Protein quality control: the who’s who, the where’s and therapeutic escapes

In cells the quality of newly synthesized proteins is monitored in regard to proper folding and correct assembly in the early secretory pathway, the cytosol and the nucleoplasm. Proteins recognized as non-native in the ER will be removed and degraded by a process termed ERAD. ERAD of aberrant proteins is accompanied by various changes of cellular organelles and results in protein folding diseases. This review focuses on how the immunocytochemical labeling and electron microscopic analyses have helped to disclose the in situ subcellular distribution pattern of some of the key machinery proteins of the cellular protein quality control, the organelle changes due to the presence of misfolded proteins, and the efficiency of synthetic chaperones to rescue disease-causing trafficking defects of aberrant proteins.     

Asperger’s Syndrome,Subjectivity and the Senses

Situated at the intersection of anthropological work on illness narratives and research on the anthropology of autism, this paper is a close reading of an autobiographical narrative recounted by Peter, a young man diagnosed with Asperger’s Syndrome, a type of autism spectrum disorder (ASD). Responding to Solomon’s (2010a:252) call for phenomenologically grounded accounts of “the subjective, sensory, and perceptual experiences of autism … based on personal narratives and practices of being and self-awareness,” this paper calls into question key assumptions in the clinical and popular literature about ASD relating to theory of mind, empathy, capacity for metaphorical thinking, and ASD as a life-long condition.     

Entangled Matters—Alzheimer’s,Interiority, and the ‘Unflattening’ of the World

When, in the 1980s, Alzheimer's disease became a disease of major public concern, 'personhood' also became an important, related topic of discussion. Those in caring professions (psychology, social work, etc.) and caregiver groups advocated for the 'person within' who was getting lost in a forgetful body and in a reductionist biomedical system. This essay aims to critically approach the dualism of this kind of argument by focusing on the moral positioning of claims such as personhood or biomedical reductionism.     

Carbonate drowning successions of the Bird’s Head,Indonesia

Drowning unconformities and their related strata are important records of key tectonic and environmental events throughout Earth’s history. In the eastern Bird’s Head region of West Papua, Indonesia, Middle Miocene strata record a drowning unconformity present over much of western New Guinea, including several offshore basins. This study records platform carbonate strata overlain by mixed shallow- and deep-water units containing benthic and planktonic foraminiferal assemblages in several outcrop locations across the eastern Bird’s Head region. These heterolithic beds are interpreted as drowning successions that are terminated by a drowning unconformity. We define a succession exposed along the Anggrisi River in the eastern Bird’s Head as a stratotype for carbonate platform drowning in the Bird’s Head, analogous to similar faunal turnovers identified in its offshore basins. Detailed facies analyses, biostratigraphic dating, and paleoenvironmental interpretations using larger benthic and planktonic foraminifera collected from the Anggrisi River succession help to constrain the drowning event recorded onshore as beginning in the Burdigalian and ending in the Serravallian. The cause of platform drowning in the Bird’s Head is attributed to a reduction in the rates of carbonate accumulation due to the presence of excess nutrients in the depositional environment. Already foundering carbonate platforms due to environmental deterioration were left vulnerable to submergence and eventually succumbed to drowning. Low rates of carbonate production were outpaced by the rate of relative sea-level rise caused by high-amplitude oscillations in global glacio-eustatic sea-level change and/or regional tectonic subsidence. The duration of the drowning event across the entire Bird’s Head region is interpreted to have lasted a duration of approximately 9.5 My, between 18.0 and 8.58 Ma. This has implications when interpreting timings of sedimentary basin fill across western New Guinea and in other basins where carbonate platform drowning is recorded.     

Mutant Bacteriophages,Frank Macfarlane Burnet,and the Changing Nature of “Genespeak” in the 1930s

In 1936, Frank Macfarlane Burnet published a paper entitled “Induced lysogenicity and the mutation of bacteriophage within lysogenic bacteria,” in which he demonstrated that the introduction of a specific bacteriophage into a bacterial strain consistently and repeatedly imparted a specific property – namely the resistance to a different phage – to the bacterial strain that was originally susceptible to lysis by that second phage. Burnet’s explanation for this change was that the first phage was causing a mutation in the bacterium which rendered it and its successive generations of offspring resistant to lysogenicity. At the time, this idea was a novel one that needed compelling evidence to be accepted. While it is difficult for us today to conceive of mutations and genes outside the context of DNA as the physico-chemical basis of genes, in the mid 1930s, when this paper was published, DNA’s role as the carrier of hereditary information had not yet been discovered and genes and mutations were yet to acquire physical and chemical forms. Also, during that time genes were considered to exist only in organisms capable of sexual modes of replication and the status of bacteria and viruses as organisms capable of containing genes and manifesting mutations was still in question. Burnet’s paper counts among those pieces of work that helped dispel the notion that genes, inheritance and mutations were tied to an organism’s sexual status. In this paper, I analyze the implications of Burnet’s paper for the understanding of various concepts – such as “mutation,” and “gene,” – at the time it was published, and how those understandings shaped the development of the meanings of these terms and our modern conceptions thereof.     

Philosophical problems, cluster concepts, and the many lives of Molyneux’s question

Molyneux’s question, whether the newly sighted might immediately recognize tactilely familiar shapes by sight alone, has produced an array of answers over three centuries of debate and discussion. I propose the first pluralist response: many different answers, both yes and no, are individually sufficient as an answer to the question as a whole. I argue that this is possible if we take the question to be cluster concept of sub-problems. This response opposes traditional answers that isolate specific perceptual features as uniquely applicable to Molyneux’s question and grant viability to only one reply. Answering Molyneux’s question as a cluster concept may also serve as a methodology for resolving other philosophical problems.     

DNA Barcodes for the FIshes of the Narmada,One of India’s Longest Rivers

This study describes the species diversity of fishes of the Narmada River in India. A total of 820 fish specimens were collected from 17 sampling locations across the whole river basin. Fish were taxonomically classified into one of 90 possible species based on morphological characters, and then DNA barcoding was employed using COI gene sequences as a supplemental identification method. A total of 314 different COI sequences were generated, and specimens were confirmed to belong to 85 species representing 63 genera, 34 families and 10 orders. Findings of this study include the identification of five putative cryptic or sibling species and 43 species not previously known from the Narmada River basin. Five species are endemic to India and three are introduced species that had not been previously reported to occur in the Narmada River. Conversely, 43 species previously reported to occur in the Narmada were not found. Genetic diversity and distance values were generated for all of the species within genera, families and orders using Kimura’s 2 parameter distance model followed by the construction of a Neighbor Joining tree. High resolution clusters generated in NJ trees aided the groupings of species corresponding to their genera and families which are in confirmation to the values generated by Automatic Barcode Gap Discovery bioinformatics platform. This aided to decide a threshold value for the discrimination of species boundary from the Narmada River. This study provides an important validation of the use of DNA barcode sequences for monitoring species diversity and changes within complex ecosystems such as the Narmada River.     

From the editor’s desk

Improving cotton fibre quality is a major breeding goal for Upland cotton in China. To investigate the genetic mechanisms of fibre quality, a diverse panel of 403 Upland cotton accessions was grown, and the fibre quality traits were measured in six different environments. Genotyping was performed with genomewide simple sequence repeats. A total of 201 markers were polymorphic and generated 394 allele loci, and 403 accessions were arranged into two subgroups using Structure software. Of the marker loci, 18.94% showed significant linkage disequilibrium (\(P< 0.05\)). A mixed linear model in association mapping showed that 51 associations were significant between 39 polymorphic loci and five fibre quality traits, according to best linear unbiased prediction, and in at least three of six environments. Of the 39 associated marker loci, 12 were coincident with previous studies. There were 41 typical accessions identified as containing favourable allele loci related to fibre quality traits. The identified favourable QTL alleles and typical accessions for fibre quality are excellent genetic resources for future cotton breeding in China.     

Black-Tailed Prairie Dogs,Cattle, and the Conservation of North America’s Arid Grasslands

Prairie dogs (Cynomys spp.) have been eliminated from over 95% of their historic range in large part from direct eradication campaigns to reduce their purported competition with cattle for forage. Despite the longstanding importance of this issue to grassland management and conservation, the ecological interactions between cattle and prairie dogs have not been well examined. We address this issue through two complementary experiments to determine if cattle and prairie dogs form a mutualistic grazing association similar to that between prairie dogs and American bison. Our experimental results show that cattle preferentially graze along prairie dog colony edges and use their colony centers for resting, resembling the mutualistic relationship prairie dogs have with American bison. Our results also show that prairie dog colonies are not only an important component of the grassland mosaic for maintaining biodiversity, but also provide benefits to cattle, thereby challenging the long-standing view of prairie dogs as an undesirable pest species in grasslands.     

More than Moore’s Mores: Computers,Genomics, and the Embrace of Innovation

The genomics community has frequently compared advances in sequencing to advances in microelectronics. Lately there have been many claims, including by the National Human Genome Research Institute (NHGRI), that genomics is outpacing developments in computing as measured by Moore's law – the notion that computers double in processing capability per dollar spent every 18-24 months. Celebrations of the “$1000 genome” and other speed-related sequencing milestones might be dismissed as a distraction from genomics' slowness in delivering clinical breakthroughs, but the fact that such celebrations have been persistently encouraged by the NHGRI reveals a great deal about the priorities and expectations of the American general public, the intended audience of the genomics–computing comparison. By delving into the history of speculative thinking about sequencing and computing, this article demonstrates just how much more receptive to high-risk/high-payoff ventures the NIH and the general public have become. The article also provides access to some of the roots and consequences of the association of “innovation talk” with genomics, and the means to look past that association to the less glamorous (but arguably much more important) contributions of the NHGRI to building the field of genomics.     

It’s the song,not the singer: an exploration of holobiosis and evolutionary theory

That holobionts (microbial communities and their animal or plant hosts) are units of selection squares poorly with the observation that microbes are often recruited (horizontally acquired) from the environment, not passed down vertically from parent to offspring, as required for collective reproduction. The taxonomic makeup of a holobiont’s microbial community may vary over its lifetime and differ from that of conspecifics. In contrast, biochemical functions of the microbiota and contributions to host biology are more conserved, with taxonomically variable but functionally similar microbes recurring across generations and hosts. To save what is of interest in holobiont thinking, we propose casting metabolic and developmental interaction patterns, rather than the taxa responsible for them, as units of selection. Such units need not directly reproduce or form parent-offspring lineages: their prior existence has created the conditions under which taxa with the genes necessary to carry out their steps have evolved in large numbers. These taxa or genes will reconstruct the original interaction patterns when favorable conditions occur. Interaction patterns will vary (for instance by the alteration or addition of intermediates) in ways that affect the likelihood of and circumstances under which such reconstruction occurs. Thus, they vary in fitness, and evolution by natural selection will occur at this level. It is on the persistence, reconstruction, and spread of such interaction patterns that students of holobiosis should concentrate, we suggest. This model also addresses other multi-species collectively beneficial interactions, such as biofilms or biogeochemical cycles maintaining all life.     

Position of the Physician’s Nametag - A Randomized,Blinded Trial

Background

The patient-physician relation begins when the physician introduces himself with name and function. Most institutions request a nametag with name and function to be worn. Although nametags are consequently worn, the optimal position for the nametag is unknown. It was the purpose of this study to identify whether positioning the nametag on the right or the left chest side provides better visibility to the patient.

Method and Material

One hundred volunteers, blinded to the experimental setup, presented for an orthopedic consultation in a standardized manner. The nametag of the physician was randomly positioned on the left chest side and presented to 50 individuals (age 35 years (range 17 to 83)) or the right chest side and then presented to 50 other individuals (35 years (range 16 to 59)). The time of the participant noticing the nametag was documented. Subsequently, the participant was questioned concerning the relevance of a nametag and verbal self-introduction of the physician.

Results

38% of the participants noticed the nametag on the right as opposed to 20% who noticed it if placed on the left upper chest (p = 0.0473). The mean time to detection was 9 (range 1–40) seconds for nametags on the right and 25.2 seconds (range 3 to 49, p = 0.006) on the left. For 87% of the participants, a nametag is expected and important and nearly all participants (96%) expected the physician to introduce himself verbally.

Conclusion

It is expected that a physician wears a nametag and introduce himself verbally at the first encounter. Positioning the nametag on the right chest side results in better and faster visibility.     

Mitochondrial dynamics,cell death and the pathogenesis of Parkinson’s disease

The structure and function of the mitochondrial network is regulated by mitochondrial biogenesis, fission, fusion, transport and degradation. A well-maintained balance of these processes (mitochondrial dynamics) is essential for neuronal signaling, plasticity and transmitter release. Core proteins of the mitochondrial dynamics machinery play important roles in the regulation of apoptosis, and mutations or abnormal expression of these factors are associated with inherited and age-dependent neurodegenerative disorders. In Parkinson’s disease (PD), oxidative stress and mitochondrial dysfunction underlie the development of neuropathology. The recessive Parkinsonism-linked genes PTEN-induced kinase 1 (PINK1) and Parkin maintain mitochondrial integrity by regulating diverse aspects of mitochondrial function, including membrane potential, calcium homeostasis, cristae structure, respiratory activity, and mtDNA integrity. In addition, Parkin is crucial for autophagy-dependent clearance of dysfunctional mitochondria. In the absence of PINK1 or Parkin, cells often develop fragmented mitochondria. Whereas excessive fission may cause apoptosis, coordinated induction of fission and autophagy is believed to facilitate the removal of damaged mitochondria through mitophagy, and has been observed in some types of cells. Compensatory mechanisms may also occur in mice lacking PINK1 that, in contrast to cells and Drosophila, have only mild mitochondrial dysfunction and lack dopaminergic neuron loss. A better understanding of the relationship between the specific changes in mitochondrial dynamics/turnover and cell death will be instrumental to identify potentially neuroprotective pathways steering PINK1-deficient cells towards survival. Such pathways may be manipulated in the future by specific drugs to treat PD and perhaps other neurodegenerative disorders characterized by abnormal mitochondrial function and dynamics.     

Hexahydrohippuric Acid,a Newly Isolated Compound from the Cattle’s Urine

A cosmid library and physical maps of mitochondrial DNA (mtDNA) from a liverwort, Marchantia polymorpha, were constructed using the cosmid clones. Electrophoresis profile and the physical maps indicated that the liverwort mtDNA was approximately 183 kb long, the smallest among plant mtDNAs, and that it consisted of a single circular molecule. Southern hybridization analysis showed that genes typical to the mitochondrial genome existed in a single copy, and also that there was no incorporation of chloroplast DNA fragments into the mitochondrial genome.     

Distribution of the Harp Seal Whelping Grounds in the White Sea 1960s–1990s

Analysis of air survey data has shown that from the 1960s to the 1990s the whelping grounds of the harp seal Phoca groenlandica formed at the end of February through the first days of March in two regions of the White Sea: in the eastern part of Bassein and in Gorlo. The areas of the whelping grounds varied depending on the current ice conditions. It was recorded that, despite ice conditions unfavorable for the pups' survival that developed in some years, in general the ice regime of the White Sea was favorable for reproduction of the White Sea population of the harp seal.