Effects of rye inclusion in dog food on fecal microbiota and short-chain fatty acids.

BACKGROUND: Rye intake has been associated with beneficial effects on health in human interventions, possibly due to dietary fiber in rye. In dogs, few studies have explored the effects on health of dietary fiber in general, and rye fiber in particular. The aim of this study was to investigate how inclusion of rye, compared with wheat, influenced fecal microbiota composition, short chain fatty acids (SCFA) and apparent total tract digestibility (ATTD) in dogs. Six male Beagle dogs (mean age 4.6 years, SEM 0.95 years; mean body weight 14.6 kg, SEM 0.32 kg) were fed three experimental diets, each for 21 days, including an adaptation period of six days and with 2-2.5 months between diet periods. The diets were similar regarding energy and protein, but had different carbohydrate sources (refined wheat (W), whole grain rye (R), or an equal mixture of both (RW)) comprising 50% of total weight on a dry matter (DM) basis. The diets were baked and titanium dioxide was added for ATTD determination. Fecal samples were collected before and in the end of each experimental period. Fecal microbiota was analyzed by sequencing 16S rRNA gene amplicons and fecal SCFA by high-performance liquid chromatography. Crude protein, crude fat, neutral detergent fiber, and gross energy (GE) in food and feces were analyzed and ATTD of each was determined. Univariate and multivariate statistical methods were applied in data evaluation. RESULTS: Faecal microbiota composition, differed depending on diet (P = 0.002), with samples collected after consumption of the R diet differing from baseline. This was primarily because of a shift in proportion of Prevotella, which increased significantly after consumption of the R diet (P < 0.001). No significant differences were found for SCFA, but there was a tendency (P < 0.06) for higher molar proportions of acetic acid following consumption of the R diet. The ATTD of crude protein, crude fat, neutral detergent fiber, and GE was lower after consumption of the R diet compared with the other diets (P < 0.05). CONCLUSIONS: Consumption of the R diet, but not RW or W diets, was associated with specific shifts in microbial community composition and function, but also with lower ATTD.

Nowcasting (Short-Term Forecasting) of COVID-19 Hospitalizations Using Syndromic Healthcare Data, Sweden, 2020.

We report on local nowcasting (short-term forecasting) of coronavirus disease (COVID-19) hospitalizations based on syndromic (symptom) data recorded in regular healthcare routines in Östergötland County (population ≈465,000), Sweden, early in the pandemic, when broad laboratory testing was unavailable. Daily nowcasts were supplied to the local healthcare management based on analyses of the time lag between telenursing calls with the chief complaints (cough by adult or fever by adult) and COVID-19 hospitalization. The complaint cough by adult showed satisfactory performance (Pearson correlation coefficient r>0.80; mean absolute percentage error <20%) in nowcasting the incidence of daily COVID-19 hospitalizations 14 days in advance until the incidence decreased to <1.5/100,000 population, whereas the corresponding performance for fever by adult was unsatisfactory. Our results support local nowcasting of hospitalizations on the basis of symptom data recorded in routine healthcare during the initial stage of a pandemic.

Quantification of true lumen helical morphology and chirality in type B aortic dissections.

Chirality is a fundamental property in many biological systems. Motivated by previous observations of helical aortic blood flow, aortic tissue fibers, and propagation of aortic dissections, we introduce methods to characterize helical morphology of aortic dissections. After validation on computer-generated phantoms, the methods were applied to patients with type B dissection. For this cohort, there was a distinct bimodal distribution of helical propagation of the dissection with either achiral or exclusively right-handed chirality, with no intermediate cases or left-handed cases. This clear grouping indicates that dissection propagation favors these two modes, which is potentially due to the right-handedness of helical aortic blood flow and cell orientation. The characterization of dissection chirality and quantification of helical morphology advances our understanding of dissection pathology and lays a foundation for applications in clinical research and treatment practice. For example, the chirality and magnitude of helical metrics of dissections may indicate risk of dissection progression, help define treatment and surveillance strategies, and enable development of novel devices that account for various helical morphologies.NEW & NOTEWORTHY A novel definition of helical propagation of type B aortic dissections reveals a distinct bimodality, with the true lumen being either achiral (nonhelical) or exclusively right-handed. This right-handed chirality is consistent with anatomic and physiological phenomena such as right-handed twist during left ventricle contraction, helical blood flow, and tissue fiber direction. The helical character of aortic dissections may be useful for pathology research, diagnostics, treatment selection, therapeutic durability prediction, and aortic device design.

Mathematical and Computational Models for Pain: A Systematic Review.

OBJECTIVE: There is no single prevailing theory of pain that explains its origin, qualities, and alleviation. Although many studies have investigated various molecular targets for pain management, few have attempted to examine the etiology or working mechanisms of pain through mathematical or computational model development. In this systematic review, we identified and classified mathematical and computational models for characterizing pain. METHODS: The databases queried were Science Direct and PubMed, yielding 560 articles published prior to January 1st, 2020. After screening for inclusion of mathematical or computational models of pain, 31 articles were deemed relevant. RESULTS: Most of the reviewed articles utilized classification algorithms to categorize pain and no-pain conditions. We found the literature heavily focused on the application of existing models or machine learning algorithms to identify the presence or absence of pain, rather than to explore features of pain that may be used for diagnostics and treatment. CONCLUSIONS: Although understudied, the development of mathematical models may augment the current understanding of pain by providing directions for testable hypotheses of its underlying mechanisms. Additional focus is needed on developing models that seek to understand the underlying mechanisms of pain, as this could potentially lead to major breakthroughs in its treatment.

New Conceptual Toxicokinetic Model to Assess Synergistic Mixture Effects between the Aromatic Hydrocarbon ß-Naphthoflavone and the Azole Nocodazole on the CYP1A Biomarker in a Fish Cell Line.

Toxicokinetic interactions with catabolic cytochrome P450 (CYP) enzymes can inhibit chemical elimination pathways and cause synergistic mixture effects. We have created a mathematical bottom-up model for a synergistic mixture effect where we fit a multidimensional function to a given data set using an auxiliary nonadditive approach. The toxicokinetic model is based on the data from a previous study on a fish cell line, where the CYP1A enzyme activity was measured over time after exposure to various combinations of the aromatic hydrocarbon ß-naphthoflavone and the azole nocodazole. To describe the toxicokinetic mechanism in this pathway and how that affects the CYP1A biomarker, the model uses ordinary differential equations. Local sensitivity and identifiability analyses revealed that all the 10 parameters estimated in the model were identified uniquely while fitting the model to the data for measuring the CYP1A enzyme activity. The model has a good prediction power and is a promising tool to test the synergistic toxicokinetic interactions between different chemicals.

Side Reactions Do Not Completely Disrupt Linear Self-Replicating Chemical Reaction Systems.

A crucial question within the fields of origins of life and metabolic networks is whether or not a self-replicating chemical reaction system is able to persist in the presence of side reactions. Due to the strong nonlinear effects involved in such systems, they are often difficult to study analytically. There are however certain conditions that allow for a wide range of these reaction systems to be well described by a set of linear ordinary differential equations. In this article, we elucidate these conditions and present a method to construct and solve such equations. For those linear self-replicating systems, we quantitatively find that the growth rate of the system is simply proportional to the sum of all the rate constants of the reactions that constitute the system (but is nontrivially determined by the relative values). We also give quantitative descriptions of how strongly side reactions need to be coupled with the system in order to completely disrupt the system.

Automated Quantification of Diseased Thoracic Aortic Longitudinal Centerline and Surface Curvatures.

Precise description of vascular morphometry is crucial to support medical device manufacturers and clinicians for improving device development and interventional outcomes. A compact and intuitive method is presented to automatically characterize the surface geometry of tubular anatomic structures and quantify surface curvatures starting from generic stereolithographic (STL) surfaces. The method was validated with software phantoms and used to quantify the longitudinal surface curvatures of 37 human thoracic aortas with aneurysm or dissection. The quantification of surface curvatures showed good agreement with analytic solutions from the software phantoms, and demonstrated better agreement as compared to estimation methods using only centerline geometry and cross-sectional radii. For the human thoracic aortas, longitudinal inner surface curvature was significantly higher than centerline curvature (0.33 ± 0.06 versus 0.16 ± 0.02 cm-1 for mean; 1.38 ± 0.48 versus 0.45 ± 0.11 cm-1 for peak; both p < 0.001). These findings show the importance of quantifying surface curvatures in order to better describe the geometry and biomechanical behavior of the thoracic aorta, which can assist in treatment planning and supplying device manufactures with more precise boundary conditions for mechanical evaluation.

Exploring the Arctic Charr Intestinal Glycome: Evidence of Increased N-Glycolylneuraminic Acid Levels and Changed Host-Pathogen Interactions in Response to Inflammation.

Disease outbreaks are a limiting factor for the sustainable development of the aquaculture industry. The intestinal tract is covered by a mucus layer mainly comprised by highly glycosylated proteins called mucins. Mucins regulate pathogen adhesion, growth, and virulence, and the glycans are vital for these functions. We analyzed intestinal mucin O-glycans on mucins from control and full-fat extruded soy-bean-fed (known to cause enteritis) Arctic charr using liquid chromatography-tandem mass spectrometry. In total, 56 glycans were identified on Arctic charr intestinal mucins, with a high prevalence of core-5-type and sialylated O-glycans. Disialic-acid-epitope-containing structures including NeuAcα2,8NeuAc, NeuAc(Gc)α2,8NeuGc(Ac), and NeuGcα2,8NeuGc were the hallmark of Arctic charr intestinal mucin glycosylation. Arctic charr fed with soy bean meal diet had lower (i) number of structures detected, (ii) interindividual variation, and (iii) N-glycolylneuraminic-acid-containing glycans compared with control Arctic charr. Furthermore, Aeromonas salmonicida grew less in response to mucins from inflamed Arctic charr than from the control group. The Arctic charr glycan repertoire differed from that of Atlantic salmon. In conclusion, the loss of N-glycolylneuraminic acid may be a biomarker for inflammation in Arctic char, and inflammation-induced glycosylation changes affect host-pathogen interactions.

Haematological and intestinal health parameters of rainbow trout are influenced by dietary live yeast and increased water temperature.

Live yeast may be a sustainable protein source in salmonid diets while exhibiting a probiotic effect to counteract environmental stressors, such as increased water temperature that is being exacerbated by climate change. The objective of this study was to evaluate the effects of feeding a high dietary inclusion of live yeast and increased water temperature on growth, haematological and intestinal physiology of rainbow trout. For six weeks, 129 g fish in 16 tanks (n = 4) were fed either a diet based on fishmeal or based on live yeast (214 g kg-1 of diet or 7.6 log CFU g-1 of Saccharomyces cerevisiae) that replaced 40% of fishmeal protein while fish were reared in water temperatures of either 11 °C (cold) or 18 °C (warm). Fish weights, caudal blood and proximal and distal intestines were collected and analysed. Fish fed live yeast resulted in reduced growth (SGR and WG) and higher FCR, while growth in cold and warm water was similar despite differences in TGC. However, increased mortality, plasma cortisol, and intestinal oedema and villous damage indicated fish reared in warm water were subjected to chronic stress. Temperature had a significant effect on haematocrit and red blood cell counts that resulted in significantly higher haemoglobin levels in fish kept in warm water attributed to an elevated oxygen demand. In the proximal intestine, increased temperature resulted in reduced expression of pro-inflammatory cytokines, e.g. TNFα and IL8, that were further reduced in fish fed live yeast. In addition, feeding live yeast reduced gene expression of CLD6 involved in gut barrier function, which suggests that the level of yeast was too high and masked any beneficial effects on fish health. In conclusion, feeding a high inclusion of live yeast reduced fish growth and expression of intestinal genes, while increasing the temperature from 11 to 18 °C subjected fish to chronic stress that restricted growth, suppressed innate immunity and induced intestinal damage. Replacing 40% of fishmeal protein with live yeast did not counteract negative effects caused by increased temperature, thus alternative strategies need to be explored and implemented to protect the growth and health of rainbow trout from seasonal and long-term rises in water temperature.

Effects of dietary yeast inclusion and acute stress on post-prandial whole blood profiles of dorsal aorta-cannulated rainbow trout.

Yeast is a potential alternative to fish meal in diets for farmed fish, yet replacing more than 50 % of fish meal results in reduced fish growth. In a 4-week experiment, 15 rainbow trout (Oncorhynchus mykiss) were cannulated and fed three diets each week: 30 % fish meal as a control (FM); 60 % replacement of fish meal protein, on a digestible basis, with Saccharomyces cerevisiae (SC); and 60 % replacement with Wickerhamomyces anomalus and S. cerevisiae mix (WA). Blood was collected at 0, 3, 6, 12 and 24 h after feeding. In the final week, fish were exposed to a 1-min netting stressor to evaluate possible diet-stress interactions. Significant increases in pH, TCO2, HCO3 and base excess were found after fish were fed the SC and WA diets compared with FM, which elevated blood alkaline tides. Yeast ingredients had lower buffering capacity and ash content than fish meal, which explained the increase in alkaline tides. In addition, fish fed the WA diet had significantly reduced erythrocyte area and fish fed SC and WA diets had increased mean corpuscular haemoglobin levels, indicating haemolytic anaemia. Higher levels of nucleic acid in yeast-based diets and potentially higher production of reactive oxygen species were suspected of damaging haemoglobin, which require replacement by smaller immature erythrocytes. Acute stress caused the expected rise in cortisol and glucose levels, but no interaction with diet was found. These results show that replacing 60 % of fish meal protein with yeasts can induce haemolytic anaemia in rainbow trout, which may limit yeast inclusion in diets for farmed fish.

Estimating the probability of coexistence in cross-feeding communities.

The dynamics of many microbial ecosystems are driven by cross-feeding interactions, in which metabolites excreted by some species are metabolised further by others. The population dynamics of such ecosystems are governed by frequency-dependent selection, which allows for stable coexistence of two or more species. We have analysed a model of cross-feeding based on the replicator equation, with the aim of establishing criteria for coexistence in ecosystems containing three species, given the information of the three species' ability to coexist in their three separate pairs, i.e. the long term dynamics in the three two-species component systems. The triple-system is studied statistically and the probability of coexistence in the species triplet is computed for two models of species interactions. The interaction parameters are modelled either as stochastically independent or organised in a hierarchy where any derived metabolite carries less energy than previous nutrients in the metabolic chain. We differentiate between different modes of coexistence with respect to the pair-wise dynamics of the species, and find that the probability of coexistence is close to 12 for triplet systems with three pair-wise coexistent pairs and for the so-called intransitive systems. Systems with two and one pair-wise coexistent pairs are more likely to exist for random interaction parameters, but are on the other hand much less likely to exhibit triplet coexistence. Hence we conclude that certain species triplets are, from a statistical point of view, rare, but if allowed to interact are likely to coexist. This knowledge might be helpful when constructing synthetic microbial communities for industrial purposes.

Importance of plasticity and local adaptation for coping with changing salinity in coastal areas: a test case with barnacles in the Baltic Sea.

BACKGROUND: Salinity plays an important role in shaping coastal marine communities. Near-future climate predictions indicate that salinity will decrease in many shallow coastal areas due to increased precipitation; however, few studies have addressed this issue. The ability of ecosystems to cope with future changes will depend on species' capacities to acclimatise or adapt to new environmental conditions. Here, we investigated the effects of a strong salinity gradient (the Baltic Sea system--Baltic, Kattegat, Skagerrak) on plasticity and adaptations in the euryhaline barnacle Balanus improvisus. We used a common-garden approach, where multiple batches of newly settled barnacles from each of three different geographical areas along the Skagerrak-Baltic salinity gradient were exposed to corresponding native salinities (6, 15 and 30 PSU), and phenotypic traits including mortality, growth, shell strength, condition index and reproductive maturity were recorded. RESULTS: We found that B. improvisus was highly euryhaline, but had highest growth and reproductive maturity at intermediate salinities. We also found that low salinity had negative effects on other fitness-related traits including initial growth and shell strength, although mortality was also lowest in low salinity. Overall, differences between populations in most measured traits were weak, indicating little local adaptation to salinity. Nonetheless, we observed some population-specific responses--notably that populations from high salinity grew stronger shells in their native salinity compared to the other populations, possibly indicating adaptation to differences in local predation pressure. CONCLUSIONS: Our study shows that B. improvisus is an example of a true brackish-water species, and that plastic responses are more likely than evolutionary tracking in coping with future changes in coastal salinity.

Expression of heat shock proteins 27 and 72 correlates with specific commensal microbes in different regions of porcine gastrointestinal tract.

The gastrointestinal (GI) tract of mammals is inhabited by trillions of microorganisms, resulting in exceedingly complex networking. The interaction between distinct bacterial species and the host immune system is essential in maintaining homeostasis in the gut ecosystem. For instance, the gut commensal microbiota dictates intestinal mucosa maturation and its abundant immune components, such as cytoprotective heat shock proteins (HSP). Here we examined physiological expression of HSP in the normal porcine GI tract and found it to be gut region- and cell type-specific in response to dietary components, microbes, and microbial metabolites to which the mucosa surface is exposed. Correlations between HSP72 expression and ileal Lactobacillus spp. and colonic clostridia species, and between HSP27 expression and uronic acid ingestion, were important interplays identified here. Thus this study provides novel insights into host-microbe interactions shaping the immune system that are modifiable by dietary regime.

Cross-feeding dynamics described by a series expansion of the replicator equation.

Understanding how ecosystems evolve and how they respond to external perturbations is critical if we are to predict the effects of human intervention. A particular class of ecosystems whose dynamics are poorly understood are those in which the species are related via cross-feeding. In these ecosystems the metabolic output of one species is being used as a nutrient or energy source by another species. In this paper we derive a mathematical description of cross-feeding dynamics based on the replicator equation. We show that under certain assumptions about the system (e.g., high flow of nutrients and time scale separation), the governing equations reduce to a second-order series expansion of the replicator equation. By analysing the case of two and three species we derive conditions for co-existence and show under which parameter conditions one can expect an increase in mean fitness. Finally, we discuss how the model can be parameterised from experimental data.

Effects of whole-grain cereals on fecal microbiota and short-chain fatty acids in dogs: a comparison of rye, oats and wheat.

Dietary fiber in dog food is reported to promote healthy gut microbiota, but few studies have investigated the effects of whole-grain cereals, which contain a variety of fiber types and other bioactive compounds. The aim of the present study was to compare the effects of diets containing whole-grain rye (RYE), oats (OAT) and wheat (WHE) on fecal microbiota and short-chain fatty acid production. Eighteen dogs were fed three experimental diets, each for four weeks, in a cross-over design. Fecal samples were collected at the end of each diet period. Analysis of 16S rRNA gene amplicons showed that family Lachnospiraceae and genus Bacteroides were the gut microbial groups most affected by diet, with lowest relative abundance following consumption of RYE and a trend for a corresponding increase in genus Prevotella_9. Fecal acetate and propionate concentrations were higher after consumption of RYE compared with OAT. In conclusion, rye had the strongest effect on gut microbiota and short-chain fatty acids, although the implications for dog gut health are not yet elucidated.

Age Rather Than Supplementation with Oat ß-Glucan Influences Development of the Intestinal Microbiota and SCFA Concentrations in Suckling Piglets.

The effects of early supplementation with oat ß-glucan during the suckling period on piglet gut microbiota composition, concentrations of short-chain fatty acids, and gut physiological markers were assessed. Fifty piglets from five litters, balanced for sex and birth weight, were divided within litters into two treatment groups: ß-glucan and control. Piglets in the ß-glucan group received the supplement three times/week from day 7 of age until weaning. Rectal swab samples were collected from 10 piglets per treatment group (balanced across litters) from week 1 to week 4, and plasma samples were collected at 1, 3, and 4 weeks of age. Additional samples of intestinal tissues and jugular and portal vein plasma were collected from 10 animals at weaning (one per treatment group and litter). The concentrations of short-chain fatty acids in plasma and the microbiota composition in rectal swabs were mainly influenced by piglet age, rather than the supplement. There were significant differences in microbiota composition between litters and several correlations between concentrations of short-chain fatty acids in plasma and specific microbial taxa in rectal swabs. Overall, ß-glucan supplementation did not have any clear impact on the gut environment in suckling piglets, whereas a clear age-related pattern emerged.

Inclusion of chicory (Cichorium intybus L.) in pigs' diets affects the intestinal microenvironment and the gut microbiota.

The content and composition of prebiotic plant fiber in the diet is important in promoting gut-related health. This study investigated the effects of the dietary inclusion of chicory forage and roots on the intestinal microenvironment of pigs. Thirty-seven-week-old pigs were fed 1 of 5 diets for 18 days, including a cereal-based control diet and 4 diets with the inclusion of 80 and 160 g kg(-1) of body weight chicory forage (CF80 and CF160), 80 g kg(-1) chicory root (CR80), and a mix of 80 g kg(-1) forage and 80 g kg(-1) chicory root (CFR). The animals maintained good performance and health irrespective of diet. Bacterial community structure and diversity in ileal and colonic samples was assessed using terminal restriction fragment length polymorphism (T-RFLP), combined with cloning and sequencing. Samples clustered perfectly according to gut segment with a higher bacterial diversity in colon than ileum. Distal ileum was dominated by lactic acid bacteria (LAB), and the relative amount of this group was increased by the CF160 and CFR diets. The colonic bacterial community was dominated by butyrate-producing bacteria and Prevotella. The increased relative abundance of butyrate-producing bacteria in the colon was positively correlated with the molar proportion of acetic acid and furthermore linked to the chicory forage diets (CF80 and CF160). Diets including chicory roots (CR80 and CFR) were correlated with a higher colonic abundance of Megasphaera elsdenii. The fermentation products and pH in digesta responded to diet type and were correlated with shifts in the microbiota, showing that chicory influences the intestinal microenvironment of pigs.

Optimization of additive chemotherapy combinations for an in vitro cell cycle model with constant drug exposures.

Proliferation of an in vitro population of cancer cells is described by a linear cell cycle model with n states, subject to provocation with m chemotherapeutic compounds. Minimization of a linear combination of constant drug exposures is considered, with stability of the system used as a constraint to ensure a stable or shrinking cell population. The main result concerns the identification of redundant compounds, and an explicit solution formula for the case where all exposures are nonzero. The orthogonal case, where each drug acts on a single and different stage of the cell cycle, leads to a version of the classic inequality between the arithmetic and geometric means. Moreover, it is shown how the general case can be solved by converting it to the orthogonal case using a linear invertible transformation. The results are illustrated with two examples corresponding to combination treatment with two and three compounds, respectively.

Predicting regional COVID-19 hospital admissions in Sweden using mobility data.

The transmission of COVID-19 is dependent on social mixing, the basic rate of which varies with sociodemographic, cultural, and geographic factors. Alterations in social mixing and subsequent changes in transmission dynamics eventually affect hospital admissions. We employ these observations to model and predict regional hospital admissions in Sweden during the COVID-19 pandemic. We use an SEIR-model for each region in Sweden in which the social mixing is assumed to depend on mobility data from public transport utilisation and locations for mobile phone usage. The results show that the model could capture the timing of the first and beginning of the second wave of the pandemic 3 weeks in advance without any additional assumptions about seasonality. Further, we show that for two major regions of Sweden, models with public transport data outperform models using mobile phone usage. We conclude that a model based on routinely collected mobility data makes it possible to predict future hospital admissions for COVID-19 3 weeks in advance.

Correlation between musculoskeletal structure of the hand and primate locomotion: Morphometric and mechanical analysis in prehension using the cross- and triple-ratios.

Biometric ratios of the relative length of the rays in the hand have been analyzed between primate species in the light of their hand function or phylogeny. However, how relative lengths among phalanges are mechanically linked to the grasping function of primates with different locomotor behaviors remains unclear. To clarify this, we calculated cross and triple-ratios, which are related to the torque distribution, and the torque generation mode at different joint angles using the lengths of the phalanges and metacarpal bones in 52 primates belonging to 25 species. The torque exerted on the finger joint and traction force of the flexor tendons necessary for a cylindrical grip and a suspensory hand posture were calculated using the moment arm of flexor tendons measured on magnetic resonance images, and were compared among Hylobates spp., Ateles sp., and Papio hamadryas. Finally, the torques calculated from the model were validated by a mechanical study detecting the force exerted on the phalanx by pulling the digital flexor muscles during suspension in these three species. Canonical discriminant analysis of cross and triple-ratios classified primates almost in accordance with their current classification based on locomotor behavior. The traction force was markedly reduced with flexion of the MCP joint parallel to the torque in brachiating primates; this was notably lower in the terrestrial quadrupedal primates than in the arboreal primates at mild flexion. Our mechanical study supported these features in the torque and traction force generation efficiencies. Our results suggest that suspensory or terrestrial quadrupedal primates have hand structures that can exert more torque at a suspensory posture, or palmigrade and digitigrade locomotion, respectively. Furthermore, our study suggests availability of the cross and triple-ratios as one of the indicators to estimate the hand function from the skeletal structure.