rectal temperatures in HS pigs increased by 1.6°C and respiration rates by 2-fold (P<0.05). As expected, HS decreased feed intake by 53% (P<0.05) and body weight (P<0.05) compared to TN pigs. Ileum heat shock protein 70 expression increased (P<0.05), while intestinal integrity was compromised in the HS pigs (ileum and colon TER decreased; P<0.05). Furthermore, HS increased serum endotoxin concentrations (P = 0.05). Intestinal permeability was accompanied by an increase in protein expression of myosin light chain kinase (P<0.05) and casein kinase II-α (P = 0.06). Protein expression of tight junction (TJ) proteins in the ileum revealed claudin 3 and occludin expression to be increased overall due to HS (P<0.05), while there were no differences in claudin 1 expression. Intestinal glucose transport and blood glucose were elevated due to HS (P<0.05). This was supported by increased ileum Na⁺/K⁺ ATPase activity in HS pigs. SGLT-1 protein expression was unaltered; however, HS increased ileal GLUT-2 protein expression (P = 0.06). Altogether, these data indicate that HS reduce intestinal integrity and increase intestinal stress and glucose transport.     

VEGFR-2 inhibiting effect and molecular modeling of newly synthesized coumarin derivatives as anti-breast cancer agents

Twenty five newly synthesized coumarin scaffold based derivatives were assayed for their in vitro anticancer activity against MCF-7 breast and PC-3 prostate cancer cell lines and were further assessed for their in vitro VEGFR-2 kinase inhibitory activity. The in vitro cytotoxic studies revealed that most of the synthesized compounds possessed very promising cytotoxicity against MCF-7, particularly; compounds 4a (IC₅₀ = 1.24 µM) and 3d (IC₅₀ = 1.65 µM) exhibited exceptional activities superior to the positive control staurosporine (IC₅₀ = 8.81 µM). Similarly, the majority of the compounds exhibited higher antiproliferative activities compared to the reference standard with IC₅₀ values ranging from 2.07 to 8.68 µM. The two cytotoxic derivatives 4a and 3d were selected to evaluate their inhibitory potencies against VEGFR-2 kinase. Remarkably, compound 4a, exhibited significant IC₅₀ of 0.36 µM comparable to staurosporine (IC₅₀; 0.33 µM). Moreover, it was capable of inducing preG1 apoptosis, cell growth arrest at G2/M phase and activating caspase-9. On the other hand, insignificant cytotoxic activity was observed for all compounds towards PC-3 cell line. Molecular docking study was carried out for the most active anti-VEGFR-2 derivative 4a, which demonstrated the ability of the tested compound to interact with the key amino acids in the target VEGFR-2 kinase binding site. Additionally, the ADME parameters and physicochemical properties of compound 4a were examined in silico.     

Remarkable enhancement in the DNA-binding ability of C2-fluoro substituted pyrrolo[2,1-c][1,4]benzodiazepines and their anticancer potential

C2-Fluoro substituted DC-81, and its dimers that comprise of two C2-fluoro substituted DC-81 subunits tethered to their C8-position through simple alkane spacers as well as piperazine moiety side-armed with symmetrical alkyloxy spacers have been designed and synthesized. These fluoro substituted pyrrolo[2,1-c][1,4]benzodiazepines have shown remarkable DNA-binding ability and most of them possess promising anticancer activity, having GI₅₀ values in micromolar to nanomolar concentration range. DNA thermal denaturation studies show that some of these compounds (14a–c and 15) increase the ΔT_m values in the range of 28.9–38 °C, and this is further confirmed by the restriction endonuclease studies. This study illustrates the importance of introducing fluoro substitution at the C2-position apart from the incorporation of a piperazine ring in between the alkyloxy linker for enhancement of the DNA-binding ability in comparison to DSB-120 and SJG-136 (ΔT_m = 10.2 and 25.7 °C). Moreover, the variations in the DNA-binding ability with respect to fluoro substitution in this class of dimers has been investigated by molecular modeling studies. Some representative C2-fluoro substituted dimers (8a and 14a) have also exhibited significant anticancer activity in the 60 cancer cell line assay of the National Cancer Institute (NCI).     

Survival and growth of microscopic fungi derived from tropical regions under future heat waves in the Pannonian Biogeographical Region

Warming and heat waves are predicted by different climate models in the near future in the Pannonian Biogeographical Region (PBR). These climatic effects may have impact on the prevalence and distribution of certain fungal species of this area. In this study the effects of predicted climate scenarios were tested on fungi being endemic or unintentionally introduced by global trade from regions of warm temperate climate. Common fungal species were selected for the study and exposed to heat waves during 7 days according to two climate scenarios: one moderately (RCP 4.5, T_avg = 27 °C, T_max = 35 °C, RH: 100%) and one strongly pessimistic (RCP 8.5, T_avg = 30 °C, T_max = 40 °C, RH: 100%) that include predictions for the Central Hungarian Region for July 2050. According to our results, Aspergillus flavus, Aspergillus niger, Aspergillus tubingensis and Fusarium strains introduced from tropical regions tolerated heat waves, unlike Penicillium and Talaromyces spp. and endemic Cladosporium spp. which were unable to grow under the RCP 8.5 treatment. The effects of climate change on fungi raise new issues not only from economic and health perspectives, but also in relation with plant protection and environment. Our results suggest that heat waves driven by climate change promote the colonization and growth of the tested strains of non-native fungi more likely than that of the native ones.     

Hybrid cooling vest for cooling between exercise bouts in the heat: Effects and practical considerations

While continuous cooling strategies may induce some ergonomic problems to occupational workers, cooling between work bouts may be an alternative for cooling them down in hot environments. The purpose of this study was to assess the effects of wearing a newly designed hybrid cooling vest (HCV) between two bouts of exercise. Inside a climatic chamber set at an air temperature of 37 °C and a relative humidity of 60%, twelve male participants underwent two bouts of intermittent exercise interspersed with a 30 min between-bout recovery session, during which HCV or a passive rest without any cooling (PAS) was administered. The results indicated that thermoregulatory, physiological, and perceptual strains were significantly lower in HCV than those in PAS during the recovery session (p≤0.022), which were accompanied with a large effect of cooling (Cohen's d=0.84–2.11). For the second exercise bout, the exercise time following HCV (22.13±12.27 min) was significantly longer than that following PAS (11.04±3.40 min, p=0.005, d=1.23) During this period, core temperature T_c was significantly lower by 0.14±0.0.15 °C in HCV than that in PAS. The heart rate drift over time was declined by 2±2 bpm min⁻¹ (p=0.001, d=1.00) and the rise in physiological strain index was reduced by 0.11±0.12 unit min⁻¹ (p=0.010, d=0.96) following the use of HCV. These findings suggested that using HCV could accelerate between-bout recovery and improve subsequent exercise performance by the enlarged body core temperature margin and blunted cardiovascular drift.     

Human umbilical cord mesenchymal stromal cells as an adjunct therapy with therapeutic hypothermia in a piglet model of perinatal asphyxia

Background: With therapeutic hypothermia (HT) for neonatal encephalopathy, disability rates are reduced, but not all babies benefit. Pre-clinical rodent studies suggest mesenchymal stromal cells (MSCs) augment HT protection. Aims:The authors studied the efficacy of intravenous (IV) or intranasal (IN) human umbilical cord-derived MSCs (huMSCs) as adjunct therapy to HT in a piglet model. Methods:A total of 17 newborn piglets underwent transient cerebral hypoxia-ischemia (HI) and were then randomized to (i) HT at 33.5°C 1–13 h after HI (n = 7), (ii) HT+IV huMSCs (30 × 10⁶ cells) at 24 h and 48 h after HI (n = 5) or (iii) HT+IN huMSCs (30 × 10⁶ cells) at 24 h and 48 h after HI (n = 5). Phosphorus-31 and hydrogen-1 magnetic resonance spectroscopy (MRS) was performed at 30 h and 72 h and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells and oligodendrocytes quantified. In two further piglets, 30 × 10⁶ IN PKH-labeled huMSCs were administered. Results:HI severity was similar between groups. Amplitude-integrated electroencephalogram (aEEG) recovery was more rapid for HT+IN huMSCs compared with HT from 25 h to 42 h and 49 h to 54 h (P ≤ 0.05). MRS phosphocreatine/inorganic phosphate was higher on day 2 in HT+IN huMSCs than HT (P = 0.035). Comparing HT+IN huMSCs with HT and HT+IV huMSCs, there were increased OLIG2 counts in hippocampus (P = 0.011 and 0.018, respectively), internal capsule (P = 0.013 and 0.037, respectively) and periventricular white matter (P = 0.15 for IN versus IV huMSCs). Reduced TUNEL-positive cells were seen in internal capsule with HT+IN huMSCs versus HT (P = 0.05). PKH-labeled huMSCs were detected in the brain 12 h after IN administration. Conclusions:After global HI, compared with HT alone, the authors saw beneficial effects of HT+IN huMSCs administered at 24 h and 48 h (30 × 10⁶ cells/kg total dose) based on more rapid aEEG recovery, improved ³¹P MRS brain energy metabolism and increased oligodendrocyte survival at 72 h.