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OBJECTIVES/GOALS: Immunomodulatory drugs (IMiDs) are critical to multiple myeloma (MM) disease control. IMiDs act by inducing Cereblon-dependent degradation of IKZF1 and IKZF3, which leads to IRF4 and MYC downregulation (collectively termed the “Ikaros axis”). We therefore hypothesized that IMiD treatment fails to downregulate the Ikaros axis in IMiD resistant MM. METHODS/STUDY POPULATION: To measure IMiD-induced Ikaros axis downregulation, we designed an intracellular flow cytometry assay that measured relative protein levels of IKZF1, IKZF3, IRF4 and MYC in MM cells following ex vivo treatment with the IMiD Pomalidomide (Pom). We established this assay using Pom-sensitive parental and dose-escalated Pom-resistant MM cell lines before assessing Ikaros axis downregulation in CD38+CD138+ MM cells in patient samples (bone marrow aspirates). To assess the Ikaros axis in the context of MM intratumoral heterogeneity, we used a 35-marker mass cytometry panel to simultaneously characterize MM subpopulations in patient samples. Lastly, we determined ex vivo drug sensitivity in patient samples via flow cytometry. RESULTS/ANTICIPATED RESULTS: Our hypothesis was supported in MM cell lines, as resistant lines showed no IMiD-induced decrease in any Ikaros axis proteins. However, when assessed in patient samples, Pom treatment caused a significant decrease in IKZF1, IKZF3 and IRF4 regardless of IMiD sensitivity. Mass cytometry in patient samples revealed that individual Ikaros axis proteins were differentially expressed between subpopulations. When correlating this with ex vivo Pom sensitivity of MM subpopulations, we observed that low IKZF1 and IKZF3 corresponded to Pom resistance. Interestingly, most of these resistant populations still expressed MYC. We therefore assessed whether IMiD resistant MM was MYC dependent by treating with MYCi975. In 88% (7/8) of patient samples tested, IMiD resistant MM cells were sensitive to MYC inhibition. DISCUSSION/SIGNIFICANCE: While our findings did not support our initial hypothesis, our data suggest a mechanism where MYC expression becomes Ikaros axis independent to drive IMiD resistance, and resistant MM is still dependent on MYC. This suggests targeting MYC directly or indirectly via a mechanism to be determined may be an effective strategy to eradicate IMiD resistant MM.
The coronavirus disease 2019 (COVID-19) pandemic has resulted in shortages of personal protective equipment (PPE), underscoring the urgent need for simple, efficient, and inexpensive methods to decontaminate masks and respirators exposed to severe acute respiratory coronavirus virus 2 (SARS-CoV-2). We hypothesized that methylene blue (MB) photochemical treatment, which has various clinical applications, could decontaminate PPE contaminated with coronavirus.
Design:
The 2 arms of the study included (1) PPE inoculation with coronaviruses followed by MB with light (MBL) decontamination treatment and (2) PPE treatment with MBL for 5 cycles of decontamination to determine maintenance of PPE performance.
Methods:
MBL treatment was used to inactivate coronaviruses on 3 N95 filtering facepiece respirator (FFR) and 2 medical mask models. We inoculated FFR and medical mask materials with 3 coronaviruses, including SARS-CoV-2, and we treated them with 10 µM MB and exposed them to 50,000 lux of white light or 12,500 lux of red light for 30 minutes. In parallel, integrity was assessed after 5 cycles of decontamination using multiple US and international test methods, and the process was compared with the FDA-authorized vaporized hydrogen peroxide plus ozone (VHP+O3) decontamination method.
Results:
Overall, MBL robustly and consistently inactivated all 3 coronaviruses with 99.8% to >99.9% virus inactivation across all FFRs and medical masks tested. FFR and medical mask integrity was maintained after 5 cycles of MBL treatment, whereas 1 FFR model failed after 5 cycles of VHP+O3.
Conclusions:
MBL treatment decontaminated respirators and masks by inactivating 3 tested coronaviruses without compromising integrity through 5 cycles of decontamination. MBL decontamination is effective, is low cost, and does not require specialized equipment, making it applicable in low- to high-resource settings.
The Eating Assessment in Toddlers FFQ (EAT FFQ) has been shown to have good reliability and comparative validity for ranking nutrient intakes in young children. With the addition of food items (n 4), we aimed to re-assess the validity of the EAT FFQ and estimate calibration factors in a sub-sample of children (n 97) participating in the Growing Up Milk – Lite (GUMLi) randomised control trial (2015–2017). Participants completed the ninety-nine-item GUMLi EAT FFQ and record-assisted 24-h recalls (24HR) on two occasions. Energy and nutrient intakes were assessed at months 9 and 12 post-randomisation and calibration factors calculated to determine predicted estimates from the GUMLi EAT FFQ. Validity was assessed using Pearson correlation coefficients, weighted kappa (κ) and exact quartile categorisation. Calibration was calculated using linear regression models on 24HR, adjusted for sex and treatment group. Nutrient intakes were significantly correlated between the GUMLi EAT FFQ and 24HR at both time points. Energy-adjusted, de-attenuated Pearson correlations ranged from 0·3 (fibre) to 0·8 (Fe) at 9 months and from 0·3 (Ca) to 0·7 (Fe) at 12 months. Weighted κ for the quartiles ranged from 0·2 (Zn) to 0·6 (Fe) at 9 months and from 0·1 (total fat) to 0·5 (Fe) at 12 months. Exact agreement ranged from 30 to 74 %. Calibration factors predicted up to 56 % of the variation in the 24HR at 9 months and 44 % at 12 months. The GUMLi EAT FFQ remained a useful tool for ranking nutrient intakes with similar estimated validity compared with other FFQ used in children under 2 years.
Jamie Gundry’s dramatic image of a white-tailed eagle (Haliaeetus albicilla) on the cover of this book reflects the twisting changes in fortune experienced by this species, with a revival that can be attributed to a successful interplay of science, policy and practice. White-tailed eagles were historically much more widely distributed than they are today (Yalden, 2007), once breeding across much of Europe, but by the early twentieth century the species was extinct across much of western and southern Europe. The main cause of its decline was persecution by farmers and shepherds, who considered the eagles a threat to their livestock, but, along with other raptors, white-tailed eagles were also seriously affected by DDT in the 1960s and 1970s, which had disastrous effects on the breeding success of remaining populations.
In the Anthropocene, when our environment is changing rapidly and the windows of opportunity for action to prevent further biodiversity loss are narrow, conservation researchers are increasingly encouraged to think and operate beyond the traditional approaches of producing peer-reviewed papers and presenting results to other members of the research community. Indeed, the perception that researchers belong in their ivory tower, from which they deliver evidence for others to interpret, disseminate and use in decision-making, is thankfully now widely recognised as outdated. The rise of fake news, a deliberate lack of consideration for scientific evidence, and changes to the ways of assessing the value of researchers’ work probably all play a role in supporting this shift in perception. Moreover, for many researchers, the prospect of their work ‘making a difference’ and having an impact on wider society is at least as great a motivation for doing research as generating new knowledge, however interesting that may be.
Conservation research is essential for advancing knowledge but to make an impact scientific evidence must influence conservation policies, decision making and practice. This raises a multitude of challenges. How should evidence be collated and presented to policymakers to maximise its impact? How can effective collaboration between conservation scientists and decision-makers be established? How can the resulting messages be communicated to bring about change? Emerging from a successful international symposium organised by the British Ecological Society and the Cambridge Conservation Initiative, this is the first book to practically address these questions across a wide range of conservation topics. Well-renowned experts guide readers through global case studies and their own experiences. A must-read for practitioners, researchers, graduate students and policymakers wishing to enhance the prospect of their work 'making a difference'. This title is also available as Open Access on Cambridge Core.
A sphere sinking through a chemical gradient drags fluid with it, deforming the gradient. The sphere leaves a trail of gradient enhancement that persists longer than the velocity disturbance in the Reynolds $10^{-2}\leqslant Re\leqslant 10^{2}$, Froude $10^{-1}\leqslant Fr\leqslant 10^{3}$ and Péclet $10^{2}<Pe\leqslant 10^{6}$ regime considered here. We quantify the enhancement of the gradient and the diffusive flux in the trail of disturbed chemical left by the passing sphere using a combination of numerical simulations and scaling analyses. When $Fr$ is large and buoyancy forces are negligible, dragged isosurfaces of chemical form a boundary layer of thickness $\unicode[STIX]{x1D6FF}_{\unicode[STIX]{x1D70C}}$ around the sphere with diameter $l$. We derive the scaling $\unicode[STIX]{x1D6FF}_{\unicode[STIX]{x1D70C}}/l\sim \mathit{Pe}^{-1/3}$ from the balance of advection and diffusion in the chemical boundary layer. The sphere displaces a single isosurface of chemical a maximum distance $\mathit{L}_{Def}$ that increases as $\mathit{L}_{Def}/l\sim l/\unicode[STIX]{x1D6FF}_{\unicode[STIX]{x1D70C}}\sim \mathit{Pe}^{1/3}$. Increased flux through the chemical boundary layer moving with the sphere is described by a Sherwood number, $Sh\sim l/\unicode[STIX]{x1D6FF}_{\unicode[STIX]{x1D70C}}\sim \mathit{Pe}^{1/3}$. The gradient enhancement trail extends much farther than $\mathit{L}_{Def}$ as displaced isosurfaces slowly return to their original positions through diffusion. In the reference frame of a chemical isosurface moving past the sphere, a new quantity describing the Lagrangian flux is found to scale as $\mathit{M}\sim (\mathit{L}_{Def}/l)^{2}\sim \mathit{Pe}^{2/3}$. The greater $\mathit{Pe}$ dependence of $\mathit{M}$ versus $Sh$ demonstrates the importance of the deformation trail for determining the total flux of chemical in the system. For $\mathit{Fr}\geqslant 10$, buoyancy forces are weak compared to the motion of the sphere and the preceding results are retained. Below $\mathit{Fr}=10$, an additional Froude dependence is found and $l/\unicode[STIX]{x1D6FF}_{\unicode[STIX]{x1D70C}}\sim Sh\sim Re^{1/6}Fr^{-1/6}Pe^{1/3}$. Buoyancy forces suppress gradient deformation downstream, resulting in $\mathit{L}_{Def}/l\sim Re^{-1/3}Fr^{1/3}Pe^{1/3}$ and $\mathit{M}\sim Re^{-1/3}Fr^{1/3}Pe^{2/3}$. The productivity of marine plankton – and therefore global carbon and oxygen cycles – depends on the availability of microscale gradients of chemicals. Because most plankton exist in the fluids regime under consideration, this work describes a new mechanism by which sinking particles and plankton can stir weak ambient chemical gradients a distance $\mathit{L}_{Def}$ and increase chemical flux in the trail by a factor of $\mathit{M}$.
This study investigated metabolic, endocrine, appetite and mood responses to a maximal eating occasion in fourteen men (mean: age 28 (sd 5) years, body mass 77·2 (sd 6·6) kg and BMI 24·2 (sd 2·2) kg/m2) who completed two trials in a randomised crossover design. On each occasion, participants ate a homogenous mixed-macronutrient meal (pizza). On one occasion, they ate until ‘comfortably full’ (ad libitum) and on the other, until they ‘could not eat another bite’ (maximal). Mean energy intake was double in the maximal (13 024 (95 % CI 10 964, 15 084) kJ; 3113 (95 % CI 2620, 3605) kcal) compared with the ad libitum trial (6627 (95 % CI 5708, 7547) kJ; 1584 (95 % CI 1364, 1804) kcal). Serum insulin incremental AUC (iAUC) increased approximately 1·5-fold in the maximal compared with ad libitum trial (mean: ad libitum 43·8 (95 % CI 28·3, 59·3) nmol/l × 240 min and maximal 67·7 (95 % CI 47·0, 88·5) nmol/l × 240 min, P < 0·01), but glucose iAUC did not differ between trials (ad libitum 94·3 (95 % CI 30·3, 158·2) mmol/l × 240 min and maximal 126·5 (95 % CI 76·9, 176·0) mmol/l × 240 min, P = 0·19). TAG iAUC was approximately 1·5-fold greater in the maximal v. ad libitum trial (ad libitum 98·6 (95 % CI 69·9, 127·2) mmol/l × 240 min and maximal 146·4 (95 % CI 88·6, 204·1) mmol/l × 240 min, P < 0·01). Total glucagon-like peptide-1, glucose-dependent insulinotropic peptide and peptide tyrosine–tyrosine iAUC were greater in the maximal compared with ad libitum trial (P < 0·05). Total ghrelin concentrations decreased to a similar extent, but AUC was slightly lower in the maximal v. ad libitum trial (P = 0·02). There were marked differences on appetite and mood between trials, most notably maximal eating caused a prolonged increase in lethargy. Healthy men have the capacity to eat twice the energy content required to achieve comfortable fullness at a single meal. Postprandial glycaemia is well regulated following initial overeating, with elevated postprandial insulinaemia probably contributing.
The propagation of a train of mode-2 internal solitary-like waves (ISWs) over a uniformly sloping, solid topographic boundary, has been studied by means of a combined laboratory and numerical investigation. The waves are generated by a lock-release method. Features of their shoaling include (i) formation of an oscillatory tail, (ii) degeneration of the wave form, (iii) wave run up, (iv) boundary layer separation, (v) vortex formation and re-suspension at the bed and (vi) a reflected wave signal. Slope steepness, $s$, is defined to be the height of the slope divided by the slope base length. In shallow slope cases ($s\leqslant 0.07$), the wave form is destroyed by the shoaling process; the leading mode-2 ISW degenerates into a train of mode-1 waves of elevation and little boundary layer activity is seen. For steeper slopes ($s\geqslant 0.13$), boundary layer separation, vortex formation and re-suspension at the bed are observed. The boundary layer dynamics is shown (numerically) to be dependent on the Reynolds number of the flow. A reflected mode-2 wave signal and wave run up are seen for slopes of steepness $s\geqslant 0.20$. The wave run up distance is shown to be proportional to the length scale $ac^{2}/g^{\prime }h_{2}\sin \unicode[STIX]{x1D703}$ where $a,c,g^{\prime },h_{2}$ and $\unicode[STIX]{x1D703}$ are wave amplitude, wave speed, reduced gravity, pycnocline thickness and slope angle respectively.