Why have we not yet solved the challenge of plastic degradation by biological means?

The invention of fossil fuel-derived plastics changed and reshaped society for the better; however, their mass production has created an unprecedented accumulation of waste and an environmental crisis. Scientists are searching for better ways to reduce plastic waste than the current methods of mechanical recycling and incineration, which are only partial solutions. Biological means of breaking down plastics have been investigated as alternatives, with studies mostly focusing on using microorganisms to biologically degrade sturdy plastics like polyethylene (PE). Unfortunately, after a few decades of research, biodegradation by microorganisms has not provided the hoped-for results. Recent studies suggest that insects could provide a new avenue for investigation into biotechnological tools, with the discovery of enzymes that can oxidize untreated PE. But how can insects provide a solution that could potentially make a difference? And how can biotechnology revolutionize the plastic industry to stop ongoing/increasing contamination?

Glucocerebrosidase (GCase) activity modulation by 2-alkyl trihydroxypiperidines: Inhibition and pharmacological chaperoning.

The enzyme glucocerebrosidase (GCase) has become an important therapeutic target due to its involvement in pathological disorders consequent to enzyme deficiency, such as the lysosomal storage Gaucher disease (GD) and the neurological Parkinson disease (PD). Pharmacological chaperones (PCs) are small compounds able to stabilize enzymes when used at sub-inhibitory concentrations, thus rescuing enzyme activity. We report the stereodivergent synthesis of trihydroxypiperidines alkylated at C-2 with both configurations, by means of the stereoselective addition of Grignard reagents to a carbohydrate-derived nitrone in the presence or absence of Lewis acids. All the target compounds behave as good GCase inhibitors, with IC50 in the micromolar range. Moreover, compound 11a behaves as a PC in fibroblasts derived from Gaucher patients bearing the N370/RecNcil mutation and the homozygous L444P mutation, rescuing the activity of the deficient enzyme by up to 1.9- and 1.8-fold, respectively. Rescues of 1.2-1.4-fold were also observed in wild-type fibroblasts, which is important for targeting sporadic forms of PD.

The effect of Astym® Therapy on muscle strength: a blinded, randomized, clinically controlled trial.

BACKGROUND: Astym(®) therapy is a manual therapy intervention used to stimulate tissue healing, decrease pain, improve mobility, and improve muscle performance associated with musculoskeletal pathology. The purpose of this study was to determine if Astym therapy administered to the lower extremity would result in an immediate change of maximal force output during a unilateral isometric squat test among individuals with a lower extremity injury. METHODS: Forty-five subjects (14 males; 31 females) between 18 and 65 years of age were randomized into 3 treatment groups: 1) Control group - received no treatment 2) Placebo group - received a sham Astym treatment 3) Astym therapy group- received Astym therapy to the lower extremity. A baseline measure of maximal force output (pre-test) during a unilateral isometric squat was performed. The subjects then received the designated treatment intervention. Immediately following the treatment intervention, maximal force output (post-test) was retested using identical testing procedures by an investigator who was blinded to the treatment intervention received by the subjects. The percent change of maximal force output from pre-test to post-test measures was compared using a one-way analysis of variance. A Tukey's post-hoc analysis determined the statistical differences between the groups. RESULTS: The treatment intervention had a significant effect on the percent change of maximal force output [F(2,42) = 7.91, p = 0.001]. Tukey's post hoc analysis demonstrated that the percent change of maximal force output was significantly greater in the Astym group (15 ± 18 % change of Newtons) compared to the placebo (-6 ± 11 % change of Newtons; p = 0.0001) and control (-1 ± 17 % change of Newtons; p = 0.0014) groups. No significant difference (p = 0.68) was noted between the control and placebo groups. CONCLUSIONS: Astym therapy to the involved lower extremity increased maximum force output during an isometric squat test immediately following treatment. The results of this study suggest that Astym therapy can immediately improve muscle performance (maximal force output) for patients presenting with muscular weakness caused by a lower extremity musculoskeletal injury. TRIAL REGISTRATION: Clinicaltrials.gov NCT02349230. Registered 23 January 2015.

A mathematical model for a T cell fate decision algorithm during immune response.

We formulate and analyze an algorithm of cell fate decision that describes the way in which division vs. apoptosis choices are made by individual T cells during an infection. Such model involves a minimal number of known biochemical mechanisms: it basically relies on the interplay between cell division and cell death inhibitors on one hand, and membrane receptors on the other. In spite of its simplicity, the proposed decision algorithm is able to account for some significant facts in immune response. At the individual level, the existence of T cells that continue to replicate in the absence of antigen and the possible occurrence of T cell apoptosis in the presence of antigen are predicted by the model. Moreover, the latter is shown to yield an emergent collective behavior, the observed delay in clonal contraction with respect to the end of antigen stimulation, which is shown to arise just from individual T cell decisions made according to the proposed mechanism.

Cognitive Training with Older Adults Using Smartphone and Web-Based Applications: A Scoping Review.

INTRODUCTION: The present scoping review focused on: i) which apps were previously studied; ii) what is the most common frequency for implementing cognitive training; and iii) what cognitive functions the interventions most focus on. METHODS: PRISMA guidelines were followed, and the search was conducted on Web of Science, PsycInfo, Cochrane, and Pubmed. From 1733 studies found, 34 were included. RESULTS: it was highlighted the necessity for forthcoming investigations to tackle the methodical restrictions and disparities in the domain. DISCUSSION: great diversity in intervention protocols was found. Incorporating evaluations of physical fitness in conjunction with cognitive evaluations can offer a more all-encompassing comprehension of the impacts of combined interventions. Furthermore, exploring the efficacy of cognitive training applications requires additional scrutiny, considering individual variances and practical outcomes in real-life settings.

A new role for erythropoietin in the homeostasis of red blood cells.

The regulation of red blood cell (RBC) homeostasis is widely assumed to rely on the control of cell production by erythropoietin (EPO) and the destruction of cells at a fixed, species-specific age. In this work, we show that such a regulatory mechanism would be a poor homeostatic solution to satisfy the changing needs of the body. Effective homeostatic control would require RBC lifespan to be variable and tightly regulated. We suggest that EPO may control RBC lifespan by determining CD47 expression in newly formed RBCs and SIRP-α expression in sinusoidal macrophages. EPO could also regulate the initiation and intensity of anti-RBC autoimmune responses that curtail RBC lifespan in some circumstances. These mechanisms would continuously modulate the rate of RBC destruction depending on oxygen availability. The control of RBC lifespan by EPO and autoimmunity emerges as a key mechanism in the homeostasis of RBCs.

The effects of six electronic apex locators on pacemaker function: an in vitro study.

AIM: To assess the effects of six electronic apex locators (EALs) on pacemaker function in vitro. METHODOLOGY: Six EALs (Mini Apex Locator®, Dentaport ZX®, Novapex®, Raypex5®, Root ZX mini®, and Justy II®) were tested for electromagnetic interference (EMI) with one pacemaker (Saint Jude Medical). The pacemaker, with a single electrode, was immersed in a saline solution bath adjusted to 400-800 hms to simulate the electrical resistance of the human body and to register the activity by the system. The pacemaker was tested with each of the EALs to analyse the presence of EMI with the EAL switched on, the EAL switched off and during EAL operation. Each series of tests began with a 15-second baseline recording (R0) and continued until all the recording conditions had been covered. The conditions were as follows: R1: recording with the lead of the EAL <2 cm from the tip of the electrode; R2: recording with the lead of the EAL <2 cm from the generator; R3: recording with the lead of the EAL <2 cm from the sensing arc; and R4: recording with the lead of the EAL 15 cm from the sensing arc. If any of the EALs produced interference, its characteristics were categorized. RESULTS: When the lead of the EAL was <2 cm from the tip of the electrode, the majority of the EALs tested produced only background noise. Only one (the Mini Apex Locator) resulted in EMI that was detected as false heart activity. When the EAL was <2 cm from the generator, just one EAL detected background noise (the Mini Apex Locator). When the EAL was <2 cm from the sensing arc or 15 cm from the sensing arc, the recordings were not affected by any of the EALs. There were no significant differences amongst the EALs analysed with respect to the production of EMI. CONCLUSIONS: EMI occurred when the EALs were placed close to the tip of the electrode and occasionally when close to the pacemaker; however, no EMI was detected when the EALs were placed near to or 15 cm from the sensing arc in this laboratory experimental model.

A cadaveric model for ligamentum teres function: a pilot study.

PURPOSE: Despite the prevalence and clinical consequences of ligamentum teres pathology, its function is poorly understood. The purpose of this study was to help define the role the ligamentum teres may have in hip joint stabilization and determine whether a ball and string model could be used to describe the function of the ligamentum teres. METHODS: Eight embalmed cadavers were dissected to remove all soft tissue from around the hip, leaving only the ligamentum teres intact. Available hip abduction, adduction, medial rotation, and lateral rotation range of motion were measured for three repeated trials. The position of the ligamentum teres in relation to the femoral head was recorded at the endpoint position of these movements. RESULTS: An endpoint position as limited by the ligamentum teres for abduction, medial rotation, and lateral rotation was identified at a mean of 73°(SD 11°), 64°(SD 11°), and 58°(SD 10°), respectively. Hip adduction was limited by bony contact and therefore was not measured. The ligamentum teres wrapped around the femoral head to prevent inferior, posterior, and anterior subluxation with abduction, medial rotation, and lateral rotation, respectively. Repeated measures ANOVA indicated no significant difference in endpoint position based on trial number for the three movements (n.s.). CONCLUSION: The ligamentum teres consistently tightened to limit hip abduction, medial rotation, and lateral rotation. These results support a ball and string model for the femoral head and ligamentum teres. This information could be important for those with hip instability and ligamentum teres pathology.

Function of the ligamentum teres during multi-planar movement of the hip joint.

PURPOSE: The purpose of this study was to describe the orientation of the ligamentum teres and quantify the limb position when the ligamentum teres reached its endpoint during a simulated squat position in human cadavers. METHODS: Dissection of eight (4 male; 4 female) cadavers resulted in the complete removal of all soft tissue attachment of the femur to the acetabulum, leaving only the ligamentum teres intact. The limb was then moved into combined flexion and abduction of the hip joint to simulate a deep squat position until a ligamentous endpoint of the ligamentum teres was achieved. The orientation of the ligamentum teres in relation to the femoral head was described and the position of the limb relative to the sagittal plane (flexion) and frontal plane (abduction) was quantified. The mean, standard deviation, 95 % confidence intervals, and standard error of the measurement were calculated for the observed angles. RESULTS: Multi-planar movement of flexion and abduction moved the ligamentum teres into an anterior/inferior position relative to the femoral head and prevented the femoral head from anterior/inferior subluxation. The ligamentum teres endpoint was obtained at a combined average position of 100.6° (range 94°-112°; SD 5.5º; 95 % CI 96º-105º) and 20.0° (range 12°-32°; SD 7.0º; 95 % CI 14º-26º) flexion and abduction angle. CONCLUSIONS: The ligamentum teres formed a "sling-like" structure to support the femoral head inferiorly as the hip joint was moved into a combined position of flexion and abduction that resembled a squat position. The results help to define a possible role of the ligamentum teres in hip joint stability and possible mechanisms of injury.

The virtual microbiome: A computational framework to evaluate microbiome analyses.

Microbiomes have been the focus of a substantial research effort in the last decades. The composition of microbial populations is normally determined by comparing DNA sequences sampled from those populations with the sequences stored in genomic databases. Therefore, the amount of information available in databanks should be expected to constrain the accuracy of microbiome analyses. Albeit normally ignored in microbiome studies, this constraint could severely compromise the reliability of microbiome data. To test this hypothesis, we generated virtual bacterial populations that exhibit the ecological structure of real-world microbiomes. Confronting the analyses of virtual microbiomes with their original composition revealed critical issues in the current approach to characterizing microbiomes, issues that were empirically confirmed by analyzing the microbiome of Galleria mellonella larvae. To reduce the uncertainty of microbiome data, the effort in the field must be channeled towards significantly increasing the amount of available genomic information and optimizing the use of this information.

Plastic degradation by insect hexamerins: Near-atomic resolution structures of the polyethylene-degrading proteins from the wax worm saliva.

Plastic waste management is a pressing ecological, social, and economic challenge. The saliva of the lepidopteran Galleria mellonella larvae is capable of oxidizing and depolymerizing polyethylene in hours at room temperature. Here, we analyze by cryo-electron microscopy (cryo-EM) G. mellonella's saliva directly from the native source. The three-dimensional reconstructions reveal that the buccal secretion is mainly composed of four hexamerins belonging to the hemocyanin/phenoloxidase family, renamed Demetra, Cibeles, Ceres, and a previously unidentified factor termed Cora. Functional assays show that this factor, as its counterparts Demetra and Ceres, is also able to oxidize and degrade polyethylene. The cryo-EM data and the x-ray analysis from purified fractions show that they self-assemble primarily into three macromolecular complexes with striking structural differences that likely modulate their activity. Overall, these results establish the ground to further explore the hexamerins' functionalities, their role in vivo, and their eventual biotechnological application.

Evidence for complex selection on four-fold degenerate sites in Drosophila melanogaster.

We considered genome-wide four-fold degenerate sites from an African Drosophila melanogaster population and compared them to short introns. To include divergence and to polarize the data, we used its close relatives Drosophila simulans, Drosophila sechellia, Drosophila erecta and Drosophila yakuba as outgroups. In D. melanogaster, the GC content at four-fold degenerate sites is higher than in short introns; compared to its relatives, more AT than GC is fixed. The former has been explained by codon usage bias (CUB) favouring GC; the latter by decreased intensity of directional selection or by increased mutation bias towards AT. With a biallelic equilibrium model, evidence for directional selection comes mostly from the GC-rich ancestral base composition. Together with a slight mutation bias, it leads to an asymmetry of the unpolarized allele frequency spectrum, from which directional selection is inferred. Using a quasi-equilibrium model and polarized spectra, however, only purifying and no directional selection is detected. Furthermore, polarized spectra are proportional to those of the presumably unselected short introns. As we have no evidence for a decrease in effective population size, relaxed CUB must be due to a reduction in the selection coefficient. Going beyond the biallelic model and considering all four bases, signs of directional selection are stronger. In contrast to short introns, complementary bases show strand specificity and allele frequency spectra depend on mutation directions. Hence, the traditional biallelic model to describe the evolution of four-fold degenerate sites should be replaced by more complex models assuming only quasi-equilibrium and accounting for all four bases.

Unconstrained evolution in short introns? - an analysis of genome-wide polymorphism and divergence data from Drosophila.

An unconstrained reference sequence facilitates the detection of selection. In Drosophila, sequence variation in short introns seems to be least influenced by selection and dominated by mutation and drift. Here, we test this with genome-wide sequences using an African population (Malawi) of D. melanogaster and data from the related outgroup species D. simulans, D. sechellia, D. erecta and D. yakuba. The distribution of mutations deviates from equilibrium, and the content of A and T (AT) nucleotides shows an excess of variance among introns. We explain this by a complex mutational pattern: a shift in mutational bias towards AT, leading to a slight nonequilibrium in base composition and context-dependent mutation rates, with G or C (GC) sites mutating most frequently in AT-rich introns. By comparing the corresponding allele frequency spectra of AT-rich vs. GC-rich introns, we can rule out the influence of directional selection or biased gene conversion on the mutational pattern. Compared with neutral equilibrium expectations, polymorphism spectra show an excess of low frequency and a paucity of intermediate frequency variants, irrespective of the direction of mutation. Combining the information from different outgroups with the polymorphism data and using a generalized linear model, we find evidence for shared ancestral polymorphism between D. melanogaster and D. simulans, D. sechellia, arguing against a bottleneck in D. melanogaster. Generally, we find that short introns can be used as a neutral reference on a genome-wide level, if the spatially and temporally varying mutational pattern is accounted for.

Killing the competition: a theoretical framework for liver-stage malaria.

The first stage of malaria infections takes place inside the host's hepatocytes. Remarkably, Plasmodium parasites do not infect hepatocytes immediately after reaching the liver. Instead, they migrate through several hepatocytes before infecting their definitive host cells, thus increasing their chances of immune destruction. Considering that malaria can proceed normally without cell traversal, this is indeed a puzzling behaviour. In fact, the role of hepatocyte traversal remains unknown to date, implying that the current understanding of malaria is incomplete. In this work, we hypothesize that the parasites traverse hepatocytes to actively trigger an immune response in the host. This behaviour would be part of a strategy of superinfection exclusion aimed to reduce intraspecific competition during the blood stage of the infection. Based on this hypothesis, we formulate a comprehensive theory of liver-stage malaria that integrates all the available knowledge about the infection. The interest of this new paradigm is not merely theoretical. It highlights major issues in the current empirical approach to the study of Plasmodium and suggests new strategies to fight malaria.

The myokinetic stimulation interface: activation of proprioceptive neural responses with remotely actuated magnets implanted in rodent forelimb muscle.

Objective. Proprioception is the sense of one's position, orientation, and movement in space, and it is of fundamental importance for motor control. When proprioception is impaired or absent, motor execution becomes error-prone, leading to poorly coordinated movements. The kinaesthetic illusion, which creates perceptions of limb movement in humans through non-invasively applying vibrations to muscles or tendons, provides an avenue for studying and restoring the sense of joint movement (kinaesthesia). This technique, however, leaves ambiguity between proprioceptive percepts that arise from muscles versus those that arise from skin receptors. Here we propose the concept of a stimulation system to activate kinaesthesia through the untethered application of localized vibration through implanted magnets.Approach. In this proof-of-concept study, we use two simplified one-DoF systems to show the feasibility of eliciting muscle-sensory responses in an animal model across multiple frequencies, including those that activate the kinaesthetic illusion (70-115 Hz). Furthermore, we generalized the concept by developing a five-DoF prototype system capable of generating directional, frequency-selective vibrations with desired displacement profiles.Main results. In-vivotests with the one-DoF systems demonstrated the feasibility to elicit muscle sensory neural responses in the median nerve of an animal model. Instead,in-vitrotests with the five-DoF prototype demonstrated high accuracy in producing directional and frequency selective vibrations along different magnet axes.Significance. These results provide evidence for a new technique that interacts with the native neuro-muscular anatomy to study proprioception and eventually pave the way towards the development of advanced limb prostheses or assistive devices for the sensory impaired.

The coordination of anti-phage immunity mechanisms in bacterial cells.

Bacterial cells are equipped with a variety of immune strategies to fight bacteriophage infections. Such strategies include unspecific mechanisms directed against any phage infecting the cell, ranging from the identification and cleavage of the viral DNA by restriction nucleases (restriction-modification systems) to the suicidal death of infected host cells (abortive infection, Abi). In addition, CRISPR-Cas systems generate an immune memory that targets specific phages in case of reinfection. However, the timing and coordination of different antiviral systems in bacterial cells are poorly understood. Here, we use simple mathematical models of immune responses in individual bacterial cells to propose that the intracellular dynamics of phage infections are key to addressing these questions. Our models suggest that the rates of viral DNA replication and cleavage inside host cells define functional categories of phages that differ in their susceptibility to bacterial anti-phage mechanisms, which could give raise to alternative phage strategies to escape bacterial immunity. From this viewpoint, the combined action of diverse bacterial defenses would be necessary to reduce the chances of phage immune evasion. The decision of individual infected cells to undergo suicidal cell death or to incorporate new phage sequences into their immune memory would be determined by dynamic interactions between the host's immune mechanisms and the phage DNA. Our work highlights the importance of within-cell dynamics to understand bacterial immunity, and formulates hypotheses that may inspire future research in this area.

'Doublecheck: a sensory confirmation is required to own a robotic hand, sending a command to feel in charge of it'.

Over a lifetime of experience, the representation of the body is built upon congruent integration of multiple elements constituting the sensorimotor loop. To investigate its robustness against the rupture of congruency between senses and with motor command, we selectively manipulated in healthy subjects the binds between sight, proprioception, and efferent motor command. Two experiments based on the Moving Hand Illusion were designed employing Tendon Vibration Illusion to modulate proprioception and generate illusory altered feedback of movement. In Experiment A, visuomotor congruency was modulated by introducing adelay between complex multifingered movements performed by arobotic hand and real movement of each participant's hand. In the presence of the motor command, visuomotor congruency enhanced ownership, agency, and skin conductance, while proprioceptive-motor congruency was not effective, confirming the prevalence of vision upon proprioception. In Experiment B, the impact of visuo-proprioceptive congruency was tested in the absence of motor command because the robotic hand moved autonomously. Intersensory congruency compensated for the absence of motor command only for ownership. Skin conductance in Exp Band Proprioceptive Drift in both experiments did not change. Results suggest that ownership and agency are independently processed, and presence of the efferent component modulates sensory feedbacks salience. The brain seems to require the integration of at least two streams of congruent information. Bodily awareness can be generated from sensory information alone, but to feel in charge of the body, senses must be double-checked with the prediction generated from efference copy, which is treated as an additional sensory modality.

Effects of anti-PD-1 immunotherapy on tumor regression: insights from a patient-derived xenograft model.

Immunotherapies, such as checkpoint blockade of programmed cell death protein-1 (PD-1), have resulted in unprecedented improvements in survival for patients with lung cancer. Nonetheless, not all patients benefit equally and many issues remain unresolved, including the mechanisms of action and the possible effector function of immune cells from non-lymphoid lineages. The purpose of this study was to investigate whether anti-PD-1 immunotherapy acts on malignant tumor cells through mechanisms beyond those related to T lymphocyte involvement. We used a murine patient-derived xenograft (PDX) model of early-stage non-small cell lung carcinoma (NSCLC) devoid of host lymphoid cells, and studied the tumor and immune non-lymphoid responses to immunotherapy with anti-PD-1 alone or in combination with standard chemotherapy (cisplatin). An antitumor effect was observed in animals that received anti-PD-1 treatment, alone or in combination with cisplatin, likely due to a mechanism independent of T lymphocytes. Indeed, anti-PD-1 treatment induced myeloid cell mobilization to the tumor concomitant with the production of exudates compatible with an acute inflammatory reaction mediated by murine polymorphonuclear leukocytes, specifically neutrophils. Thus, while keeping in mind that more research is needed to corroborate our findings, we report preliminary evidence for a previously undescribed immunotherapy mechanism in this model, suggesting a potential cytotoxic action of neutrophils as PD-1 inhibitor effector cells responsible for tumor regression by necrotic extension.

Calcium and pancreatic secretion. I. Subcellular distribution of calcium and magnesium in the exocrine pancreas of the guinea pig.

The distribution of calcium and magnesium has been studied in the acinar cells of the pancreas of the guinea pig. Most of the magnesium was found to be associated with the rough microsomes (probably bound to the ribosomes) and with the postmicrosomal supernate. In contrast, calcium was distributed among all the particulate fractions, primarily the mitochondria, microsomes (especially smooth surfaced), zymogen granules, and the plasmalemma, and was low in the postmicrosomal supernate. Most of the calcium recovered in the particulate fractions was found to be membrane bound. The highest concentrations were found in the membranes of the zymogen granules and in the plasmalemma. By means of control experiments using -45Ca as the tracer, it was established that a considerable redistribution of calcium occurs during homogenization and cell fractionation. At least some of the resulting artifacts were estimated quantitatively and the data were corrected accordingly. The biochemical results were confirmed with the cytochemical antimonate technique carried out on the tissue as well as on isolated fractions. The role of calcium associated with the zymogen granules and with their limiting membranes is discussed in relation to the architecture of the granule and to the functionality of the pancreatic juice.

Optimal integration of intraneural somatosensory feedback with visual information: a single-case study.

Providing somatosensory feedback to amputees is a long-standing objective in prosthesis research. Recently, implantable neural interfaces have yielded promising results in this direction. There is now considerable evidence that the nervous system integrates redundant signals optimally, weighting each signal according to its reliability. One question of interest is whether artificial sensory feedback is combined with other sensory information in a natural manner. In this single-case study, we show that an amputee with a bidirectional prosthesis integrated artificial somatosensory feedback and blurred visual information in a statistically optimal fashion when estimating the size of a hand-held object. The patient controlled the opening and closing of the prosthetic hand through surface electromyography, and received intraneural stimulation proportional to the object's size in the ulnar nerve when closing the robotic hand on the object. The intraneural stimulation elicited a vibration sensation in the phantom hand that substituted the missing haptic feedback. This result indicates that sensory substitution based on intraneural feedback can be integrated with visual feedback and make way for a promising method to investigate multimodal integration processes.