A disruptive alternative to semi-continuous multi-column chromatography processes

Protein purification to date is still dominated by expensive chromatography operations. Within the bioprocessing segment of the biopharmaceutical industry, enormous advances in upstream processing performance have moved the cost-reduction bottleneck to downstream processing (DSP). In an effort to reduce DSP costs, the industry is progressively turning to multi-column semi-continuous manufacturing techniques, adapted from neighbouring chemical processing industries. In the case of Affinity Chromatography, the primary theoretical advantage lies in alleviating particularly expensive bind/elute capture steps by allowing saturation of any given unit of resin with product feed while routing the partially depleted effluent flow-through material to follow-on unsaturated resin through the use of multiple columns in a sequence. The saturation better utilises the resin in each of its cycles allowing a reduction in per gram cost and improved time usage, and since saturation can achieve the full static binding capacity without being limited by a dynamic flow, this allows the system to flow faster, saving even more time. However, industrial adoption of these new techniques has been slow, owing to their significant increase in developmental and operational complexity and the capital expense of additional hardware requirements. In this presentation we will reveal and discuss processing factors that may significantly impact the true benefits in speed for multi-column processes, particularly relating to the necessary scheduling effects of aligning multiple synchronous columns, and to back pressure and column height effects that both slow the achievable productivity and mask true comparisons with traditional batch chromatography. We have found scenarios where these factors can combine to make semi-continuous multi-column processes significantly slower than equivalent batch processes, and the loss in productivity can, in some circumstances, cancel much of the cost savings on resin consumption. In an effort to understand, improve and simplify these semi-continuous processes, we internally developed a novel and potentially disruptive operational method that matches or exceeds the benefits of a semi-continuous process, without the complexity. Data from a prototype un-optimised version tested at pilot scale will show that significant performance gains can be achieved on standard chromatography equipment with minimal modification

Evidence-based medicine and progress in the medical sciences

The question what scientific progress means for a particular domain such as medicine seems importantly different from the question what scientific progress is in general. While the latter question received ample treatment in the philosophical literature, the former question is hardly discussed. I argue that it is nonetheless important to think about this question in view of the methodological choices we make. I raise specific questions that should be tackled regarding scientific progress in the medical sciences and demonstrate their importance by means of an analysis of what evidence-based medicine (EBM) has, and has not, to offer in terms of progress. I show how critically thinking about EBM from the point of view of progress can help us in putting EBM and its favoured methodologies in the right perspective. My conclusion will be that blindly favouring certain methods because of their immediately tangible short-term benefits implies that we parry the important question of how best to advance progress in the long run. This leads us to losing sight of our general goals in doing research in the medical sciences

The fate of redundant cues: Further analysis of the redundancy effect

Pearce, Dopson, Haselgrove, and Esber (Journal of Experimental Psychology: Animal Behavior Processes, 38, 167–179, 2012) conducted a series of experiments with rats and pigeons in which the conditioned responding elicited by two types of redundant cue was compared. One of these redundant cues was a blocked cue X from A+ AX+ training, whereas the other was cue Y from a simple discrimination BY+ CY–. Greater conditioned responding was elicited by X than by Y; we refer to this difference as the redundancy effect. To test an explanation of this effect in terms of comparator theory (Denniston, Savastano, & Miller, 2001), a single group of rats in Experiment 1 received training of the form A+ AX+ BY+ CY–, followed by an A– Y+ discrimination. Responding to the individual cues was tested both before and after the latter discrimination. In addition to a replication of the redundancy effect during the earlier test, we observed stronger responding to B than to X, both during the earlier test and, in contradiction of the theory, after the A– Y+ discrimination. In Experiment 2, a blocking group received A+ AX+, a continuous group received AX+ BX–, and a partial group received AX± BX± training. Subsequent tests with X again demonstrated the redundancy effect, but also revealed a stronger response in the partial than in the continuous group. This pattern of results is difficult to explain with error-correction theories that assume that stimuli compete for associative strength during conditioning. We suggest, instead, that the influence of a redundant cue is determined by its relationship with the event with which it is paired, and by the attention it is paid

A neoproterozoic age for the chromitite and gabbro of the Tapo Ultramafic Massif, Eastern Cordillera, Central Peru, and its tectonic implications

The ultramafic-mafic rocks of the Tapo Complex are exposed in the Eastern Cordillera of the Central Peruvian Andes. This complex is composed of serpentinised peridotites and metabasites with some podiform chromitite lenses and chromite disseminations and overlies the sandstones, conglomerates, and tuffs of the Carboniferous Ambo Group. The metagabbros and amphibolites showa tholeiitic affiliation and a flat REE spider diagram, with a slight LREE depletion and a positive Eu anomaly suggesting magmatic accumulation of plagioclase, in an ocean ridge or ocean island environment. Sm-Nd isotopic analyses were performed on chromite as well as on whole rock from the gabbro. All samples yielded an Sm-Nd isochrone age of718 ± 47 Ma with an initial 143Nd/l44Nd of0.51213 ± 0.00005. The Nd (718 Ma) values calculated for both chromite and gabbro are in close agreement, around 8.0, implying that they were formed at the same time from the same mantelic magma source. Furthermore a K-Ar age on amphibole of 448 ± 26 Ma was obtained, interpreted as the cooling age of a younger orogenic event. These rocks represent slices of oceanic crust (from a dismembered ophiolitic complex), metamorphosed and later overthrust on upper Palaeozoic continental formations

Repeated Maximal Exercise Measures are Very Reliable Among Healthy College-aged Individuals

The most common way to assess cardiovascular fitness is with a maximal graded exercise test (GXT) to determine the maximal rate of oxygen consumption (VO2 max). Maximal exercise efforts during GXT testing have been shown to be quite repeatable among active and sedentary adults, as well as cardiac patients and the elderly. With young, healthy participants, familiarization and motivation could result in improved performance measures with repeated testing. The reliability of maximal exercise measures among healthy college-aged individuals during repeated Bruce Protocol GXT assessments are yet unclear. PURPOSE: To determine how repeatable the VO2max and other maximal exercise indices were with repeated GXT measures among healthy, college-aged adults. METHODS: Thirty-six apparently healthy participants (20 men, 16 women) aged 21.47 ± 0.5 years completed three GXT testing sessions following the Bruce Protocol. The maximal values for VO2, blood lactate, VE, HR and Borg Rating of Perceived Exertion (RPE) as well as time to exhaustion were recorded at the end of each session. RESULTS: Statistical analysis of the data was conducted using a one-way ANOVA by order of visit and a Tukey post-hoc analysis. With all participants combined, there were no differences in measured variables with one exception. Maximal RPE was higher in Visit 3 compared to Baseline (p=0.02). When men and the women were analyzed separately, there were no differences in RPE values among the men. Women reported a higher Max RPE in both Visit 2 and Visit 3 compared to Baseline. Despite the higher RPE values no other maximal measures were significantly different across testing sessions. CONCLUSION: This research confirms that repeated maximal GXT measures are very reliable among healthy college-aged individuals. The exception being a small but significant difference in self-reported maximal RPE values among women compared to baseline measures. Future studies could address potential reasons for the significant difference in women’s self-reported RPE values

Is conditioning a useful framework for understanding the development and treatment of phobias?

Despite the prevalence of therapeutic interventions based on conditioning models of fear acquisition, conditioning has been seen by many as a poor explanation of how fears develop: partly because research on conditioning has become less mainstream and models of teaming have become increasingly more complex. This article reviews some of what is now known about conditioning/associative teaming and describes how these findings account for some early criticisms of conditioning models of fear acquisition. It also describes how pathways to fear such as vicarious teaming and fear information can be conceptualised as forms of associative teaming that obey the same teaming rules. Some popular models of conditioning are then described with a view to highlighting the important components in teaming. Finally, suggestions are made about how what we know about conditioning can be applied to improve therapeutic interventions and prevention programs for child anxiety. (c) 2006 Elsevier Ltd. All rights reserved

First identification and characterization of Borrobol-type tephra in the Greenland ice cores::new deposits and improved age estimates

Contiguous sampling of ice spanning key intervals of the deglaciation from the Greenland ice cores of NGRIP, GRIP and NEEM has revealed three new silicic cryptotephra deposits that are geochemically similar to the well-known Borrobol Tephra (BT). The BT is complex and confounded by the younger closely timed and compositionally similar Penifiler Tephra (PT). Two of the deposits found in the ice are in Greenland Interstadial 1e (GI-1e) and an older deposit is found in Greenland Stadial 2.1 (GS-2.1). Until now, the BT was confined to GI-1-equivalent lacustrine sequences in the British Isles, Sweden and Germany, and our discovery in Greenland ice extends its distribution and geochemical composition. However, the two cryptotephras that fall within GI-1e ice cannot be separated on the basis of geochemistry and are dated to 14358 ± 177 a b2k and 14252 ± 173 a b2k, just 106 ± 3 years apart. The older deposit is consistent with BT age estimates derived from Scottish sites, while the younger deposit overlaps with both BT and PT age estimates. We suggest that either the BT in Northern European terrestrial sequences represents an amalgamation of tephra from both of the GI-1e events identified in the ice-cores or that it relates to just one of the ice-core events. A firm correlation cannot be established at present due to their strong geochemical similarities. The older tephra horizon, found within all three ice-cores and dated to 17326 ± 319 a b2k, can be correlated to a known layer within marine sediment cores from the North Iceland Shelf (ca. 17179-16754 cal a BP). Despite showing similarities to the BT, this deposit can be distinguished on the basis of lower CaO and TiO2 and is a valuable new tie-point that could eventually be used in high-resolution marine records to compare the climate signals from the ocean and atmosphere

Rationale, description and baseline findings of a community-based prospective cohort study of kidney function amongst the young rural population of Northwest Nicaragua.

BACKGROUND: An epidemic of Mesoamerican Nephropathy (MeN) is killing thousands of agricultural workers along the Pacific coast of Central America, but the natural history and aetiology of the disease remain poorly understood. We have recently commenced a community-based longitudinal study to investigate Chronic Kidney Disease (CKD) in Nicaragua. Although logistically challenging, study designs of this type have the potential to provide important insights that other study designs cannot. In this paper we discuss the rationale for conducting this study and summarize the findings of the baseline visit. METHODS: The baseline visit of the community-based cohort study was conducted in 9 communities in the North Western Nicaragua in October and November 2014. All of the young men, and a random sample of young women (aged 18-30) without a pre-existing diagnosis of CKD were invited to participate. Glomerular filtration rate (eGFR) was estimated with CKD-EPI equation, along with clinical measurements, questionnaires, biological and environmental samples to evaluate participants' exposures to proposed risk factors for MeN. RESULTS: We identified 520 young adults (286 males and 234 females) in the 9 different communities. Of these, 16 males with self-reported CKD and 5 females with diagnoses of either diabetes or hypertension were excluded from the study population. All remaining 270 men and 90 women, selected at random, were then invited to participate in the study; 350 (97%) agreed to participate. At baseline, 29 (11%) men and 1 (1%) woman had an eGFR <90 mL/min/1.73 m2. CONCLUSION: Conducting a community based study of this type requires active the involvement of communities and commitment from local leaders. Furthermore, a research team with strong links to the area and broad understanding of the context of the problem being studied is essential. The key findings will arise from follow-up, but it is striking that 5% of males under aged 30 had to be excluded because of pre-existing kidney disease, and that despite doing so 11% of males had an eGFR <90 mL/min/1.73 m2 at baseline

The redshift evolution of bias and baryonic matter distribution

We study the distribution of baryonic and luminous matter within the framework of a hierarchical scenario. Using an analytical model for structure formation which has already been checked against observations for galaxies, Lyman-$\alpha$ clouds, clusters and reionization processes, we present its predictions for the bias of these objects. We describe its dependence on the luminosity (for galaxies or quasars) or the column density (for Lyman-$\alpha$ absorbers) of the considered objects. We also study its redshift evolution, which can exhibit an intricate behaviour. These astrophysical objects do not trace the dark matter density field, the Lyman-$\alpha$ forest clouds being undercorrelated and the bright galaxies overcorrelated, while the intermediate class of Lyman-limit systems is seen to sample the matter field quite well. We also present the distribution of baryonic matter over these various objects. We show that light does not trace baryonic mass, since bright galaxies which contain most of the stars only form a small fraction of the mass associated with virialized and cooled halos. We consider two cosmologies: a critical density universe and an open universe. In both cases, our results agree with observations and show that hierarchical scenarios provide a good model for structure formation and can describe a wide range of objects which spans at least the seven orders of magnitude in mass for which data exist. More detailed observations, in particular of the clustering evolution of galaxies, will constrain the astrophysical models involved.Comment: 13 pages, final version published in A&

Last Glacial Period Cryptotephra Deposits in an Eastern North Atlantic Marine Sequence: Exploring Linkages to the Greenland Ice-Cores

The establishment of a tephra framework for the Greenland ice-cores spanning the last glacial period, particularly between 25 and 45 ka b2k, provides strong potential for precisely correlating other palaeoclimatic records to these key archives. Tephra-based synchronisation allows the relative timing of past climatic changes recorded within different depositional environments and potential causal mechanisms to be assessed. Recent studies of North Atlantic marine records have demonstrated the potential of tracing cryptotephra horizons in these sequences and the development of protocols now allows a careful assessment of the isochronous nature of such horizons. Here we report on tephrochronological investigations of a marine sequence retrieved from the Goban Spur, Eastern North Atlantic, covering ?25–60 ka b2k. Density and magnetic separation techniques and an assessment of potential transport and depositional mechanisms have identified three previously unknown isochronous tephra horizons along with deposits of the widespread North Atlantic Ash Zone II and Faroe Marine Ash Zone III. Correlations between the new horizons and the Greenland ice-core tephra framework are explored and despite no tie-lines being identified the key roles that high-resolution climatostratigraphy and shard-specific trace element analysis can play within the assessment of correlations is demonstrated. The previously unknown horizons are new additions to the overall North Atlantic tephra framework for the last glacial period and could be key horizons for future correlations