Probenecid, an Old Drug with Potential New Uses for Central Nervous System Disorders and Neuroinflammation.

Probenecid is an old uricosuric agent used in clinics to treat gout and reduce the renal excretion of antibiotics. In recent years, probenecid has gained attention due to its ability to interact with membrane proteins such as TRPV2 channels, organic anion transporters, and pannexin 1 hemichannels, which suggests new potential therapeutic utilities in medicine. Some current functions of probenecid include their use as an adjuvant to increase the bioavailability of several drugs in the Central Nervous System (CNS). Numerous studies also suggest that this drug has important neuroprotective, antiepileptic, and anti-inflammatory properties, as evidenced by their effect against neurological and neurodegenerative diseases. In these studies, the use of probenecid as a Panx1 hemichannel blocker to reduce neuroinflammation is highlighted since neuroinflammation is a major trigger for diverse CNS alterations. Although the clinical use of probenecid has declined over the years, advances in its use in preclinical research indicate that it may be useful to improve conventional therapies in the psychiatric field where the drugs used have a low bioavailability, either because of a deficient passage through the blood-brain barrier or a high efflux from the CNS or also a high urinary clearance. This review summarizes the history, pharmacological properties, and recent research uses of probenecid and discusses its future projections as a potential pharmacological strategy to intervene in neurodegeneration as an outcome of neuroinflammation.

Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging.

Aging is a major risk factor to develop neurodegenerative diseases and is associated with decreased buffering capacity of the proteostasis network. We investigated the significance of the unfolded protein response (UPR), a major signaling pathway activated to cope with endoplasmic reticulum (ER) stress, in the functional deterioration of the mammalian brain during aging. We report that genetic disruption of the ER stress sensor IRE1 accelerated age-related cognitive decline. In mouse models, overexpressing an active form of the UPR transcription factor XBP1 restored synaptic and cognitive function, in addition to reducing cell senescence. Proteomic profiling of hippocampal tissue showed that XBP1 expression significantly restore changes associated with aging, including factors involved in synaptic function and pathways linked to neurodegenerative diseases. The genes modified by XBP1 in the aged hippocampus where also altered. Collectively, our results demonstrate that strategies to manipulate the UPR in mammals may help sustain healthy brain aging.

Consumer attitudes toward dairy products from sheep and goats: A cross-continental perspective.

This study aimed to assess consumer knowledge, attitudes, and perceptions toward dairy products from sheep and goats. A web-based survey was conducted in Latin America (Mexico and Chile), Europe (Italy, Spain, Greece, and Denmark), and Asia (Bangladesh). From March to June 2021, adult participants answered an online survey available in 5 languages. In total, 1,879 surveys were completed. Categorical and ordinal data were analyzed as frequencies and percentages. To determine the relationship between the variables for purchasing and consumption behaviors of respondents who declared that they consume dairy products, a multiple correspondence analysis was carried out. Most completed surveys were from Mexico and Italy (30% and 33.7%, respectively). Most respondents were between 18 and 29 yr old, female, highly educated, and employed. The majority of respondents (70.8%) declared that they consume dairy products from small ruminants. Consumers preferred products from both sheep and goats (49.4%); however, it was observed that in Mexico, Denmark, and Bangladesh, more than 50% preferred goat dairy products. The most-consumed products were mature and fresh cheeses. Mature cheese was the most-preferred product in Chile; in Mexico, Italy, Greece, and Denmark, it was fresh cheese. Unlike the rest of the countries, in Bangladesh, dairy product consumption from small ruminants was observed by more than 30% of respondents. In Mexico, a higher percentage of people do not consume sheep or goat dairy products because they are unfamiliar with them. In Mexico, Chile, and Bangladesh, limited market availability was also a variable responsible for nonconsumption. In European and Asian countries, sheep and goat dairy products are not consumed because consumers dislike them, in addition to a greater awareness of sustainability and climate change issues. The multiple correspondence analysis defined 5 dimensions. Dimension 1 was associated with the geographic location of the respondent (country and continent), the type of milk (sheep or goat), and the consideration of well-being and health as characteristics associated with the consumption of dairy products from small ruminants. Dimension 2 was associated with the respondent's country of origin and the frequency of consumption. Dimension 3 was associated with gender, education, and employment status. Dimension 4 was associated with the respondent's age, the association of the "healthy" concept of sheep and goat dairy products, and the consideration of the nutritional benefits of dairy as responsible for considering them healthy. Dimension 5 was associated with a "strong smell and taste" of sheep and goat dairy products. This study showed that consumer attitudes toward dairy products from sheep and goats vary between continents. In conclusion, results showed consumer interest in animal welfare and environmental impact issues related to small ruminant farming as well as a general attraction to local products. It seems that these factors contribute to consumers' perception of the quality of dairy products, so the industry and select farmers should carefully consider incorporating them into their supply chain.

Knowledge and Perception on Animal Welfare in Chilean Undergraduate Students with Emphasis on Dairy Cattle.

The objectives of this study were to determine differences in knowledge and perception of animal welfare (with emphasis on dairy cattle) among undergraduate students from two universities with different missions and visions and between students from different faculties. One thousand surveys were obtained from Universidad de Chile (UChile; n = 500) and Pontificia Universidad Católica de Chile (PUC; n = 500) students. The students from both universities were from the following faculties: Agronomy, Architecture, Biology, Economic Sciences, Psychology, Law, Philosophy, Basic Education, Civil Engineering and Medicine. The majority (77%) of students from both universities were aware of animal welfare. Most (56%) students understand animal welfare as the 'mental and physical state of animals'. Regardless of their faculty, around 97% of the total respondents perceived animal welfare as important for production systems. Regarding specific knowledge about cows' welfare related to milk management and behavior, students from Economic Sciences, Psychology, Law, Philosophy, Basic Education, and Civil Engineering had less (p < 0.001) self-reported knowledge about cows' basic behavior and specific management practices such as milking and were more negative in their perceptions of dairy production. Overall, results showed that the students' faculty explained most of the differences among undergraduate students in relation to their perceptions and knowledge about animal welfare. Our data is important, as undergraduate students will make purchasing and power decisions as well as having potential influence on future policies that could modify the animal production industry.

Evaluation of Feed Strategies and Changes of Stocking Rate to Decrease the Carbon Footprint in a Traditional Cow-Calf System: A Simulation Model.

One of the main production challenges associated with climate change is the reduction of carbon emissions. Increasing the efficiency of resource utilization is one way to achieve this purpose. The modification of production systems through improved reproductive, genetic, feed, and grazing management practices has been proposed to increase technical-economic efficiency, even though the "environmental viability" of these modifications has not always been evaluated. The objective of this study was to evaluate the use of feeding and management strategies on the carbon footprint (CF) and economic variables in the traditional cow-calf system in southern Chile using a simulation model. The modifications evaluated corresponded to combinations of stocking rate, use of creep feeding practices with different supplementation levels, and the incorporation of feed additives to the supplement, using factorial experiments. Additionally, the scenarios were evaluated with and without carbon sequestration. The CF for the baseline scenarios was 12.5 ± 0.3 kg of CO2-eq/kg of live weight (LW) when carbon sequestration was considered and 13.0 ± 0.4 kg of CO2-eq/kg of LW in the opposite case. Changes in stocking rate, supplementation level, and consideration of carbon sequestration in pasture and soil had a significant effect on the CF in all simulated scenarios. The inclusion of additives in the supplement did not have a significant effect on production costs. With regard to reducing greenhouse gas (GHG) emissions, incorporating canola oil presented the best average results. The model developed made the selection of environmentally viable feed strategies or management adaptations possible.

Chemical and fatty acid composition of Manchego type and Panela cheeses manufactured from either hair sheep milk or cow milk.

This study compared the chemical composition and fatty acid (FA) profile of Manchego type cheese and Panela cheese made from hair sheep milk and compared these with both types of cheese manufactured with cow milk as a reference. In addition, this study aimed to determine differences in sensory characteristics between Manchego type cheeses manufactured with either hair sheep milk or cow milk. A total of 25 and 14 Manchego type cheeses from hair sheep milk and cow milk were manufactured, respectively. In addition, 30 and 15 Panela cheeses from hair sheep milk and cow milk were manufactured, respectively. The chemical composition and FA profile were determined in all cheeses. In addition, a sensory analysis was performed in Manchego type cheeses manufactured from either hair sheep milk or cow milk. Moisture content was lower in Manchego type cheeses (37.5 ± 1.26 and 37.5 ± 1.26 g/100 g in cheeses manufactured from hair sheep milk and cow milk, respectively) than in Panela cheeses (54.0 ± 1.26 and 56.1 ± 1.26 g/100 g in cheeses manufactured from hair sheep milk and cow milk, respectively). Ash, protein, and sodium contents were higher in Manchego type cheeses than in Panela cheeses. Manchego type cheese manufactured from hair sheep milk contained more C4:0, C6:0, C8:0, C10:0, C12:0, C14:0, C18:2 cis-9,cis-12, total saturated FA, total short-chain FA, total medium-chain FA, total polyunsaturated FA, and de novo FA than Manchego type cheeses from cow milk. Total content of short-chain FA was higher in hair sheep cheeses (24.4 ± 1.30 and 19.6 ± 1.30 g/100 g in Manchego type and Panela cheeses, respectively) than in cow cheeses (8.89 ± 1.30 and 8.26 ± 1.30 g/100 g in Manchego type and Panela cheeses, respectively). Manchego type cheeses from hair sheep milk obtained higher scores for odor (7.05), texture (6.82), flavor (7.16), and overall acceptance (7.16) compared with those made from cow milk (6.37, 6.12, 6.17, and 6.83, respectively). In conclusion, both Manchego type cheese and Panela cheese manufactured with hair sheep milk had a similar chemical composition and contained higher levels of short-chain FA, total polyunsaturated FA, and de novo FA than those manufactured with cow milk.

Incorporating a Fresh Mixed Annual Ryegrass and Berseem Clover Forage Into the Winter Diet of Dairy Cows Resulted in Reduced Milk Yield, but Reduced Nitrogen Excretion and Reduced Methane Yield.

The winter diet of dairy cows in Mediterranean climate regions is usually a total mixed ration with a base of conserved summer crops such as corn silage and alfalfa hay. However, there is increased labor and financial cost related to this kind of feeding, which could be reduced if fresh forages were used in place of some of the conserved forage in the cow diet. The objective of our study was to evaluate the effect of including fresh mixed annual ryegrass and berseem clover into the diet of dairy cows on milk, nitrogen utilization, and methane emission. Twenty-four lactating dairy cows were split into two groups and offered either a diet similar to that usually offered to the cows (CON) or one where a mixture of fresh annual ryegrass and berseem clover was used to partially substitute the corn silage and alfalfa hay in the diet (MIX). Milk yield was recorded automatically, and methane emissions were estimated using the SF6 tracer technique. The MIX diet had lower crude protein concentration (148 vs. 170 g/kg DM) but higher DM digestibility (81.6 vs. 78.6%) than the CON diet. Compared to the cows offered the CON diet, milk yield was reduced when cows were fed the MIX diet (36.4 vs. 31.9 kg/d), but methane emissions (381 vs. 332 g/d) and nitrogen excretion were also reduced (238 vs. 180 g/d). Nitrogen use efficiency was unaffected (30.8%). In addition, milk from cows fed the MIX diet had a fatty acid profile considered to be more beneficial to human health than that of the milk from cows fed the CON diet. Increasing the protein concentration in the MIX diet, either by direct supplementation or increasing the proportion of legume in the mixed herbage, could overcome the reduction on milk and positively affect methane emission and N use efficiency.

Physico-Chemical, Sensory and Texture Properties of an Aged Mexican Manchego-Style Cheese Produced from Hair Sheep Milk.

The objective of this study was to evaluate the physicochemical and texture changes of the Manchego-style cheese produced from hair sheep (Pelibuey) throughout 180 days of ripening, as well as consumer's acceptance. Cheese pH was constant from 1 to 180 days of ripening. Moisture, water activity, fat, elasticity and hardness decreased from day 1 to day 180, while protein, trichloroacetic acid-soluble N and free amino acid increased. Cheese lightness decreased as ripening time increased, while elasticity and hardness decreased. Principal Component Analysis was useful in discriminating cheeses according to their physicochemical composition and that allowed cheeses to be classified in two groups according to their ripening time and this resulted in those with less than 60 days and those with more than 90 days of ripening. Compared with cheeses ripened at 1 and 90 days, aged cheeses at 180 days reduced scores for appearance, color, odor, taste, texture and overall acceptance. Overall, Manchego-style cheeses from hair sheep had the usual ripened-cheese physicochemical changes.

Acute Pannexin 1 Blockade Mitigates Early Synaptic Plasticity Defects in a Mouse Model of Alzheimer's Disease.

Synaptic loss induced by soluble oligomeric forms of the amyloid ß peptide (sAßos) is one of the earliest events in Alzheimer's disease (AD) and is thought to be the major cause of the cognitive deficits. These abnormalities rely on defects in synaptic plasticity, a series of events manifested as activity-dependent modifications in synaptic structure and function. It has been reported that pannexin 1 (Panx1), a nonselective channel implicated in cell communication and intracellular signaling, modulates the induction of excitatory synaptic plasticity under physiological contexts and contributes to neuronal death under inflammatory conditions. Here, we decided to study the involvement of Panx1 in functional and structural defects observed in excitatory synapses of the amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic (Tg) mice, an animal model of AD. We found an age-dependent increase in the Panx1 expression that correlates with increased Aß levels in hippocampal tissue from Tg mice. Congruently, we also observed an exacerbated Panx1 activity upon basal conditions and in response to glutamate receptor activation. The acute inhibition of Panx1 activity with the drug probenecid (PBN) did not change neurodegenerative parameters such as amyloid deposition or astrogliosis, but it significantly reduced excitatory synaptic defects in the AD model by normalizing long-term potentiation (LTP) and depression and improving dendritic arborization and spine density in hippocampal neurons of the Tg mice. These results suggest a major contribution of Panx1 in the early mechanisms leading to the synaptopathy in AD. Indeed, PBN induced a reduction in the activation of p38 mitogen-activated protein kinase (MAPK), a kinase widely implicated in the early neurotoxic signaling in AD. Our data strongly suggest that an enhanced expression and activation of Panx1 channels contribute to the Aß-induced cascades leading to synaptic dysfunction in AD.

Structural and Technological Characterization of Tropical Smallholder Farms of Dual-Purpose Cattle in Mexico.

Dual-purpose cattle smallholder farms (DP) exhibit a critical economic situation. The objective of this research was building a typology for DP in tropical conditions and characterizing them technologically. This will help developing more effective public policies in DP farms located in tropical conditions. A sample of 1.475 farms located in the tropical area of Mexico was selected. The typology was built using multiple correspondence analysis (MCA). Subsequently, five groups were identified by a hierarchical cluster analysis with Ward's method. Groups 1 and 2, covered a 46.5% of the farms; these ones presented a small-scale productive model with low levels of technological adoption, improvements were mainly associated to the area of reproduction and genetics. Very small farms (Group 3) showed orientation to subsistence. They need to improve all the technological areas. Groups 4 and 5 (29.4% of the sample) were the biggest and more specialized farms. Group four farms were located in dry tropics and showed the highest levels of technological adoption in the areas of reproduction, management, and feeding. These farms require improvement in the areas of reproduction, animal health, and feeding. Group 5 farms were located in the wet tropics and showed specialization in reproduction, genetics, and animal health areas. In this last group, it is necessary to improve management and feeding areas.

Trends and Drivers of Change of Pastoral Beef Production Systems in a Mediterranean-Temperate Climate Zone of Chile.

The present study used surveys of the cattle sector over the period of 2009-2015 to develop a typology of cattle farms to evaluate their evolution over time and to identify variables that may be associated with systems' adaptive changes and continuance. Four groups of farms were defined using multivariate analyses as follows: Group I are small calf-cow operations using non-specialized beef breeds; Group II is similar to Group I but employs specialized beef breeds; Group III is dedicated to finishing cattle, and Group IV are larger farms (>1000 animals) with a complete cycle of breeding and fattening. In general, beef cattle production in the temperate-Mediterranean Southern Zone of Chile is declining in response to the opening up of the economy that allows for ample imports, the high opportunity cost of land, and recurrent droughts associated with climate change. Current policies and regulations have modified farms' businesses models depending on their ease of access to markets, farm size and financial capacity. The defined groups require different development paths and strategies. Sustainable intensification is an alternative strategy for farms in Group I and II, particularly if they were to contract the finishing stage of their cattle with Group III farms. In contrast, it is suggested that Group IV farms concentrate on pastoral production using low external inputs to enhance the production of "natural" beef for high-value niche markets, with positive externalities.

Short communication: Discrimination between retail bovine milks with different fat contents using chemometrics and fatty acid profiling.

We used a multivariate chemometric approach to differentiate or associate retail bovine milks with different fat contents and non-dairy beverages, using fatty acid profiles and statistical analysis. We collected samples of bovine milk (whole, semi-skim, and skim; n = 62) and non-dairy beverages (n = 27), and we analyzed them using gas-liquid chromatography. Principal component analysis of the fatty acid data yielded 3 significant principal components, which accounted for 72% of the total variance in the data set. Principal component 1 was related to saturated fatty acids (C4:0, C6:0, C8:0, C12:0, C14:0, C17:0, and C18:0) and monounsaturated fatty acids (C14:1 cis-9, C16:1 cis-9, C17:1 cis-9, and C18:1 trans-11); whole milk samples were clearly differentiated from the rest using this principal component. Principal component 2 differentiated semi-skim milk samples by n-3 fatty acid content (C20:3n-3, C20:5n-3, and C22:6n-3). Principal component 3 was related to C18:2 trans-9,trans-12 and C20:4n-6, and its lower scores were observed in skim milk and non-dairy beverages. A cluster analysis yielded 3 groups: group 1 consisted of only whole milk samples, group 2 was represented mainly by semi-skim milks, and group 3 included skim milk and non-dairy beverages. Overall, the present study showed that a multivariate chemometric approach is a useful tool for differentiating or associating retail bovine milks and non-dairy beverages using their fatty acid profile.

Connexinopathies: a structural and functional glimpse.

Mutations in human connexin (Cx) genes have been related to diseases, which we termed connexinopathies. Such hereditary disorders include nonsyndromic or syndromic deafness (Cx26, Cx30), Charcot Marie Tooth disease (Cx32), occulodentodigital dysplasia and cardiopathies (Cx43), and cataracts (Cx46, Cx50). Despite the clinical phenotypes of connexinopathies have been well documented, their pathogenic molecular determinants remain elusive. The purpose of this work is to identify common/uncommon patterns in channels function among Cx mutations linked to human diseases. To this end, we compiled and discussed the effect of mutations associated to Cx26, Cx32, Cx43, and Cx50 over gap junction channels and hemichannels, highlighting the function of the structural channel domains in which mutations are located and their possible role affecting oligomerization, gating and perm/selectivity processes.

From Hyperactive Connexin26 Hemichannels to Impairments in Epidermal Calcium Gradient and Permeability Barrier in the Keratitis-Ichthyosis-Deafness Syndrome.

The keratitis-ichthyosis-deafness (KID) syndrome is characterized by corneal, skin, and hearing abnormalities. KID has been linked to heterozygous dominant missense mutations in the GJB2 and GJB6 genes, encoding connexin26 and 30, respectively. In vitro evidence indicates that KID mutations lead to hyperactive (open) hemichannels, which in some cases is accompanied by abnormal function of gap junction channels. Transgenic mouse models expressing connexin26 KID mutations reproduce human phenotypes and present impaired epidermal calcium homeostasis and abnormal lipid composition of the stratum corneum affecting the water barrier. Here we have compiled relevant data regarding the KID syndrome and propose a mechanism for the epidermal aspects of the disease.