The need for muscle co-contraction prior to a landing

In landings from a flight phase the mass centre of an athlete experiences rapid decelerations. This study investigated the extent to which co-contraction is beneficial or necessary in drop landings, using both experimental data and computer simulations. High speed video and force recordings were made of an elite martial artist performing drop landings onto a force plate from heights of 1.2, 1.5 and 1.8 m. Matching simulations of these landings were produced using a planar 8-segment torque-driven subject-specific computer simulation model. It was found that there was substantial co-activation of joint flexor and extensor torques at touchdown in all three landings. Optimisations were carried out to determine whether landings could be effected without any co-contraction at touchdown. The model was not capable of landing from higher than 1.05 m with no initial flexor or extensor activations. Due to the force–velocity properties of muscle, co-contraction with net zero joint torque at touchdown leads to increased extensor torque and decreased flexor torque as joint flexion velocity increases. The same considerations apply in any activity where rapid changes in net joint torque are required, as for example in jumps from a running approach.     

The use of photographs of postoperative results prior to melanoma resection

A total of 99 patients scheduled for resection of stage I melanoma were assigned randomly to be shown individually relevant photographs of anticipated postoperative results. All patients had received verbal information on this subject during discussions with their plastic surgeons. Anticipated and actual cosmetic impact or distress was measured with a self-report questionnaire given prior to and 6 months following surgery. Patients were least distressed postoperatively when their scars were not larger than anticipated. However, photographs failed to achieve the expected benefit of increasing the accuracy of patients' expectations of their postoperative appearance. Consequently, photographs had no effect on levels of preoperative or postoperative distress. Selective attention and preferences for limited information among some patients are suggested explanations for these results.     

The immune response to melanoma is limited by thymic selection of self-antigens

The expression of melanoma-associated antigens (MAA) being limited to normal melanocytes and melanomas, MAAs are ideal targets for immunotherapy and melanoma vaccines. As MAAs are derived from self, immune responses to these may be limited by thymic tolerance. The extent to which self-tolerance prevents efficient immune responses to MAAs remains unknown. The autoimmune regulator (AIRE) controls the expression of tissue-specific self-antigens in thymic epithelial cells (TECs). The level of antigens expressed in the TECs determines the fate of auto-reactive thymocytes. Deficiency in AIRE leads in both humans (APECED patients) and mice to enlarged autoreactive immune repertoires. Here we show increased IgG levels to melanoma cells in APECED patients correlating with autoimmune skin features. Similarly, the enlarged T cell repertoire in AIRE(-/-) mice enables them to mount anti-MAA and anti-melanoma responses as shown by increased anti-melanoma antibodies, and enhanced CD4(+) and MAA-specific CD8(+) T cell responses after melanoma challenge. We show that thymic expression of gp100 is under the control of AIRE, leading to increased gp100-specific CD8(+) T cell frequencies in AIRE(-/-) mice. TRP-2 (tyrosinase-related protein), on the other hand, is absent from TECs and consequently TRP-2 specific CD8(+) T cells were found in both AIRE(-/-) and AIRE(+/+) mice. This study emphasizes the importance of investigating thymic expression of self-antigens prior to their inclusion in vaccination and immunotherapy strategies.     

The need and means to characterize sediment structure and behaviour prior to the selection and implementation of remediation plans

Remediation of contaminated sediments requires detailed characterizations of the speciation of the toxic substances and their transformations with regard to time and spatial distribution. While many approaches exist to address dissolved species of toxicants, there is a need to characterize sediments per se in terms of materials or particles which bind toxicants and modulate their bioavailability and rate of burial. Such specific information can be achieved through the correlative use of analytical microscopies, applied directly to native aquatic materials and used in conjunction with novel particle isolation methods and standard techniques of analytical chemistry. Such sedimentary `materials' are dominated by clays and other colloidal minerals, microorganisms, humic substances, organic debris, iron and manganese oxide coatings and extracellular polymeric substances. By using new technology to (1) identify particles and their relative abundances, (2) examine specific toxicant/particle associations at the scale of individual abundant particles, and (3) follow transformations over time, we produce information more insightful than was obtainable previously. Such knowledge will assist in determining which remediation technologies would be best for a given contaminated sediment (i.e. `intrinsic remediation' or dredging/disposal).     

On down-regulation of the immune response to metastatic malignant melanoma

Treatment of metastatic malignant melanoma with interferon alpha (IFNalpha) results in objective remission in approximately 15% of patients. In a previous investigation, we found that about 50% of the patients achieved at least minor or short-lived remissions. In some tumours extensive areas of regressive tumour change occurred. However, even in these areas remnants of tumour cells were generally found. The short duration of the immune response in some patients and the incomplete eradication of the tumour can be due either to selection of non-immunogenic tumour cells or to down-regulation of the immune reactivity to the tumour. In the present paper, the expression of the zeta chain of the T cell receptor in CD3+ lymphocytes and the expression of CD28 in CD3+, CD4+ and CD8+ lymphocytes was studied in resectable melanoma metastases from 20 treated (IFNalpha or IFNalpha in combination with cisplatinum and dacarbazine) and 16 untreated patients. A double-staining technique was used, and the occurrence and distribution of lymphocytes showing down-regulation of the zeta chain or CD28 were separately registered in different areas of the metastases: close to the tumour cells in areas of unaffected tumour growth, in areas with regressive tumour changes, in areas with marked fibrosis and in stromal areas with densely packed lymphocytes. CD3+ zeta lymphocytes were found in all metastases, but their number and distribution varied considerably. Down-regulation of the zeta chain was most often found in areas of regressive changes. In contrast, T lymphocytes infiltrating close to the tumour cells had a stronger expression of the zeta chain (P = 0.016). Down-regulation was also found in stromal areas of densely packed lymphocytes and in areas of fibrosis. The pattern of down-regulation of CD28 in various subsets of lymphocytes was similar to that of zeta chain. The same pattern of down-regulation of CD28 and the zeta chain was found in both untreated and treated patients, indicating that the down-regulation is not due to treatment but to the release of immunosuppressor factors from areas with high tumour cell density or extensive destruction of tumour cells. These results concur well with the view that IFNalpha treatment can result in immune-mediated tumour cell destruction early in the treatment period and that this immune response to the tumour can be followed by immunosuppression within a few weeks.     

The evaluation of the transport medium for extracted premolars prior to cryopreservation: a systematic literature review

Prior to cryopreservation, a tooth is transported from a contaminated oral environment to the tooth bank. Our objective was to identify all studies reporting or investigating a transport protocol prior to the cryopreservation of teeth, in terms of decontamination of the subjects. The systematic literature search (1970–2017) was based on MEDLINE via PubMed, Web of Science and the Cochrane Library. The reference lists of the included studies and the Science Citation Index were used for hand searching (snowballing). Only studies reporting the transport conditions of the transplant were included. Language restrictions for English, Dutch or French were applied. The search led to 14 eligible studies. Almost all studies were laboratory studies, so the methodological quality of evidence was low. The majority of the included studies was performed by only five different research groups and the number of subjects varied between 1 and 120 teeth. In general, the teeth were stored in a tissue culture medium supplemented with fetal calf serum and/or different combinations of antibiotics and/or antimycotics. The teeth were transported cooled (4 °C) or at room temperature, for a period of time not exceeding 24 h. Only three studies reported the irrigation of the teeth with phosphate buffered saline prior to the transport. The optimisation of the decontamination during transport was investigated in three studies (from 1971, 1980 and 1982). It was concluded that the literature on this topic is scarce, and the decontamination protocol for teeth, prior to cryopreservation has not been validated recently.     

Modeling insights into SARS-CoV-2 respiratory tract infections prior to immune protection

Mechanistic insights into human respiratory tract (RT) infections from SARS-CoV-2 can inform public awareness as well as guide medical prevention and treatment for COVID-19 disease. Yet the complexity of the RT and the inability to access diverse regions pose fundamental roadblocks to evaluation of potential mechanisms for the onset and progression of infection (and transmission). We present a model that incorporates detailed RT anatomy and physiology, including airway geometry, physical dimensions, thicknesses of airway surface liquids (ASLs), and mucus layer transport by cilia. The model further incorporates SARS-CoV-2 diffusivity in ASLs and best-known data for epithelial cell infection probabilities, and, once infected, duration of eclipse and replication phases, and replication rate of infectious virions. We apply this baseline model in the absence of immune protection to explore immediate, short-term outcomes from novel SARS-CoV-2 depositions onto the air-ASL interface. For each RT location, we compute probability to clear versus infect; per infected cell, we compute dynamics of viral load and cell infection. Results reveal that nasal infections are highly likely within 1–2 days from minimal exposure, and alveolar pneumonia occurs only if infectious virions are deposited directly into alveolar ducts and sacs, not via retrograde propagation to the deep lung. Furthermore, to infect just 1% of the 140 m² of alveolar surface area within 1 week, either 10³ boluses each with 10⁶ infectious virions or 10⁶ aerosols with one infectious virion, all physically separated, must be directly deposited. These results strongly suggest that COVID-19 disease occurs in stages: a nasal/upper RT infection, followed by self-transmission of infection to the deep lung. Two mechanisms of self-transmission are persistent aspiration of infected nasal boluses that drain to the deep lung and repeated rupture of nasal aerosols from infected mucosal membranes by speaking, singing, or cheering that are partially inhaled, exhaled, and re-inhaled, to the deep lung.     

Empirical evaluation of a prior for Bayesian phylogenetic inference

The Bayesian method of phylogenetic inference often produces high posterior probabilities (PPs) for trees or clades, even when the trees are clearly incorrect. The problem appears to be mainly due to large sizes of molecular datasets and to the large-sample properties of Bayesian model selection and its sensitivity to the prior when several of the models under comparison are nearly equally correct (or nearly equally wrong) and are of the same dimension. A previous suggestion to alleviate the problem is to let the internal branch lengths in the tree become increasingly small in the prior with the increase in the data size so that the bifurcating trees are increasingly star-like. In particular, if the internal branch lengths are assigned the exponential prior, the prior mean mu0 should approach zero faster than 1/square root n but more slowly than 1/n, where n is the sequence length. This paper examines the usefulness of this data size-dependent prior using a dataset of the mitochondrial protein-coding genes from the baleen whales, with the prior mean fixed at mu0=0.1n(-2/3). In this dataset, phylogeny reconstruction is sensitive to the assumed evolutionary model, species sampling and the type of data (DNA or protein sequences), but Bayesian inference using the default prior attaches high PPs for conflicting phylogenetic relationships. The data size-dependent prior alleviates the problem to some extent, giving weaker support for unstable relationships. This prior may be useful in reducing apparent conflicts in the results of Bayesian analysis or in making the method less sensitive to model violations.     

Escape mechanisms of melanoma from immune system by soluble melanoma antigen

We demonstrate in the B16 melanoma (C57BL/6 derived) system that the soluble form of tumor Ag preferentially suppresses immune responses 1) by inhibiting CTL activity in the effector phase and 2) by induction of specific Ts that block CTL generation in the induction phase. Soluble melanoma antigen Ag injected i.p. into the tumor-bearing host can effectively augment melanoma growth in vivo. Two T cell types with the L3T4+ or double-negative/I-J+ phenotype are involved in the suppression of anti-melanoma CTL responses and can easily be generated in the in vitro primary 12 h-culture. Anti-melanoma Ts recognizes the GM3(NeuAc) structure and distinguishes GM3 molecular species. This is because liposomes constructed with GM3(NeuAc) but not with GM3(NeuGc) gangliosides alone can effectively induce the melanoma-specific Ts. It is thus likely that tumor cells can escape from the immunologic surveillance system by stimulating the repertoire of Ts for self-Ag, GM3, which has existed even in the unprimed conditions in order to maintain self-tolerance. These would appear to be the major escape mechanisms.     

Randomized controlled trial of adjuvant chemoimmunotherapy with DTIC and BCG after complete excision of primary melanoma with a poor prognosis or melanoma metastases.

A clinical study was undertaken in 57 patients with completely excised nodular or superficial spreading melanoma invasive to Clark''s level 3, 4 or 5 (stage I) and 37 patients with completely resected in transit or lymph node metastases (stage III). The patients were randomly allocated to either a treatment group or a control group. Those in the treatment group received dimethyltriazeno imidazole carboxamide (DTIC) and bacille Calmette-Guérin (BCG). Those in the control group received only careful observation--the same periodic clinical and laboratory investigation that the treatment group underwent. Among the patients in the treatment group a delay in recurrence and an increase in survival were noted only in those with stage III disease, and the improvement was not statistically significant. The survival rates of the control subjects were much higher than those suggested from previously reported studies involving historical or nonrandomized control subjects, and they provide a basis on which to estimate the number of patients required for further trials of adjuvant treatment in melanoma.     

The need for speed

DNA sequence data are being produced at an ever-increasing rate. The Bowtie sequence-alignment algorithm uses advanced data structures to help data analysis keep pace with data generation.     

Systemic immune parameters after prior radiation therapy in patients receiving immune checkpoint inhibitors

IntroductionPreclinical studies have demonstrated the ability of radiation therapy (RT) to augment immune response and tumor control by immune checkpoint inhibitors (ICI). However, numerous clinical trials combining RT and ICI have yielded relatively disappointing results. To improve understanding of optimal use of these therapies, we assessed systemic immune effects of prior RT in patients receiving ICI.Methods and MaterialsPre- and post-ICI blood samples were collected from patients enrolled in a prospective immunotherapy biospecimen protocol. Mutiplex panels of 40 cytokines and 120 autoantibodies (Ab) were analyzed. We identified differences in these parameters according to receipt, timing, and type of prior RT. We calculated P values using the Pearson product-moment correlation coefficient and false discovery rate (FDR) using the Benjamini-Hochberg Procedure.ResultsAmong 277 total patients, 69 (25%) received RT in the 6 months prior to ICI initiation. Among RT-treated patients, 23 (33%) received stereotactic RT, and 33 (48%) received curative intent RT. There was no significant difference in demographics or type of immunotherapy between patients according to prior RT exposure. Baseline complement C8 Ab and MIP-1d/CCL15 were significantly higher among patients with prior RT. For MIP-1d/CCL15, only prior stereotactic RT was associated with significant differences.ConclusionsPrior RT is associated with few changes in systemic immune parameters in patients receiving ICI. The underlying mechanisms and optimal approach to harnessing the potential synergy of RT and ICI require further prospective clinical investigation.     

The need to 'maintain the rage'

Personal reflections are presented on the need to ensure that appropriate attention is given to malaria. The importance of political and financial commitments is stressed and the investment in people is considered a major priority.