Survivorship of geographic Pomacea canaliculata populations in responses to cold acclimation

1. Pomacea canaliculata, a freshwater snail from South America, has rapidly established natural populations from south to north subtropical region in China, since its original introductions in the 1980s. Low temperature in winter is a limiting factor in the geographic expansion and successfully establishment for apple snail populations. There have been some studies on population level of low temperature tolerance for P. canaliculata, yet little is quantified about its life‐history traits in responses to cold temperatures. Whether these responses vary with the acclimation location is also unclear. We investigated the survivorship and longevity of P. canaliculata in responses to cold temperatures and examine whether these responses vary with the location and snail size. We hypothesized that survival of the snails depends on their shell height and the level of low temperature, and P. canaliculata population from the mid-subtropical zone may exhibit the highest viability over the cold thermal range.
2. We sampled P. canaliculata populations from five latitude and longitude ranges of subtropical China: Guangzhou population in southernmost (SM‐GZ), three populations of Yingtan (MR‐YT), Ningbo (MR‐NB), Ya'an (MR‐YA) in midrange, and Huanggang population in northernmost (NM‐HG) subtropical zone. For each P. canaliculata population, survival and longevity at six cold acclimation temperature levels (12, 9, 6, 3, 0, and ?3°C) were quantified, and the effects of location and shell height were examined.
3. The MR‐YA population from mid-subtropical zone of China exhibited the highest survival rate and prolonged survival time regardless of the temperature acclimation treatments, whereas the SM‐GZ population from southern subtropical was the most sensitive to cold temperatures, particular temperatures below 9°C. No individuals of the SM‐GZ population could survive after stressed for 30 days (3°C), 5 days (0°C) and 2 days (?3°C), respectively. For each experimental P. canaliculata population held at 3, 0, and ?3°C, individuals with intermediate shell height of 15.0–25.0 mm had significantly higher survivals.
4. The results highlight a request of a more thorough investigation on acclimation responses in each of the life table demographic parameters for P. canaliculata, and pose the question of whether natural selection or some genetic changes may have facilitated adaptation in invasive locations.

     

Melanoma targeting property of a Lu-177-labeled lactam bridge-cyclized alpha-MSH peptide

The purpose of this study was to determine the melanoma targeting property of ¹⁷⁷Lu-DOTA-GGNle-CycMSH_hex in B16/F1 melanoma-bearing C57 mice. ¹⁷⁷Lu-DOTA-GGNle-CycMSH_hex exhibited high receptor-mediated melanoma uptake and fast urinary clearance. The tumor uptake of ¹⁷⁷Lu-DOTA-GGNle-CycMSH_hex was 20.25 ± 4.59 and 21.63 ± 6.27% ID/g at 0.5 and 2 h post-injection, respectively. Approximately 83% of injected dose cleared out the body via urinary system at 2 h post-injection. ¹⁷⁷Lu-DOTA-GGNle-CycMSH_hex showed high tumor to normal organ uptake ratios except for the kidneys. The tumor/kidney uptake ratios of ¹⁷⁷Lu-DOTA-GGNle-CycMSH_hex were 2.76 and 1.74 at 2 and 24 h post-injection. The melanoma lesions were clearly visualized by SPECT/CT using ¹⁷⁷Lu-DOTA-GGNle-CycMSH_hex as an imaging probe at 2 h post-injection. Overall, high melanoma uptake coupled with fast urinary clearance of ¹⁷⁷Lu-DOTA-GGNle-CycMSH_hex underscored its potential for melanoma treatment in the future.     

Differential expression of microRNAs associated with neurodegenerative diseases and diabetic nephropathy in protein l-isoaspartyl methyltransferase-deficient mice

Protein l -isoaspartyl methyltransferase (PIMT/PCMT1), an enzyme repairing isoaspartate residues in peptides and proteins that result from the spontaneous decomposition of normal l -aspartyl and l -asparaginyl residues during aging, has been revealed to be involved in neurodegenerative diseases (NDDs) and diabetes. However, the molecular mechanisms for a putative association of PIMT dysfunction with these diseases have not been clarified. Our study aimed to identify differentially expressed microRNAs (miRNAs) in the brain and kidneys of PIMT-deficient mice and uncover the epigenetic mechanism of PIMT-involved NDDs and diabetic nephropathy (DN). Differentially expressed miRNAs by sequencing underwent target prediction and enrichment analysis in the brain and kidney of PIMT knockout (KO) mice and age-matched wild-type (WT) littermates. Sequence analysis revealed 40 differentially expressed miRNAs in the PIMT KO mouse brain including 25 upregulated miRNAs and 15 downregulated miRNAs. In the PIMT KO mouse kidney, there were 80 differentially expressed miRNAs including 40 upregulated miRNAs and 40 downregulated miRNAs. Enrichment analysis and a systematic literature review of differentially expressed miRNAs indicated the involvement of PIMT deficiency in the pathogenesis in NDDs and DN. Some overlapped differentially expressed miRNAs between the brain and kidney were quantitatively assessed in the brain, kidney, and serum-derived exosomes, respectively. Despite being preliminary, these results may aid in investigating the pathological hallmarks and identify the potential therapeutic targets and biomarkers for PIMT dysfunction-related NDDs and DN.     

Defective Mitochondrial Dynamics Is an Early Event in Skeletal Muscle of an Amyotrophic Lateral Sclerosis Mouse Model

Mitochondria are dynamic organelles that constantly undergo fusion and fission to maintain their normal functionality. Impairment of mitochondrial dynamics is implicated in various neurodegenerative disorders. Amyotrophic lateral sclerosis (ALS) is an adult-onset neuromuscular degenerative disorder characterized by motor neuron death and muscle atrophy. ALS onset and progression clearly involve motor neuron degeneration but accumulating evidence suggests primary muscle pathology may also be involved. Here, we examined mitochondrial dynamics in live skeletal muscle of an ALS mouse model (G93A) harboring a superoxide dismutase mutation (SOD1^G93A). Using confocal microscopy combined with overexpression of mitochondria-targeted photoactivatable fluorescent proteins, we discovered abnormal mitochondrial dynamics in skeletal muscle of young G93A mice before disease onset. We further demonstrated that similar abnormalities in mitochondrial dynamics were induced by overexpression of mutant SOD1^G93A in skeletal muscle of normal mice, indicating the SOD1 mutation drives ALS-like muscle pathology in the absence of motor neuron degeneration. Mutant SOD1^G93A forms aggregates inside muscle mitochondria and leads to fragmentation of the mitochondrial network as well as mitochondrial depolarization. Partial depolarization of mitochondrial membrane potential in normal muscle by carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) caused abnormalities in mitochondrial dynamics similar to that in the SOD1^G93A model muscle. A specific mitochondrial fission inhibitor (Mdivi-1) reversed the SOD1^G93A action on mitochondrial dynamics, indicating SOD1^G93A likely promotes mitochondrial fission process. Our results suggest that accumulation of mutant SOD1^G93A inside mitochondria, depolarization of mitochondrial membrane potential and abnormal mitochondrial dynamics are causally linked and cause intrinsic muscle pathology, which occurs early in the course of ALS and may actively promote ALS progression.     

The subtype-specific molecular function of SPDEF in breast cancer and insights into prognostic significance

Breast cancer (BC) is a molecular diverse disease which becomes the most common malignancy among women worldwide. There are four BC subtypes (Luminal A, Luminal B, HER2-enriched and Basal-like) robustly established following gene expression pattern-based characterization, behave significant differences in terms of their incidence, risk factors, prognosis and therapeutic sensitivity. Thus, there is an urgent need to provide mechanism research, treatment strategies and/or prognosis evaluation based on the patient stratification of BC subtypes. The prostate-derived ETS factor SPDEF was first identified as an activator of prostate specific antigen, and then, the involvements in many aspects of BC have been proposed. However, the subtype-specific molecular function of SPDEF in BC and insights into prognostic significance have not been clearly elucidated. This study demonstrated for the first time that SPDEF may play a diversity role in the expression levels, clinicopathologic importance, biological function and prognostic evaluation in BC via bioinformatics and experimental evidence, which mainly depends on different BC subtyping. In summary, our findings would help to better understand the possible mechanisms of various BC subtypes and to find possible candidate genes for prognostic and therapeutic usage.     

Over-Expression of TRESK K+ Channels Reduces the Excitability of Trigeminal Ganglion Nociceptors

TWIK-related spinal cord K⁺ (TRESK) channel is abundantly expressed in trigeminal ganglion (TG) and dorsal root ganglion neurons and is one of the major background K⁺ channels in primary afferent neurons. Mutations in TRESK channels are associated with familial and sporadic migraine. In rats, both chronic nerve injury and inflammation alter the expression level of TRESK mRNA. Functional studies indicate that reduction of endogenous TRESK channel activity results in hyper-excitation of primary afferent neurons, suggesting that TRESK is a potential target for the development of new analgesics. However, whether and how enhancing TRESK channel activity would decrease the excitability of primary afferent neurons has not been directly tested. Here, we over-expressed TRESK subunits in cultured mouse TG neurons by lipofectamine-mediated transfection and investigated how this altered the membrane properties and the excitability of the small-diameter TG population. To account for the heterogeneity of neurons, we further divided small TG neurons into two groups, based on their ability to bind to fluorescently-labeled isolectin B (IB4). The transfected TG neurons showed a 2-fold increase in the level of TRESK proteins. This was accompanied by a significant increase in the fraction of lamotrigine-sensitive persistent K⁺ currents as well as the size of total background K⁺ currents. Consequently, both IB4-positive and IB4-negative TG neurons over-expressing TRESK subunits exhibited a lower input resistance and a 2-fold increase in the current threshold for action potential initiation. IB4-negative TG neurons over-expressing TRESK subunits also showed a significant reduction of the spike frequency in response to supra-threshold stimuli. Importantly, an increase in TRESK channel activity effectively inhibited capsaicin-evoked spikes in TG neurons. Taken together, our results suggest that potent and specific TRESK channel openers likely would reduce the excitability of primary afferent neurons and therefore are potential therapeutics for the treatment of migraine and other chronic pain symptoms.     

LncRNA TP73-AS1 enhances the malignant properties of pancreatic ductal adenocarcinoma by increasing MMP14 expression through miRNA -200a sponging

Pancreatic ductal adenocarcinoma (PDAC) is an invasive and aggressive cancer that remains a major threat to human health across the globe. Despite advances in cancer treatments and diagnosis, the prognosis of PDAC patients remains poor. New and more effective PDAC therapies are therefore urgently required. In this study, we identified a novel host factor, namely the LncRNA TP73-AS1, as overexpressed in PDAC tissues compared to adjacent healthy tissue samples. The overexpression of TP-73-AS1 was found to correlate with both PDAC stage and lymph node metastasis. To reveal its role in PDCA, we targeted TP73-AS1 using LnRNA inhibitors in a range of pancreatic cancer (PC) cell lines. We found that the inhibition of TP73-AS1 led to a loss of MMP14 expression in PC cells and significantly inhibited their migratory and invasive capacity. No effects of TP73-AS1 on cell survival or proliferation were observed. Mechanistically, we found that TP73-AS1 suppressed the expression of the known oncogenic miR-200a. Taken together, these data highlight the prognostic potential of TP73-AS1 for PC patients and highlight it as a potential anti-PDAC therapeutic target.