Vestibular evidence for the evolution of aquatic behaviour in early cetaceans

Early cetaceans evolved from terrestrial quadrupeds to obligate swimmers, a change that is traditionally studied by functional analysis of the postcranial skeleton. Here we assess the evolution of cetacean locomotor behaviour from an independent perspective by looking at the semicircular canal system, one of the main sense organs involved in neural control of locomotion. Extant cetaceans are found to be unique in that their canal arc size, corrected for body mass, is approximately three times smaller than in other mammals. This reduces the sensitivity of the canal system, most plausibly to match the fast body rotations that characterize cetacean behaviour. Eocene fossils show that the new sensory regime, incompatible with terrestrial competence, developed quickly and early in cetacean evolution, as soon as the taxa are associated with marine environments. Dedicated agile swimming of cetaceans thus appeared to have originated as a rapid and fundamental shift in locomotion rather than as the gradual transition suggested by postcranial evidence. We hypothesize that the unparalleled modification of the semicircular canal system represented a key 'point of no return' event in early cetacean evolution, leading to full independence from life on land

A fossil mammal from marine Eocene strata (Jaintia Group) of the Mikir hills, Assam, northeastern India

We report the occurrence of a mammalian lumbar vertebra and several associated fish teeth from Dillai Parbat, in the southeastern part of the Mikir Hills of Assam, in northeastern India. The specimens were recovered from a shallow marine limestone unit of upper middle Eocene age (40-37 Ma). The vertebra is tentatively described as that of an archaeocete cetacean. This is the first report of Eocene vertebrates from the northeastern part of India, and it significantly expands the geographical distribution of Eocene marine mammals of India. Further fieldwork is required to assess the potential of this new locality

New early Eocene tapiromorph perissodactyls from the Ghazij Formation of Pakistan, with implications for mammalian biochronology in Asia

Early Eocene mammals from Indo-Pakistan have only recently come under study. Here we describe the first tapiromorph perissodactyls from the subcontinent. Gandheralophus minor n. gen. and n. sp. and G. robustus n. sp. are two species of Isectolophidae differing in size and in reduction of the anterior dentition. Gandheralophus is probably derived from a primitive isectolophid such as Orientolophus hengdongensis from the earliest Eocene of China, and may be part of a South Asian lineage that also contains Karagalax from the middle Eocene of Pakistan. Two specimens are referred to a new, unnamed species of Lophialetidae. Finally, a highly diagnostic M3 and a molar fragment are described as the new eomoropid chalicothere Litolophus ghazijensis sp. nov. The perissodactyls described here, in contrast to most other mammalian groups published from the early Eocene of Indo-Pakistan, are most closely related to forms known from East and Central Asia. Tapiromorpha are diverse and biochronologically important in the Eocene there and our results allow the first biochronological correlation between early Eocene mammal faunas in Indo-Pakistan and the rest of Asia. We suggest that the upper Ghazij Formation of Pakistan is best correlated with the middle or late part of the Bumbanian Asian Land-Mammal Age, while the Kuldana and Subathu Formations of Pakistan and India are best correlated with the Arshantan Asian Land-Mammal Age

Relationships of Cetacea (Artiodactyla) Among Mammals: Increased Taxon Sampling Alters Interpretations of Key Fossils and Character Evolution

BACKGROUND: Integration of diverse data (molecules, fossils) provides the most robust test of the phylogeny of cetaceans. Positioning key fossils is critical for reconstructing the character change from life on land to life in the water. METHODOLOGY/PRINCIPAL FINDINGS: We reexamine relationships of critical extinct taxa that impact our understanding of the origin of Cetacea. We do this in the context of the largest total evidence analysis of morphological and molecular information for Artiodactyla (661 phenotypic characters and 46,587 molecular characters, coded for 33 extant and 48 extinct taxa). We score morphological data for Carnivoramorpha, Creodonta, Lipotyphla, and the raoellid artiodactylan Indohyus and concentrate on determining which fossils are positioned along stem lineages to major artiodactylan crown clades. Shortest trees place Cetacea within Artiodactyla and close to Indohyus, with Mesonychia outside of Artiodactyla. The relationships of Mesonychia and Indohyus are highly unstable, however--in trees only two steps longer than minimum length, Mesonychia falls inside Artiodactyla and displaces Indohyus from a position close to Cetacea. Trees based only on data that fossilize continue to show the classic arrangement of relationships within Artiodactyla with Cetacea grouping outside the clade, a signal incongruent with the molecular data that dominate the total evidence result. CONCLUSIONS/SIGNIFICANCE: Integration of new fossil material of Indohyus impacts placement of another extinct clade Mesonychia, pushing it much farther down the tree. The phylogenetic position of Indohyus suggests that the cetacean stem lineage included herbivorous and carnivorous aquatic species. We also conclude that extinct members of Cetancodonta (whales+hippopotamids) shared a derived ability to hear underwater sounds, even though several cetancodontans lack a pachyostotic auditory bulla. We revise the taxonomy of living and extinct artiodactylans and propose explicit node and stem-based definitions for the ingroup

Extinction of cue-evoked drug-seeking relies on degrading hierarchical instrumental expectancies

There has long been need for a behavioural intervention that attenuates cue-evoked drug-seeking, but the optimal method remains obscure. To address this, we report three approaches to extinguish cue-evoked drug-seeking measured in a Pavlovian to instrumental transfer design, in non-treatment seeking adult smokers and alcohol drinkers. The results showed that the ability of a drug stimulus to transfer control over a separately trained drug-seeking response was not affected by the stimulus undergoing Pavlovian extinction training in experiment 1, but was abolished by the stimulus undergoing discriminative extinction training in experiment 2, and was abolished by explicit verbal instructions stating that the stimulus did not signal a more effective response-drug contingency in experiment 3. These data suggest that cue-evoked drug-seeking is mediated by a propositional hierarchical instrumental expectancy that the drug-seeking response is more likely to be rewarded in that stimulus. Methods which degraded this hierarchical expectancy were effective in the laboratory, and so may have therapeutic potential

Assessment of the burden of outpatient clinic and MRI-guided needle muscle biopsies as reported by patients with facioscapulohumeral muscular dystrophy

Muscle biopsies are used in clinical trials to measure target engagement of the investigational product. With many upcoming therapies for patients with facioscapulohumeral dystrophy (FSHD), the frequency of biopsies in FSHD patients is expected to increase. Muscle biopsies were performed either in the outpatient clinic using a Bergström needle (BN-biopsy) or in a Magnetic Resonance Imaging machine (MRI-biopsy). This study assessed the FSHD patients’ experience of biopsies using a customized questionnaire. The questionnaire was sent to all FSHD patients who had undergone a needle muscle biopsy for research purposes, inquiring about biopsy characteristics and burden, and willingness to undergo a subsequent biopsy. Forty-nine of 56 invited patients (88%) completed the questionnaire, reporting on 91 biopsies. The median pain score (scale 0-10) during the procedure was 5 [2-8], reducing to 3 [1-5] and 2 [1-3] after one and 24 h, respectively. Twelve biopsies (13.2%) resulted in complications, eleven resolved within 30 days. BN-biopsies were less painful compared to MRI-biopsies (median NRS: 4 [2-6] vs. 7 [3-9], p = 0.001). The burden of needle muscle biopsies in a research setting is considerate and should not be underestimated. MRI-biopsies have a higher burden compared to BN-biopsies. Neurological Motor Disorder

Oral ribose supplementation in dystroglycanopathy:A single case study

Three forms of muscular dystrophy-dystroglycanopathies are linked to the ribitol pathway. These include mutations in the isoprenoid synthase domain-containing protein (ISPD), fukutin-related protein (FKRP), and fukutin (FKTN) genes. The aforementioned enzymes are required for generation of the ribitol phosphate linkage in the O-glycan of alpha-dystroglycan. Mild cases of dystroglycanopathy present with slowly progressive muscle weakness, while in severe cases the eyes and brain are also involved. Previous research showed that ribose increased the intracellular concentrations of cytidine diphosphate-ribitol (CDP-ribitol) and had a therapeutic effect. Here, we report the safety and effects of oral ribose supplementation during 6 months in a patient with limb girdle muscular dystrophy type 2I (LGMD2I) due to a homozygous FKRP mutation. Ribose was well tolerated in doses of 9 g or 18 g/day. Supplementation with 18 g of ribose resulted in a decrease of creatine kinase levels of 70%. Moreover, metabolomics showed a significant increase in CDP-ribitol levels with 18 g of ribose supplementation (p &lt; 0.001). Although objective improvement in clinical and patient-reported outcome measures was not observed, the patient reported subjective improvement of muscle strength, fatigue, and pain. This case study indicates that ribose supplementation in patients with dystroglycanopathy is safe and highlights the importance for future studies regarding its potential effects.</p

CD28null CD4 T-cell expansions in autoimmune disease suggest a link with cytomegalovirus infection

Immunosenescence is thought to contribute to the increase of autoimmune diseases in older people. Immunosenescence is often associated with the presence of an expanded population of CD4 T cells lacking expression of CD28 (CD28null). These highly cytotoxic CD4 T cells were isolated from disease-affected tissues in patients with rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, or other chronic inflammatory diseases and their numbers appeared to be linked to disease severity. However, we recently demonstrated that the common herpes virus, cytomegalovirus (CMV), not ageing, is the major driver of this subset of cytotoxic T cells. In this review, we discuss how CMV might potentiate and exacerbate autoimmune disease through the expansion of CD28null CD4 T cells

Electrophysiological correlates of associative learning in smokers: a higher-order conditioning experiment

Background: Classical conditioning has been suggested to play an important role in the development, maintenance, and relapse of tobacco smoking. Several studies have shown that initially neutral stimuli that are directly paired with smoking are able to elicit conditioned responses. However, there have been few human studies that demonstrate the contribution of higher-order conditioning to smoking addiction, although it is assumed that higher-order conditioning predominates learning in the outside world. In the present study a higher-order conditioning task was designed in which brain responses of smokers and non-smokers were conditioned by pairing smoking-related and neutral stimuli (CS1smokeand CS1neutral) with two geometrical figures (CS2smokeand CS2neutral). ERPs were recorded to all CSs.Results: Data showed that the geometrical figure that was paired with smoking stimuli elicited significantly larger P2 and P3 waves than the geometrical figure that was paired with neutral stimuli. During the first half of the experiment this effect was only present in smokers whereas non-smokers displayed no significant differences between both stimuli, indicating that neutral cues paired with motivationally relevant smoking-related stimuli gain more motivational significance even though they were never paired directly with smoking. These conclusions are underscored by self-reported evidence of enhanced second-order conditioning in smokers.Conclusions: It can be concluded that smokers show associative learning for higher-order smoking-related stimuli. The present study directly shows the contribution of higher-order conditioning to smoking addiction and is the first to reveal its electrophysiological correlates. Although results are preliminary, they may help in understanding the etiology of smoking addiction and its persistence