Starvation Period Research Articles

Anatomy of a diamondiferous gravel barrier spit at the palaeo‐Orange River mouth, south‐western Namibia

ABSTRACTThe sedimentary facies architecture of a Plio‐Pleistocene diamond‐bearing gravel barrier spit within the palaeo‐Orange River mouth in south‐western Namibia has been revealed during onshore mining activities. Four sedimentary facies associations build this ancient coastal landform and have been interpreted, from a seaward to landward direction, as sediments in: (i) the foreshore, represented by an intertidal beach; (ii) a subtidal spit platform on which the spit developed; (iii) storm‐constructed spit head recurves on the landward side of the spit; and (iv) an estuarine back‐barrier. This sedimentary record reflects an evolving spit that grew in response to a combination of marine and fluvial processes in a wave‐dominated, high‐energy coastal regime. Here, the southern Atlantic Ocean aggressively dispersed sediment delivered by a Plio‐Pleistocene Orange River, ensuring that the fine‐grained sediments were removed to allow only the gravel fraction to build up along the coastline. This extreme dispersal of sediment also precluded the construction of a classic delta; hence sediment storage offshore of the river mouth was limited and spit growth was dependent on the direct supply of river sediment. In response to the intermittent supply of sediment, spit growth and decay alternated during periods of sediment abundance and starvation, respectively. During positive sediment budget, the spit extended northward and cut off parts of the mainland to form an estuarine back‐barrier. Foreshore and spit head progradation was sustained under these conditions, and formed a beach‐ridge plain with a topographic expression of several coast‐parallel ridges that curved at the spit head into the back‐barrier. Spit extension and recurve development were controlled by a combination of high sediment supply, a vigorous longshore drift and powerful waves approaching from various directions. This Plio‐Pleistocene coastal landform in Namibia offers a depositional model relevant to gravel‐dominated barrier spits near river mouths along wave‐dominated clastic coasts.

Euglycaemic ketoacidosis during pregnancy: More common than you think

Background: Euglycaemic ketoacidosis is a rare type of metabolic acidosis, with increased production of ketonic bodies and normal serum glucose. When it occurs during pregnancy, it might lead to adverse maternal and fetal outcomes. Pregnancy itself is a diabetogenic state that might predispose the patient to develop ketoacidosis following even relatively short periods of starvation and as such, a high index of suspicion is required for the diagnosis to be made and for the management plan to be established. Case presentation: We present a case of euglycaemic ketoacidosis in a twin pregnancy, which occurred in the second trimester, necessitating prompt and aggressive management, that eventually required early delivery due to the development of preeclampsia. Discussion/Conclusion: The physiology and pathology of euglycaemic ketoacidosis during pregnancy and the management required to avoid the potential maternal and fetal risks that such a condition might be complicated with.

Seasonality and growth in tropical freshwater ectotherm vertebrates: Results from 1-year experimentation in the African gray bichir, giraffe catfish, and the West African mud turtle.

Growth in ectotherm vertebrates is strongly rhythmed by seasonal variation in environmental parameters. To track the seasonal variation in ancient times in a continental and tropical context, we aim to develop a method based on the use of the growth rate of fossil ectotherm vertebrates (actinopterygians and chelonians) influenced by seasonal environmental fluctuations they experienced in their lifetime. However, the impact of environmental parameters on growth, positive or negative, and its intensity, depends on the taxa considered, and data are scarce for tropical species. For 1 year, an experiment was conducted to better understand the effect of seasonal variation in environmental parameters (food abundance, temperature, and photoperiod) on the somatic growth rate of three species of tropical freshwater ectotherm vertebrates: the fishes Polypterus senegalus and Auchenoglanis occidentalis and the turtle Pelusios castaneus. Mimicking seasonal shifts expected to be experienced by the animals in the wild, the experiment highlighted the preponderant effect of food abundance on the growth rate of those three species. Water temperature variation had a significant effect on the growth rate of Po. senegalus and Pe. castaneus. Moreover, the photoperiod demonstrated no significant effect on the growth of the three species. The duration of application of starvation or cool water conditions, ranging from 1 to 3months, did not affect the growth rate of the animals. However, Pelusios castaneus showed a temporary sensitivity to the return of ad libitum feeding or of warm water, after a period of starvation or cool water, by a period of compensatory growth. Finally, this experiment revealed, in the three species, fluctuations in the growth rate under controlled and constant conditions. This variation, similar to the variation in precipitation and temperature observed in their native environment, could be linked to a strong effect of an internal rhythm controlling somatic growth rate.

Performance Evaluation of a Novel Bio-Trickling Filter for Styrene Waste Gas Treatment

In recent years, styrene waste gas has become a hot issue in the waste gas treatment industry due to its hydrophobicity and easy polymerization. This study is aimed at the problems of long empty bed residence time and low removal capacity of waste gas from styrene degradation by bio-trickling filter (BTF). A novel bio-trickling filter (NBTF) that we designed was used to explore the effects of styrene inlet concentration, empty bed residence time (EBRT), and starvation period on the performance of NBTF in the degradation of styrene waste gas. The experimental results show that the NBTF can be started in 17 days; when the inlet concentration was lower than 1750 mg/m3 and the EBRT was 59.66 s, the removal efficiency (RE) of styrene can reach 100%. When the inlet concentration was 1000 mg/m3 and the EBRT was greater than 39.77 s, styrene waste gas can also be completely degraded. The above proves that NBTF can complete the degradation of styrene waste gas with high concentration under the condition of short EBRT; in the whole operation process, the maximum elimination capability (EC) of styrene was 112.96 g/m3/h, and NBTF shows excellent degradation performance of styrene. When the starvation period was 2 days, 7 days and 15 days, respectively, NBTF can recover high degradation performance within 2 days after restart. The NBTF has good operation performance in 124 days of operation, which proves that the NBTF can effectively degrade styrene waste gas. This provides a reference basis for industrial treatment of styrene waste gas in the future.

Performance of Anaerobic Membrane Bioreactor (AnMBR) with Sugarcane Bagasse Ash-based Ceramic Membrane treating Simulated Low-strength Municipal Wastewater: Effect of Operation Conditions.

The online version contains supplementary material available at 10.1007/s11270-023-06173-3.

Response of dissimilatory perchlorate reducing granular sludge (DPR-GS) system to high-strength perchlorate and starvation stress in UASB reactor: Performance, kinetics and recovery mechanism

Under high-strength perchlorate concentration ranging from 300 to 1300 mg/L, the dissimilatory perchlorate reducing granular sludge (DPR-GS) was successfully cultivated in an up-flow anaerobic sludge blanket (UASB) reactor to investigate performance and starvation recovery for treating perchlorate wastewater. The mature DPR-GS had excellent perchlorate removal efficiency (98.47%) at 1200 mg/L. Microbial community analysis suggested that the dominant genera in mature DPR-GS were Sulfurospirillum and Acinetobacter. The DPR-GS system conformed well to the modified Stover-Kincannon model with the maximum substrate utilization (Umax) of 90.01 kg/(m3·d) and the saturation value constant (KB) of 83.93 kg/(m3·d). Additionally, the starvation recovery of DPR-GS system was first investigated. The perchlorate removal efficiency recovered to 91.39% after 8 days under the 30-day starvation stress, and the microbial activity also recovered to normal condition. The three-dimensional excitation-emission matrix (3D-EEM) proved that the tryptophan-like component in extracellular polymeric substance (EPS) increased during the starvation period, which was associated with immune functions and played an important role in maintaining the microbial activity. Meanwhile, the secretion of humic acid-like component in EPS promoted electron transfer efficiency, thus improving microbial metabolic activity during the recovery period. Further analysis by the parallel factor (PARAFAC) of 3D-EEM confirmed that the decrease of immune substances and the increase of metabolic products in EPS during the starvation recovery period, which enhanced the recovery of microbial activity and the improvement of perchlorate removal performance. This study revealed the response of the DPR-GS system to high-strength perchlorate and starvation stress, thus provided a further basis of perchlorate tolerance and starvation recovery for the application of DPR-GS system to remove high-strength concentrated perchlorate from contaminated water.

Retrogressive moulting in khapra beetle, Trogoderma granarium (Coleoptera: Dermestidae)

AbstractInsect larvae typically moult to grow, but here we investigate insect larvae that moult to shrink; that is, retrogressive moulting or retrogressive development. We demonstrate this phenomenon in khapra beetle, Trogoderma granarium Everts (Dermestidae), among the world's most invasive pests of stored grains and cereal products, and a quarantine pest of interest for many countries. Larvae survived a 3‐month period of starvation, moulting up to six times and reducing their body mass by about half, on average. When reprovisioned with food, most larvae resumed the normal trajectory of development and pupated within a month. Thus, retrogressive development is a mechanism that may favour species whose resources exhibit feast‐or‐famine dynamics. By enabling survival during periods of privation, retrogressive development contributes to the invasiveness of the khapra beetle by allowing them to persist for long periods in empty storage facilities or empty containers used for international grain shipments.

Using inorganic acids to stop purple phototrophic bacteria metabolism improves PHA recovery at a large scale

Polyhydroxyalkanoate (PHA) production at a large scale by purple phototrophic bacteria (PPB) is hindered due to high production costs and limited recovery due to its consumption during starvation periods. The present study identified cost-effective inorganic acids as inactivation methods for PPB to obtain higher PHA recovery. The study was performed on reactors of different scales (10 L and 0.5 L) to grow PPB and recover PHA subsequently. The permanent feast strategy was adopted to obtain higher PHA in an anaerobic environment. As a result, the study achieved 33% (dry weight) PHA recovery using inorganic acid inactivation, while formaldehyde inactivation (traditional method) achieved significantly lower PHA recovery (20% only). The results from inorganic acid inactivation were further examined for their stability. The samples were stable even after day 14, and the PHA recovery was the same as on day 0. This pioneering study shows that inorganic acids can be used to inactivate the PPB metabolism to obtain higher PHA recovery; inorganic acid inactivation could be economical for large-scale PHA production.Graphical

From shallow-water carbonate ramp to hemipelagic deep-marine carbonate deposition: Part 2. Sirogojno (Klisura quarry) - the reference section of the Middle to Late Anisian Bulog sedimentary succession in the Inner Dinarides (SW Serbia)

The Middle to Late Anisian sedimentary succession preserved in the Klisura quarry in Sirogojno (Zlatibor Mt., SW Serbia) preserves the most complete deepening depositional history in the Inner Dinarides in Serbia. In this section, extensional tectonic movements that took place in connection with the Neo-Tethys break-up are reflected in the exceptional well-preserved record of the depositional history. The Pelsonian Ravni Formation at the base of the section is dissected by two generations of neptunian dikes formed in A) the late Pelsonian, and B) the late Illyrian. Above the late Pelsonian drowning unconformity a deepening trend of the depositional environment is mirrored by the litho- and microfacies characteristics of the more than 21 meter thick red nodular limestones of the Bulog Formation. Periods of starvation with deposition of Fossillagerstatten beds and hardgrounds mark characteristic changes in deposition. Two phases of distinct tectonic motions result in unconformities and a stepwise deepening of the depositional realm. The first and major unconformity is the drowning surface on the top of the Ravni Carbonate Ramp which led to the nearly total demise of shallow-water carbonate production, i.e. the change in deposition from shallow- to deepwater limestones. The second phase of tectonic motions is expressed by the formation of an angular unconformity after a phase of starvation in the basin. No Bulog Limestone section in the Dinarides, even not in the type region near Sarajevo, preserves all these characteristic sedimentological features as preserved in the Klisura quarry section in Sirogojno. Therefore this section is proposed to be the reference section for the sedimentological evolution and depositional environment reconstruction of the Bulog Formation in the Inner Dinarides, located in SW Serbia.

Spectroscopic analysis of sequestered chloroplasts in Elphidium williamsoni (Foraminifera).

Foraminifera are unicellular, marine organisms that occur worldwide. A very common species in the German Wadden Sea is Elphidium williamsoni. Some foraminifera (such as elphidia) are able to use kleptoplastidy, which allows them to incorporate chloroplasts from their algal food source into their own cell body. The experiments reported here are based on the fact that chlorophyll (a and c) can be detected in the intact cells with spectroscopic methods in the visible spectral range, which allows an indirect investigation of the presence of sequestered chloroplasts. Starving experiments of E. williamsoni in the light (24h continuous) showed that the greatest decrease in chlorophyll content was recorded within the first 20-30days. From day 60 on, chlorophyll was hardly detectable. Through subsequent feeding on a renewed algal food source a significant increase in the chlorophyll content in foraminifera was noticed. The degradation of chlorophyll in the dark (24h continuous darkness) during the starving period was much more complex. Chlorophyll was still detected in the cells after 113days of starving time. Therefore, we hypotheses that the effect of photoinhibition applies to chloroplasts in foraminifera under continuous illumination.

Glutamine Produces Ammonium to Tune Lysosomal pH and Regulate Lysosomal Function.

Glutamine is one of the most abundant amino acids in the cell. In mitochondria, glutaminases 1 and 2 (GLS1/2) hydrolyze glutamine to glutamate, which serves as the precursor of multiple metabolites. Here, we show that ammonium generated during GLS1/2-mediated glutaminolysis regulates lysosomal pH and in turn lysosomal degradation. In primary human skin fibroblasts BJ cells and mouse embryonic fibroblasts, deprivation of total amino acids for 1 h increased lysosomal degradation capacity as shown by the increased turnover of lipidated microtubule-associated proteins 1A/1B light chain 3B (LC3-II), several autophagic receptors, and endocytosed DQ-BSA. Removal of glutamine but not any other amino acids from the culture medium enhanced lysosomal degradation similarly as total amino acid starvation. The presence of glutamine in regular culture media increased lysosomal pH by >0.5 pH unit and the removal of glutamine caused lysosomal acidification. GLS1/2 knockdown, GLS1 antagonist, or ammonium scavengers reduced lysosomal pH in the presence of glutamine. The addition of glutamine or NH4Cl prevented the increase in lysosomal degradation and curtailed the extension of mTORC1 function during the early time period of amino acid starvation. Our findings suggest that glutamine tunes lysosomal pH by producing ammonium, which regulates lysosomal degradation to meet the demands of cellular activities. During the early stage of amino acid starvation, the glutamine-dependent mechanism allows more efficient use of internal reserves and endocytosed proteins to extend mTORC1 activation such that the normal anabolism is not easily interrupted by a brief disruption of the amino acid supply.

Yolk Absorption Rate and Mouth Development in Larvae of Dormitator latifrons (Perciformes: Eleotridae)

Fish larvae suffer high starvation mortality during the transition from yolk absorption to exogenous feeding, and the size of the developing buccal structures limits the food they can consume. Determining the suitable timing and size of live or inert foods could decrease this mortality. We described mouth development and determined the yolk absorption rate and point-of-no-return (PNR) of Dormitator latifrons larvae. One male and one female specimen were induced to spawn using salmon GnRHa implants, and 45 of their larvae were sedated and observed under a microscope every 24 h to measure total length, standard length, yolk sac length, yolk sac width, oil globule length, oil globule width, width of the oesophagus, and length of the upper and lower jaw longitudinal. The growth model, maximum mouth opening, daily survival, and starvation period were determined. The larval growth was fastest during the first 24 h post−hatching (HPH) at 28 ± 1 °C with an average increase of 625.42 µm in total length and 573.51 µm in standard length. The highest percentage of yolk absorption (52%) occurred within 24 HPH and at 96 HPH the yolk sac was completely reabsorbed. The PNR was reached at 156.41 HPH (p < 0.05). At 96 HPH, the upper and lower jaw were distinguishable by mouth movements. Our results suggest that the larvae of D. latifrons should be fed at 96 HPH with prey measuring 50–65 µm.

Regulation of protein and oxidative energy metabolism are down-regulated in the skeletal muscles of Asiatic black bears during hibernation

Hibernating animals exhibit an unexplained physiological characteristic of skeletal muscles being atrophy resistance, in which case muscle mass and strength remain almost unchanged both before and after hibernation. In this study, we examined the alterations in the regulatory systems of protein and energy metabolism in the skeletal muscles of Asiatic black bears during hibernation. Skeletal muscle samples (vastus lateralis muscle) were collected from identical individuals (n = 8) during the active (July) and hibernating (February) periods, while histochemical and biochemical analyses were performed. We observed no significant alterations in body weight, muscle fiber size, and fiber type composition during the active and hibernating periods, indicating that the skeletal muscles of bears are very well preserved during hibernation. In hibernating bear skeletal muscles, both regulatory pathways of muscle protein synthesis (Akt/mechanistic target of rapamycin and mitogen-activated protein kinase systems) and proteolysis (ubiquitin–proteasome and autophagy systems) were down-regulated. Gene expression levels of factors regulating oxidative metabolism were also decreased in hibernating bear skeletal muscles. This is likely an adaptive strategy to minimize the energy wasting of amino acids and lipids during hibernation, which is accompanied by a prolonged period of disuse and starvation.

DHODH: A Promising New Therapeutic Target in Pediatric T-ALL

Acute T-cell lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy in children and young adults. When compared to B-ALL, T-ALL has a higher rate of induction failure as well as relapse, with very poor overall survival in both scenarios. T-ALL has not benefitted from the same immune-mediated therapies (e.g., anti-CD19 CAR-T cells) and poses an ongoing treatment challenge as well as an unmet therapeutic need. Here, we demonstrate that inhibition of dihydroorotate dehydrogenase (DHODH), an enzyme that converts dihydroorotate to orotate as part of the de novo synthesis of uridine, has a robust anti-leukemia effect in both in vitro and in vivo models of T-ALL. DHODH is ubiquitously-expressed, and inhibition of DHODH (DHODHi) leads to rapid depletion of pyrimidine ribo- and deoxyribonucleotides. A cell's ability to tolerate periods of pyrimidine starvation is dependent on a variety of alternative salvage pathways and is not well-understood. Clinical grade DHODH inhibitors are currently under investigation in trials assessing their effect in myeloid malignancies, where they are also known to have a pre-clinical anti-leukemic effect. We sought to understand the mechanism underlying the sensitivity of T-lymphoblasts to DHODHi, and to develop new DHODHi therapeutic combinations for patients with T-ALL. It is known that the intracellular concentration of nucleotides is high in activated T-lymphocytes, underlying the fact that two low-potency DHODHi's are approved for the treatment of autoimmune T-cell diseases (e.g., teriflunomide for multiple sclerosis and leflunomide for rheumatoid arthritis). We hypothesized that T-cells may have a particular addiction to de novo nucleotide synthesis and that this can be exploited as a vulnerability by the small molecule inhibition of DHODH. We demonstrated that T-ALL is highly sensitive to both chemical and genetic DHODHi using a variety of in vitro models (Figure A). Furthermore, we show that T-lymphoblasts respond to DHODHi by undergoing rapid cell cycle arrest and apoptosis. Additionally, we quantified the changes in intracellular nucleotides using PCA extraction and high-performance liquid chromatography (HPLC). The abundance of UTP, CTP, ATP, and GTP were determined across a panel of T-ALL cell lines at baseline and following treatment with a small molecular inhibitor of DHODH. The depletion of intracellular pyrimidines is rapid, falling to ~30% of baseline at 6 hours and confirming that the extracellular salvage is not able to meet the nucleotide demands of these cells even in the presence of complete media. Of note, the concentration of ATP and GTP are unaffected, confirming the specificity of DHODH on de novo pyrimidine synthesis as well as the viability of the cells over the 24-hour treatment. In several in vivo T-ALL models, we demonstrated that DHODH inhibition (specifically using the small molecule inhibitor brequinar) led to rapid, robust disease response (Figure B). These single agent treatment studies (brequinar, 50 mg/kg given every 3-days) were initiated between day 7 - 14 when the leukemias had engrafted and were established with detectable disease in the bone marrow. Three model systems were used: (1) a genetically engineered mouse model (GEMM) of immature T-ALL in which an activated intracellular NOTCH is expressed by retroviral transduction, (2) a transgenic mouse model of mature T-cell leukemia/lymphoma driven by the HTLV1 protein Tax, and (3) a human PDX from a young man with relapsed/refractory T-ALL. DHODH inhibitor therapy was effective in all three models, though clearly and most dramatically prolonged the survival in the GEMM model, driven by dysregulated NOTCH. We are now focused on elucidating the mechanisms by which T-lymphoblasts are so incredibly sensitive to inhibition of DHODH. New data suggests that changes in mitochondrial membrane potential and mitochondrial mass following exposure to DHODHi may offer additional insights into this sensitivity. We are also studying DHODHi in combination with other approved and experimental agents toward the goal of a new therapeutic combination that is safe, well-tolerated, and efficacious for this patient population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Bacteriocyte plasticity in pea aphids facing amino acid stress or starvation during development.

An important contributing factor to the evolutionary success of insects is nutritional association with microbial symbionts, which provide the host insects with nutrients lacking in their unbalanced diets. These symbionts are often compartmentalized in specialized cells of the host, the bacteriocytes. Even though bacteriocytes were first described more than a century ago, few studies have explored their dynamics throughout the insect life cycle and in response to environmental stressors. Here, we use the Buchnera aphidicola/pea aphid symbiotic system to study how bacteriocytes are regulated in response to nutritional stress throughout aphid development. Using artificial diets, we analyzed the effects of depletion or excess of phenylalanine or leucine, two amino acids essential for aphid growth and whose biosynthetic pathways are shared between the host and the symbiont. Bacteriocytes responded dynamically to those treatments, while other tissues showed no obvious morphological change. Amino acid depletion resulted in an increase in bacteriocyte numbers, with the extent of the increase depending on the amino acid, while excess either caused a decrease (for leucine) or an increase (for phenylalanine). Only a limited impact on survival and fecundity was observed, suggesting that the adjustment in bacteriocyte (and symbiont) numbers is sufficient to withstand these nutritional challenges. We also studied the impact of more extreme conditions by exposing aphids to a 24h starvation period at the beginning of nymphal development. This led to a dramatic drop in aphid survival and fecundity and a significant developmental delay. Again, bacteriocytes responded dynamically, with a considerable decrease in number and size, correlated with a decrease in the number of symbionts, which were prematurely degraded by the lysosomal system. This study shows how bacteriocyte dynamics is integrated in the physiology of insects and highlights the high plasticity of these cells.

Outcome of Early Oral Feeding after Primary Repair of Traumatic Intestinal Injury: Prospective Observation in a Tertiary Hospital in Bangladesh

Introduction: A period of starvation is common practice after intestinal anastomosis. Starved patient became malnourished and underwent catabolic state, impairing the host immune response and thus increasing the risk of postoperative infections thereby long hospital stay. Objective: To observe the outcome of early oral feeding in patients having primary repair of traumatic intestinal injury and to assess its beneficial effect. Methods: This prospective observational study was conducted on 80 patients who underwent urgent intestinal resection with or without covering stoma in the Department of Casualty Surgery at Dhaka Medical College Hospital. Results: Early oral feeding is safe in the recently performed anastomosis even in emergency situations as there were no cases of clinical anastomotic dehiscence and no increase in morbidity. Among 80 patients 58(72.5%) patients had no complaints; rest 22(27.5%) patients had complication. Wound infection seen in 14(17.5%) patients among them 8(10%) patients had burst abdomen and 1(1.25%) patient had intraabdominal abscess. 14(17.5%) patients had chest infection. 10(12.5%) patients complained nausea and among them 8(10%) patients suffered from few episodes of vomiting. 1(1.25%) patient had diarrhoea. Abdominal distension was seen in 9(11.25%) patients. Hospital stay was significantly shorter in with a mean length of stay (9 ± 1) days. No hospital readmission rate was recorded. Conclusion: Early postoperative feeding is timely, safe and tolerable after emergency intestinal resection anastomosis without raised morbidity and mortality and has a considerable reduction in hospital stay with its physical, psychological and fiscal benefits. JAFMC Bangladesh. Vol 18, No 1 (June) 2022: 75-79

The entry of unclosed autophagosomes into vacuoles and its physiological relevance.

It is widely stated in the literature that closed mature autophagosomes (APs) fuse with lysosomes/vacuoles during macroautophagy/autophagy. Previously, we showed that unclosed APs accumulated as clusters outside vacuoles in Vps21/Rab5 and ESCRT mutants after a short period of nitrogen starvation. However, the fate of such unclosed APs remains unclear. In this study, we used a combination of cellular and biochemical approaches to show that unclosed double-membrane APs entered vacuoles and formed unclosed single-membrane autophagic bodies after prolonged nitrogen starvation or rapamycin treatment. Vacuolar hydrolases, vacuolar transport chaperon (VTC) proteins, Ypt7, and Vam3 were all involved in the entry of unclosed double-membrane APs into vacuoles in Vps21-mutant cells. Overexpression of the vacuolar hydrolases, Pep4 or Prb1, or depletion of most VTC proteins promoted the entry of unclosed APs into vacuoles in Vps21-mutant cells, whereas depletion of Pep4 and/or Prb1 delayed the entry into vacuoles. In contrast to the complete infertility of diploid cells of typical autophagy mutants, diploid cells of Vps21 mutant progressed through meiosis to sporulation, benefiting from the entry of unclosed APs into vacuoles after prolonged nitrogen starvation. Overall, these data represent a new observation that unclosed double-membrane APs can enter vacuoles after prolonged autophagy induction, most likely as a survival strategy.

Destabilization of TP53 by USP10 is essential for neonatal autophagy and survival.

Autophagy is essential for the maintenance of energy homeostasis and for survival during the neonatal starvation period. At birth, the trans-placental nutrient supply is suddenly interrupted, and neonates adapt to this adverse circumstance by activating autophagy. However, the mechanisms underlying the precise regulation of neonatal autophagy remain undefined. Here, we show that the destabilization of TP53 by the deubiquitylase ubiquitin-specific peptidase 10 (USP10) is essential for neonatal autophagy and survival. Usp10 deficiency results in decreased E3 ligase activity of MDM2 and accumulation of cytoplasmic TP53, which interferes with the conjugation of ATG12 and ATG5, the key autophagy-related genes, and ultimately inhibits autophagy in neonatal mice. Combined deletion of Tp53 and Usp10 recovers the nutrition supply and rescues the death phenotype of Usp10-deficient neonates. These findings reveal a role of the USP10-MDM2-TP53 axis in nutrient homeostasis and neonatal viability and provide insights into the long-perplexing mechanism by which cytoplasmic TP53 inhibits autophagy.

Starvation and cadmium affect energy reserves and oxidative stress in individuals of Spodoptera exigua

Different factors, such as starvation and metal exposure, may affect development and cause oxidative stress in insects. Some host plants may contain a high concentration of cadmium due to their hyperaccumulating property. The negative effects of metals and hunger may be manifested by low availability of energetic substrates. This study aimed to assess whether the insect population with a history of long metal exposure may better manage metal stress or/and starvation at different developmental stages, with the use of energetic substrates. Two strains of Spodoptera exigua model organism were tested: control strain and cadmium strain (treated continuously for over 200 generations with subtoxic amounts of cadmium). The effects of different factors, individually and in combination, on the tested strains were assessed, first by determining the body weight of larvae and pupae and then by estimating the concentration of biomolecules (proteins, carbohydrates, lipids, or glycogen) in the 4th and 5th larval stages and in pupae, and the total antioxidant capacity and lipid peroxidation level in the 4th larval stage. Compared to control strain, cadmium strain individuals exhibited changes in the concentration of soluble carbohydrates and protein. This was partly related to earlier 1-day starvation. In particular, changes in carbohydrate concentration seemed to be a sensitive biomarker of metal stress, independent of the age of individuals and period of starvation. However, the increase in the total antioxidant capacity and the concentration of lipid peroxidation products in the 4th larval stage under the effect of cadmium was dependent on strain origin.

Effect of TP53 deficiency and KRAS signaling on the bioenergetics of colon cancer cells in response to different substrates: A single cell study.

Metabolic reprogramming is a hallmark of cancer. Somatic mutations in genes involved in oncogenic signaling pathways, including KRAS and TP53, rewire the metabolic machinery in cancer cells. We here set out to determine, at the single cell level, metabolic signatures in human colon cancer cells engineered to express combinations of activating KRAS gene mutations and TP53 gene deletions. Specifically, we explored how somatic mutations in these genes and substrate availability (lactate, glucose, substrate deprivation) from the extracellular microenvironment affect bioenergetic parameters, including cellular ATP, NADH and mitochondrial membrane potential dynamics. Employing cytosolic and mitochondrial FRET-based ATP probes, fluorescent NADH sensors, and the membrane-permeant cationic fluorescent probe TMRM in HCT-116 cells as a model system, we observed that TP53 deletion and KRAS mutations drive a shift in metabolic signatures enabling lactate to become an efficient metabolite to replenish both ATP and NADH following nutrient deprivation. Intriguingly, cytosolic, mitochondrial and overall cellular ATP measurements revealed that, in WT KRAS cells, TP53 deficiency leads to an enhanced ATP production in the presence of extracellular lactate and glucose, and to the greatest increase in ATP following a starvation period. On the other hand, oncogenic KRAS in TP53-deficient cells reversed the alterations in cellular ATP levels. Moreover, cell population measurements of mitochondrial and glycolytic metabolism using a Seahorse analyzer demonstrated that WT KRAS TP53-silenced cells display an increase of the basal respiration and tightly-coupled mitochondria, in the presence of glucose as substrate, compared to TP53 competent cells. Furthermore, cells possessing oncogenic KRAS, independently of TP53 status, showed less pronounced mitochondrial membrane potential changes in response to metabolic nutrients. Furthermore, analysis of cytosolic and mitochondrial NADH levels revealed that the simultaneous presence of TP53 deletion and oncogenic KRAS showed the most pronounced alteration in cytosolic and mitochondrial NADH during metabolic stress. In conclusion, our findings demonstrate how activating KRAS mutation and loss of TP53 remodel cancer metabolism and lead to alterations in bioenergetics under metabolic stress conditions by modulating cellular ATP production, NADH oxidation, mitochondrial respiration and function.