What really happened in the late Triassic?

Major extinctions occurred both in the sea and on land during the Late Triassic in two major phases, in the middle to late Carnian and, 12–17 Myr later, at the Triassic‐Jurassic boundary. Many recent reports have discounted the role of the earlier event, suggesting that it is (1) an artefact of a subsequent gap in the record, (2) a complex turnover phenomenon, or (3) local to Europe. These three views are disputed, with evidence from both the marine and terrestrial realms. New data on terrestrial tetrapods suggests that the late Carnian event was more important than the end‐Triassic event. For tetrapods, the end‐Triassic extinction was a whimper that was followed by the radiation of five families of dinosaurs and mammal‐like reptiles, while the late Carnian event saw the disappearance of nine diverse families, and subsequent radiation of 13 families of turtles, crocodilomorphs, pterosaurs, dinosaurs, lepidosaurs and mammals. Also, for many groups of marine animals, the Carnian event marked a more significant turning point in diversification than did the end‐Triassic event.     

Drug resistance in Leishmania: does it really matter?

Treatment failure (TF) jeopardizes the management of parasitic diseases, including leishmaniasis. From the parasite’s point of view, drug resistance (DR) is generally considered as central to TF. However, the link between TF and DR, as measured by in vitro drug susceptibility assays, is unclear, some studies revealing an association between treatment outcome and drug susceptibility, others not. Here we address three fundamental questions aiming to shed light on these ambiguities. First, are the right assays being used to measure DR? Second, are the parasites studied, which are generally those that adapt to in vitro culture, actually appropriate? Finally, are other parasite factors – such as the development of quiescent forms that are recalcitrant to drugs – responsible for TF without DR?     

Measuring bone mass in children: can we really do it?

Bone densitometry is used to assess skeletal health in clinical and research settings, with the goal of achieving reproducible measurements of bone mass that help to identify individuals predisposed to fracture. The search is now on for better methods of capturing additional factors that contribute to bone strength, including bone size, geometry, microarchitecture, and turnover rates. This has proved particularly challenging in growing children, whose bones continually change in size, shape, and mass. Dual energy X-ray absorptiometry is the preferred method for measuring bone mass in children, but the technique has several limitations, and interpreting the findings can be problematic. Peripheral quantitative computed tomography is a promising method for assessing bone mass and other indices correlating with bone strength, but a lack of precision and paediatric norms currently restricts its clinical utility. Although bone mineral density is predictive of future fracture risk in adults, the evidence in children is less conclusive, and a diagnosis of osteoporosis in a child should not be made on densitometric findings alone. Developing a clearer understanding of how measures of bone mass and strength correlate with bone fracture in children will help target preventive strategies for those in greatest need.     

The Messinian event: What happened to the peri-Mediterranean mammalian communities and local climate?

What truly happened in the terrestrial ecosystems in response to the famous Messinian salinity crisis is still the matter of extensive discussions. Did mammals record any faunal and/or a climatic or environmental fluctuation is a question that still remains open. Our objective is to investigate mammalian faunas before, during and after the crisis within different terrestrial basins surrounding the Mediterranean Sea. We therefore apply here two methods, the cenogram method and a transfer function based on murine (rodents) species richness to better understand if our proxies can record any qualitative or quantitative climatic or environmental change. The results indicate that mammal faunas do not record any particular shift in climate or environment at the scale of the whole peri-Mediterranean area. The trend is different at the regional scale of terrestrial basins as temperatures increase (Calatayud-Daroca-Teruel Basin) or decrease (Languedoc-Roussillon region) punctually occurs just after the crisis; stable conditions in different areas (e.g. Greece) contradict these trends. Biases in the fossil record or in the methodologies could produce such discrepancies.     

The evolution of human adiposity and obesity: where did it all go wrong?

Because obesity is associated with diverse chronic diseases, little attention has been directed to the multiple beneficial functions of adipose tissue. Adipose tissue not only provides energy for growth, reproduction and immune function, but also secretes and receives diverse signaling molecules that coordinate energy allocation between these functions in response to ecological conditions. Importantly, many relevant ecological cues act on growth and physique, with adiposity responding as a counterbalancing risk management strategy. The large number of individual alleles associated with adipose tissue illustrates its integration with diverse metabolic pathways. However, phenotypic variation in age, sex, ethnicity and social status is further associated with different strategies for storing and using energy. Adiposity therefore represents a key means of phenotypic flexibility within and across generations, enabling a coherent life-history strategy in the face of ecological stochasticity. The sensitivity of numerous metabolic pathways to ecological cues makes our species vulnerable to manipulative globalized economic forces. The aim of this article is to understand how human adipose tissue biology interacts with modern environmental pressures to generate excess weight gain and obesity. The disease component of obesity might lie not in adipose tissue itself, but in its perturbation by our modern industrialized niche. Efforts to combat obesity could be more effective if they prioritized ‘external’ environmental change rather than attempting to manipulate ‘internal’ biology through pharmaceutical or behavioral means.     

The ATM gene and breast cancer: is it really a risk factor?

The genetic determinants for most breast cancer cases remain elusive. Whilst mutations in BRCA1 and BRCA2 significantly contribute to familial breast cancer risk, their contribution to sporadic breast cancer is low. In such cases genes frequently altered in the general population, such as the gene mutated in Ataxia telangiectasia (AT), ATM may be important risk factors. The initial interest in studying ATM heterozygosity in breast cancer arose from the findings of epidemiological studies of AT families in which AT heterozygote women had an increased risk of breast cancer and estimations that 1% of the population are AT heterozygotes. One of the clinical features of AT patients is extreme cellular sensitivity to ionising radiation. This observation, together with the finding that a significant proportion of breast cancer patients show an exaggerated acute or late normal tissue reactions after radiotherapy, has lead to the suggestion that AT heterozygosity plays a role in radiosensitivity and breast cancer development. Loss of heterozygosity in the region of the ATM gene on chromosome 11, has been found in about 40% of sporadic breast tumours. However, screening for ATM mutations in sporadic breast cancer cases, showing or not adverse effects to radiotherapy, has not revealed the magnitude of involvement of the ATM gene expected. Their size and the use of the protein truncation test to identify mutations limit many of these studies. This latter parameter is critical as the profile of mutations in AT patients may not be representative of the ATM mutations in other diseases. The potential role of rare sequence variants within the ATM gene, sometimes reported as polymorphisms, also needs to be fully assessed in larger cohorts of breast cancer patients and controls in order to determine whether they represent cancer and/or radiation sensitivity predisposing mutations.     

The ATM gene and breast cancer: is it really a risk factor?

The genetic determinants for most breast cancer cases remain elusive. Whilst mutations in BRCA1 and BRCA2 significantly contribute to familial breast cancer risk, their contribution to sporadic breast cancer is low. In such cases genes frequently altered in the general population, such as the gene mutated in Ataxia telangiectasia (AT), ATM may be important risk factors. The initial interest in studying ATM heterozygosity in breast cancer arose from the findings of epidemiological studies of AT families in which AT heterozygote women had an increased risk of breast cancer and estimations that 1% of the population are AT heterozygotes. One of the clinical features of AT patients is extreme cellular sensitivity to ionising radiation. This observation, together with the finding that a significant proportion of breast cancer patients show an exaggerated acute or late normal tissue reactions after radiotherapy, has lead to the suggestion that AT heterozygosity plays a role in radiosensitivity and breast cancer development. Loss of heterozygosity in the region of the ATM gene on chromosome 11, has been found in about 40% of sporadic breast tumours. However, screening for ATM mutations in sporadic breast cancer cases, showing or not adverse effects to radiotherapy, has not revealed the magnitude of involvement of the ATM gene expected. Their size and the use of the protein truncation test to identify mutations limit many of these studies. This latter parameter is critical as the profile of mutations in AT patients may not be representative of the ATM mutations in other diseases. The potential role of rare sequence variants within the ATM gene, sometimes reported as polymorphisms, also needs to be fully assessed in larger cohorts of breast cancer patients and controls in order to determine whether they represent cancer and/or radiation sensitivity predisposing mutations.     

The fateful encounter of mitochondria with calcium: How did it happen?

A number of findings in the 1950s had offered indirect indications that mitochondria could accumulate Ca²⁺. In 1961, the phenomenon was directly demonstrated using isolated mitochondria: the uptake process was driven by respiratory chain activity or by the hydrolysis of added ATP. It could be accompanied by the simultaneous uptake of inorganic phosphate, in which case precipitates of hydroxyapatite were formed in the matrix, buffering its free Ca²⁺ concentration. The properties of the uptake process were established in the 1960s and 1970s: the uptake of Ca²⁺ occurred electrophoretically on a carrier that has not yet been molecularly identified, and was released from mitochondria via a Na⁺/Ca²⁺ antiporter. A H⁺/Ca²⁺ release exchanger was also found to operate in some mitochondrial types. The permeability transition pore was later also found to mediate the efflux of Ca²⁺ from mitochondria. In the mitochondrial matrix two TCA cycle dehydrogenases and pyruvate dehydrogenase phosphate phosphatase were found to be regulated in the matrix by the cycling of Ca²⁺ across the inner membrane. In conditions of cytoplasmic Ca²⁺ overload mitochondria could store for a time large amounts of precipitated Ca²⁺-phosphate, thus permitting cells to survive situations of Ca²⁺ emergency. The uptake process was found to have very low affinity for Ca²⁺: since the bulk concentration of Ca²⁺ in the cytoplasm is in the low to mid-nM range, it became increasingly difficult to postulate a role of mitochondria in the regulation of cytoplsmic Ca²⁺. A number of findings had nevertheless shown that energy linked Ca²⁺ transport occurred efficiently in mitochondria of various tissues in situ. The paradox was only solved in the 1990s, when it was found that the concentration of Ca²⁺ in the cytoplasm is not uniform: perimitochondrial micropools are created by the agonist-promoted discharge of Ca²⁺ from vicinal stores in which the concentration of Ca²⁺ is high enough to activate the low affinity mitochondrial uniporter. Mitochondria thus regained center stage as important regulators of cytoplasmic Ca²⁺ (not only of their own internal Ca²⁺). Their Ca²⁺ uptake systems was found to react very rapidly to cytoplasmic Ca²⁺ demands, even in the 150-200 msec time scale of processes like the contraction and relaxation of heart. An important recent development in the area of mitochondrial Ca²⁺ transport is its involvement in the disease process. Ca²⁺ signaling defects are now gaining increasing importance in the pathogenesis of diseases, e.g., neurodegenerative diseases. Since mitochondria have now regained a central role in the regulation of cytoplasmic Ca²⁺, dysfunctions of their Ca²⁺ controlling systems have expectedly been found to be involved in the pathogenesis of numerous disease processes.     

The continuity of living matter and the discontinuities of its constituents: do plankton and benthos really exist?

Plankton and benthos are popular concepts identifying two ways of life of aquatic organisms. Their spatial separation led to the development of different sampling techniques and to separate conceptualizations of the principles governing these subsets of the aquatic environment. Reciprocal connections between plankton and benthos, however, are very strong both from a functional (energy fluxes) and a structural (life cycle dynamics) point of view. A full appreciation of such links is forcing marine ecology towards a more integrated approach.     

What happened to plant caspases?

The extent of conservation in the programmed cell death pathways that are activated in species belonging to different kingdoms is not clear. Caspases are key components of animal apoptosis; caspase activities are detected in both animal and plant cells. Yet, while animals have caspase genes, plants do not have orthologous sequences in their genomes. It is 10 years since the first caspase activity was reported in plants, and there are now at least eight caspase activities that have been measured in plant extracts using caspase substrates. Various caspase inhibitors can block many forms of plant programmed cell death, suggesting that caspase-like activities are required for completion of the process. Since plant metacaspases do not have caspase activities, a major challenge is to identify the plant proteases that are responsible for the caspase-like activities and to understand how they relate, if at all, to animal caspases. The protease vacuolar processing enzyme, a legumain, is responsible for the cleavage of caspase-1 synthetic substrate in plant extracts. Saspase, a serine protease, cleaves caspase-8 and some caspase-6 synthetic substrates. Possible scenarios that could explain why plants have caspase activities without caspases are discussed.     

Sodium bicarbonate supplementation and ingestion timing: does it matter?

Although a considerable amount of literature exists on the ergogenic potential of ingesting sodium bicarbonate (NaHCO3) before short-term, high-intensity exercise, very little exists on optimal loading times before exercise. The purpose of this study was to determine the influence of NaHCO3 supplementation timing on repeated sprint ability (RSA). Eight men completed 3 (randomized and counterbalanced) trials of ten 10-second sprints separated by 50 seconds of active recovery (1:5 work-to-rest) on a nonmotorized treadmill. Before each trial, the subjects ingested 0.3 g·kg(-1) body weight of NaHCO3 at 60 (H1), 120 (H2), or 180 (H3) minutes before exercise. Additionally, the subjects were assessed for any side effects (gastrointestinal [GI] discomfort) from the NaHCO3 ingestion via a visual analog scale (VAS). Blood buffering was assessed using a 2-way analysis of variance (ANOVA) with repeated measures, whereas repeated sprint performance and GI discomfort were assessed via a 1-way ANOVA with repeated measures. Blood-buffering capacity was not different at preexercise times (HCO3(-) [millimoles per liter] H1: 30.2 ± 0.4, H2: 30.9 ± 0.6, H3: 31.2 ± 0.6; p > 0.74). Average speed, average power, and total distance covered progressively declined over the 10 sprints; however, there was no difference between conditions (p > 0.22). The incidence of GI discomfort was significantly higher (p < 0.05) from preingestion at all time points with the exception of 180 minutes, whereas severity was only different between 90 and 180 minutes. Ingestion times (between 60 and 180 minutes) did not influence the blood buffering or the ergogenic potential of NaHCO3 as assessed by RSA. However, VAS scores indicated that at 180 minutes postingestion, an individual is less prone to experiencing significant GI discomfort.     

What is MRI bone oedema in rheumatoid arthritis and why does it matter?

MRI bone oedema occurs in various forms of inflammatory and non-inflammatory arthritis and probably represents a cellular infiltrate within bone. It is common in early rheumatoid arthritis and is associated with erosive progression and poor functional outcome. Histopathological studies suggest that a cellular infiltrate comprising lymphocytes and osteoclasts may be detected in subchondral bone and could mediate the development of erosions from the marrow towards the joint surface. There is emerging evidence from animal models that such an infiltrate corresponds with MRI bone oedema, pointing towards the bone marrow as a site for important pathology driving joint damage in rheumatoid arthritis.