Salubrinal enhances eIF2α phosphorylation and improves fertility in a mouse model of Classic Galactosemia

Loss of galactose-1 phosphate uridylyltransferase (GALT) activity in humans results in Classic Galactosemia, and the GalT-deficient (GalT^?/?) mouse mimics the patient condition. GalT^?/? ovaries display elevated endoplasmic reticulum (ER) stress marker, BiP, and downregulated canonical phosphatidylinositol 3-kinase (Pi3k)/protein kinase B (Akt) growth/pro-survival signaling. Numbers of primordial follicles are reduced in the mutants, recapitulating the accelerated ovarian aging seen in human patients. We previously found that oral administration of the compound Salubrinal (an eIF2α phosphatase inhibitor), resulted in reduction of ovarian BiP expression, rescued Pi3k/Akt signaling, and a doubling of primordial follicles in GalT^?/? adults. Here, we further characterized galactosemic stress in GalT^?/? mice versus wild-type (WT) controls, and examined whether Salubrinal treatment improved broader reproductive parameters. We assessed the expression levels of factors of the unfolded protein response (UPR), and found that BiP, phospho-Perk, and phospho-eIF2α were all elevated in GalT^?/? ovaries. However, neither IKK activation (NFκB pathway) nor alternative Xbp1 splicing downstream of ER membrane protein Ire1α activation was induced, suggesting an Xbp1-independent UPR in galactosemic stress. Moreover, Salubrinal treatment significantly increased the number of ovulated eggs in mutant animals after gonadotrophic superovulation. Salubrinal treatment also normalized estrus cycle stage lengths and resulted in significantly larger litter sizes than vehicle-treated mutants. Overall, we show that Salubrinal protects against galactosemia-induced primordial follicle loss in a fashion that includes suppressing the de-phosphorylation of eIF2α, and that intervention in this way significantly improves and extends ovarian function, fertility, and fecundity.     

Second-generation aryl isonitrile compounds targeting multidrug-resistant Staphylococcus aureus

Antibiotic resistance remains a major global public health threat that requires sustained discovery of novel antibacterial agents with unexploited scaffolds. Structure-activity relationship of the first-generation aryl isonitrile compounds we synthesized led to an initial lead molecule that informed the synthesis of a second-generation of aryl isonitriles. From this new series of 20 compounds, three analogues inhibited growth of methicillin-resistant Staphylococcus aureus (MRSA) (from 1 to 4?µM) and were safe to human keratinocytes. Compound 19, with an additional isonitrile group exhibited improved activity against MRSA compared to the first-generation lead compound. This compound emerged as a candidate worthy of further investigation and further reinforced the importance of the isonitrile functionality in the compounds’ anti-MRSA activity. In a murine skin wound model, 19 significantly reduced the burden of MRSA, similar to the antibiotic fusidic acid. In summary, 19 was identified as a new lead aryl isonitrile compound effective against MRSA.     

Hybrids made from antimicrobial peptides with different mechanisms of action show enhanced membrane permeabilization

Combining two known antimicrobial peptides (AMPs) into a hybrid peptide is one promising avenue in the design of agents with increased antibacterial activity. However, very few previous studies have considered the effect of creating a hybrid from one AMP that permeabilizes membranes and another AMP that acts intracellularly after translocating across the membrane. Moreover, very few studies have systematically evaluated the order of parent peptides or the presence of linkers in the design of hybrid AMPs. Here, we use a combination of antibacterial measurements, cellular assays and semi-quantitative confocal microscopy to characterize the activity and mechanism for a library of sixteen hybrid peptides. These hybrids consist of permutations of two primarily membrane translocating peptides, buforin II and DesHDAP1, and two primarily membrane permeabilizing peptides, magainin 2 and parasin. For all hybrids, the permeabilizing peptide appeared to dominate the mechanism, with hybrids primarily killing bacteria through membrane permeabilization. We also observed increased hybrid activity when the permeabilizing parent peptide was placed at the N-terminus. Activity data also highlighted the potential value of considering AMP cocktails in addition to hybrid peptides. Together, these observations will guide future design efforts aiming to design more active hybrid AMPs.     

Multiple recycling routes: Canonical vs. non-canonical mitophagy in the heart

The heart is composed of cardiomyocytes that require large amounts of energy to sustain contraction. Mitochondria are distinctive organelles of bacterial origin that generate most of the energy for the heart via oxidative phosphorylation. To ensure a healthy population of mitochondria that efficiently produce ATP, myocytes quickly eliminate any unhealthy or unwanted mitochondria via a process known as mitochondrial autophagy, or mitophagy. It is especially important to selectively remove damaged or aged mitochondria since they can become excessive producers of reactive oxygen species and release pro-death proteins. Because this is such a crucial cellular process, cells have several mechanisms in place to deal with potentially harmful mitochondria. Here, we review the various pathways identified to date and how they are regulated. We also discuss the importance of these canonical and non-canonical pathways in the heart and their link to cardiovascular health, disease and aging.     

Molecular and cellular bases of diabetes: Focus on type 2 diabetes mouse model-TallyHo

Diabetes is a chronic lifestyle disorder that affects millions of people worldwide. Diabetes is a condition where the body does not produce sufficient insulin or does not use it efficiently. Insulin resistance in diabetes or obesity causes the pancreatic β-cells to increase the insulin output. Diabetes occurs in multiple forms, including type 1, type 2, type 3 and gestational. Type 2 diabetes accounts for ～90–95% of total affected population and is associated with both impaired insulin production by the β-cells of the pancreas and impaired insulin release in response to high blood glucose levels. Diabetes is tightly linked with genetic mutations and genetic and lifestyle activities, including diet and exercise. Recent epidemiological studies established a close link between the diabetes and progression to Alzheimer's disease. This article summarizes various molecular mechanisms involved in the developments of diabetes, including biochemical characteristics, genetic and molecular links with Alzheimer's disease, β-cell function, and factors associated with diabetes. This will help us in the development of novel therapeutic strategies targeting AD in future.     

Hypoxia-inducible factor 1 signalling,metabolism and its therapeutic potential in cardiovascular disease

Cardiovascular disease (CVD) accounts for the largest number of deaths worldwide, necessitating the development of novel treatments and prevention strategies. Given the huge energy demands placed on the heart, it is not surprising that changes in energy metabolism play a key role in the development of cardiac dysfunction in CVD. A reduction in oxygen delivery to the heart, hypoxia, is sensed and responded to by the hypoxia-inducible factor (HIF) and its family of proteins, by regulating the oxygen-dependent signalling cascade and subsequent response. Hypoxia is one of the main drivers of metabolic change in ischaemic disease and myocardial infarction, and we therefore suggest that HIF may be an attractive therapeutic target. In this review, we assess cardiac energy metabolism in health and disease, and how these can be regulated by HIF-1α activation. We then present an overview of research in the field of hypoxia-mimetic drugs recently developed in other treatment fields, which provide insight into the potential of systemic HIF-1α activation therapy for treating the heart.     

The role of posttranslational modifications of α-synuclein and LRRK2 in Parkinson's disease: Potential contributions of environmental factors

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease (AD), and the most prevalent movement disorder. PD is characterized by dopaminergic neurodegeneration in the substantia nigra, but its etiology has yet to be established. Among several genetic variants contributing to PD pathogenesis, α-synuclein and leucine-rich repeat kinase (LRRK2) are widely associated with neuropathological phenotypes in familial and sporadic PD. α-Synuclein and LRRK2 found in Lewy bodies, a pathogenic hallmark of PD, are often posttranslationally modified. As posttranslational modifications (PTMs) are key processes in regulating the stability, localization, and function of proteins, PTMs have emerged as important modulators of α-synuclein and LRRK2 pathology. Aberrant PTMs altering phosphorylation, ubiquitination, nitration and truncation of these proteins promote PD pathogenesis, while other PTMs such as sumoylation may be protective. Although the causes of many aberrant PTMs are unknown, environmental risk factors may contribute to their aberrancy. Environmental toxicants such as rotenone and paraquat have been shown to interact with these proteins and promote their abnormal PTMs. Notably, manganese (Mn) exposure leads to a PD-like neurological disorder referred to as manganism—and induces pathogenic PTMs of α-synuclein and LRRK2. In this review, we highlight the role of PTMs of α-synuclein and LRRK2 in PD pathogenesis and discuss the impact of environmental risk factors on their aberrancy.     

Distribution and Broadscale Habitat Relations of the Wolverine in the Contiguous United States

ABSTRACT Conservation of the wolverine (Gulo gulo) at the southern extent of its North American range requires reliable understandings of past and present distribution patterns and broad-scale habitat relations. We compiled 820 verifiable and documented records of wolverine occurrence (specimens, DNA detections, photos, and accounts of wolverines being killed or captured) in the contiguous United States from museums, the literature, and institutional archives. We spatially referenced 729 records with areal precision ≤1 township (93.2 km²) and temporal precision ≤10 years. Historical records (1827–1960) were located primarily in the western mountains and Great Lakes region. However, our data suggest that the historical distribution of wolverines in the Cascade Range and Sierra Nevada was disjunct, contradicting previous interpretations. Our results indicate that wolverine range in the contiguous United States had contracted substantially by the mid-1900s. Current records (1995–2005) are limited to north-central Washington, northern and central Idaho, western Montana, and northwestern Wyoming. We investigated potential relations between wolverines and alpine vegetation, cold temperatures, and spring snow cover by comparing the distribution of historical wolverine records with Kuchler's potential natural vegetation types, Holdridge's climatic life zones, and EASE snow-cover maps during the latter portion of the wolverine denning period (15 Apr-14 May). In the western mountains, historical wolverine records generally occurred in or near alpine vegetation and climatic conditions, especially at the limits of their distribution in the Cascade Range, Sierra Nevada, and southern Rocky Mountains. However, the only habitat layer that fully accounted for historical distribution patterns was spring snow cover. Causal factors for the extirpation of wolverines from the southern portions of their range in the contiguous United States are unknown, but are likely related to high levels of human-caused mortality and low to nonexistent immigration rates.     

Mineral soil carbon pool responses to forest clearing in Northeastern hardwood forests

Harvesting forests introduces substantial changes to the ecosystem, including physical and chemical alterations to the soil. In the Northeastern United States, soils account for at least 50% of total ecosystem C storage, with mineral soils comprising the majority of that storage. However, mineral soils are sometimes omitted from whole‐system C accounting models due to variability, lack of data, and sample collection challenges. This study aimed to provide a better understanding of how forest harvest affects mineral soil C pools over the century following disturbance. We hypothesized that mineral soil C pools would be lower in forests that had been harvested in the last one hundred years vs. forests that were >100 years old. We collected mineral soil cores (to 60 cm depth) from 20 forest stands across the Northeastern United States, representing seven geographic areas and a range of times since last harvest. We compared recently harvested forests to >100‐year‐old forests and used an information theoretic approach to model C pool dynamics over time after disturbance. We found no significant differences between soil C pools in >100‐year‐old and harvested forests. However, we found a significant negative relationship between time since forest harvest and the size of mineral soil C pools, which suggested a gradual decline in C pools across the region after harvesting. We found a positive trend between C : N ratio and % SOM in harvested forests, but in >100‐year‐old forests a weak negative trend was found. Our study suggests that forest harvest does cause biogeochemical changes in mineral soil, but that a small change in a C pool may be difficult to detect when comparing large, variable C pools. Our results are consistent with previous studies that found that soil C pools have a gradual and slow response to disturbance, which may last for several decades following harvest.     

Phenology and production of Hassaoui grapevines as affected by climate anomalies in Al Ahsa region

Climate change is a dramatic crisis that has left severe impacts on viticulture. Phenological events over 41 years and annual climatic anomalies’ data over these years in Al Ahsa region were procured. Annual temperature and wind speed anomalies had the strongest influence on all phenological events of the varieties White and Red Hassaoui, starting from the beginning of budburst until harvest. Moreover, the average yield of both varieties decreased significantly by 319.4 and 317 kg ha^?1 respectively between 1997 and 2019 in comparison with the interval of years 1979–1996. Earlier phenological events were positively correlated with annual temperature anomaly and negatively correlated with annual wind speed anomaly. The latter shortened the dates of occurrence of beginning and full veraison. Yield decreased with higher annual temperature, wind speed and total cloud cover anomalies, and lower annual total precipitation anomaly. Higher annual temperature and wind speed anomalies were correlated with a shorter period between beginning of budburst to beginning of veraison (P3). Shorter periods between beginning and full veraison (P6) and beginning of veraison and harvest (P7) of Red Hassaoui were positively correlated with annual precipitable water anomaly. Results suggest a high level of adaptation of both tested varieties to changing climate conditions in Al Ahsa, though irrigating vines after harvest on a weekly basis would help overcoming the minimal reduction in yield which was caused by the shortage in precipitation.