Introductory programming: a systematic literature review

As computing becomes a mainstream discipline embedded in the school curriculum and acts as an enabler for an increasing range of academic disciplines in higher education, the literature on introductory programming is growing. Although there have been several reviews that focus on specific aspects of introductory programming, there has been no broad overview of the literature exploring recent trends across the breadth of introductory programming. This paper is the report of an ITiCSE working group that conducted a systematic review in order to gain an overview of the introductory programming literature. Partitioning the literature into papers addressing the student, teaching, the curriculum, and assessment, we explore trends, highlight advances in knowledge over the past 15 years, and indicate possible directions for future research

Impaired Macrophage and Satellite Cell Infiltration Occurs in a Muscle-Specific Fashion Following Injury in Diabetic Skeletal Muscle

<div><p>Background</p><p>Systemic elevations in PAI-1 suppress the fibrinolytic pathway leading to poor collagen remodelling and delayed regeneration of tibialis anterior (TA) muscles in type-1 diabetic Akita mice. However, how impaired collagen remodelling was specifically attenuating regeneration in Akita mice remained unknown. Furthermore, given intrinsic differences between muscle groups, it was unclear if the reparative responses between muscle groups were different.</p><p>Principal Findings</p><p>Here we reveal that diabetic Akita muscles display differential regenerative responses with the TA and gastrocnemius muscles exhibiting reduced regenerating myofiber area compared to wild-type mice, while soleus muscles displayed no difference between animal groups following injury. Collagen levels in TA and gastrocnemius, but not soleus, were significantly increased post-injury versus controls. At 5 days post-injury, when degenerating/necrotic regions were present in both animal groups, Akita TA and gastrocnemius muscles displayed reduced macrophage and satellite cell infiltration and poor myofiber formation. By 10 days post-injury, necrotic regions were absent in wild-type TA but persisted in Akita TA. In contrast, Akita soleus exhibited no impairment in any of these measures compared to wild-type soleus. In an effort to define how impaired collagen turnover was attenuating regeneration in Akita TA, a PAI-1 inhibitor (PAI-039) was orally administered to Akita mice following cardiotoxin injury. PAI-039 administration promoted macrophage and satellite cell infiltration into necrotic areas of the TA and gastrocnemius. Importantly, soleus muscles exhibit the highest inducible expression of MMP-9 following injury, providing a mechanism for normative collagen degradation and injury recovery in this muscle despite systemically elevated PAI-1.</p><p>Conclusions</p><p>Our findings suggest the mechanism underlying how impaired collagen remodelling in type-1 diabetes results in delayed regeneration is an impairment in macrophage infiltration and satellite cell recruitment to degenerating areas; a phenomena that occurs differentially between muscle groups.</p></div

Macrophage and satellite cell infiltration into necrotic muscle is impaired in Akita diabetic mice at 5 days post injury.

<p>(A) The necrotic area of the TA demonstrates a reduced number of macrophages as evidenced by less F4/80 positive cells. * denotes significant difference by t-test (p<0.05). (B) A similar, though non-significant, trend of attenuated F4/80 positive cells was observed in necrotic gastrocnemius (GAS) (P = 0.09). (C) Representative images of necrotic regions of TA and GAS immunofluorescently stained for F4/80 (red), costained for type I collagen (green) and nuclei with DAPI (blue). Satellite cells (Pax7+ cells) were also reduced in number within necrotic areas of (D) Akita TA and (E) GAS (P = 0.06). (F) Representative images of Pax7 positive cells within necrotic regions of WT and Akita TA. Scale bar represents 50 um.</p

Soleus muscle is resilient to the regenerative defects found in other muscles from Akita mice.

<p>(A) H&E stained cryosections of tibialis anterior (TA), gastrocnemius (GAS), and soleus (SOL) illustrate decrements in muscle regeneration in diabetic Akita mouse muscles. (B) TA demonstrates the worst impairment in regeneration, as determined by cross sectional area of regenerating (centrally-nucleated) fibers (significant main effect of diabetes and interaction [P<0.05]). GAS (C) also demonstrates impaired regeneration (significant main effect of diabetes and interaction [P<0.05]), while SOL (D) does not. In panels E–F, TA (E), GAS (F), and SOL (G) CTX-injured fiber area data are expressed relative to fiber area from the contralateral uninjured muscles. The TA (significant main effect of diabetes and interaction [P<0.05]) and GAS (significant main effect of diabetes [P<0.05]) both demonstrate poor regeneration even when expressed in these relative terms. The mass of muscles that had been injured with cardiotoxin further illustrate poor regeneration. The muscle mass of the injured TA (H; significant main effect of diabetes and interaction [P<0.05]) and gastrocnemius-plantaris-soleus (GPS) complex (I; significant main effect of diabetes [P<0.05]) are illustrated here. * denotes significant post-hoc analysis differences (P<0.05). Scale bar represents 50 um.</p

Characteristics of wild type and Akita diabetic mice.

<p>Data collected at 6 weeks of diabetes (6 weeks group), or at 5, 10, or 35 days following cardiotoxin muscle injury at 8 weeks of diabetes (9–13 weeks group). All measures except for soleus fiber area were found to be significantly altered in the diabetic mice. All muscle mass and fiber area measures presented here are from the uninjured muscle; the cardiotoxin injured contralateral leg muscle data are presented in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0070971#pone-0070971-g001" target="_blank">Figure 1</a>. NEFA, non-esterified fatty acids; PAI-1, plasminogen activator inhibitor-1; TA, tibialis anterior; GPS, gastrocnemius-plantaris-soleus complex; GAS, gastrocnemius; SOL, soleus. * denotes significant difference in Akita compared to matching wild type (WT) value as assessed by t-test (P<0.05).</p

Macrophage and satellite cell infiltration into necrotic Akita diabetic muscle is restored with PAI-039 treatment.

<p>(A) Representative images of the necrotic area of the TA muscles of WT, Akita and Akita+PAI-039. Sections were stained with F4/80 (macrophage marker; red), collagen type 1 (green) and DAPI (nuclear dye; blue). A visible decrease in the number of F4/80 positive cells is seen in Akita muscle sections with a detectable increase in F4/80 cells in Akita TA muscles of mice treated with a PAI-1 inhibitor (PAI-039). (B) The number of F4/80 positive cells within the necrotic area of injured Akita TA muscles was returned to WT levels when these mice were treated with PAI-039. The number of F4/80 positive cells was greater in Akita+PAI-039 TA (panel B; P = 0.06) and gastrocnemius (panel C; P = 0.07) muscles compared to untreated Akita animals. A similar trend was observed for Pax7 positive cells which were also found to be improved in necrotic TA (D) and gastrocnemius (E) with PAI-039 treatment (P<0.05).</p

Tibialis anterior muscle of Akita mice demonstrate transient, excessive fibrosis during early regeneration.

<p>(A) TA demonstrates elevated collagen during regeneration, particularly at 5 days post-injury (significant main effect of diabetes [P<0.05]), while gastrocnemius (GAS) (B) demonstrates a non-significant trend (main effect of diabetes [P = 0.11]). Conversely, soleus (SOL) (C) does not demonstrate dysregulated collagen expression. * denotes significant post-hoc analysis differences (p<0.05). (D) Representative picrosirius red staining of 5 and 10 day post-injury TA muscles. Note the elevated presence of collagen (red) and smaller size of myofibers (yellow) in Akita TA. Scale bar represents 50 um.</p

Necrosis of muscle fibers persists throughout muscle regeneration in Akita tibialis anterior muscle.

<p>(A) Uninjured (left), necrotic (center), and actively regenerating (right) regions of skeletal muscle are easily identified in collagen type I immunostain (green) with DAPI (blue) counterstain. Note the presence of centrally located nuclei in muscle fibers in regenerating muscle, indicative of new myofiber formation. (B) TA of diabetic mice have clearly defined areas of necrosis remaining at 10 days post-injury (significant interaction [P<0.05]; * denotes post-hoc difference). Similarly, gastrocnemius (GAS) (C) follows this pattern although not statistically significant (P = 0.21). In contrast, both WT and Akita soleus (SOL) display no areas of necrosis at 5 or 10 days post-injury (not shown). (D) Representative image of TA muscle undergoing regeneration at 10 days post-injury in WT and Akita TA. Note the distinct area of necrosis in the Akita TA. Scale bar represents 500 um.</p

Initiation of muscle regeneration is delayed in tibialis anterior and gastrocnemius muscles in Akita mice.

<p>Regions of necrotic muscle tissue in (A) TA and (B) gastrocnemius (GAS) demonstrate attenuated response of Myh3-expressing myofibers in diabetic mice. An * denotes a significant difference detected by t-test (p<0.05). (C) Representative image of Myh3 immunofluorescent stained (red) TA and GAS necrotic regions. Co-staining of laminin (green) and nuclei with DAPI (blue) was performed. In the actively regenerating regions of the (D) TA and (E) GAS, the attenuation of Myh3 expression was not as severe, and at 10 days post-injury, was found to be significantly elevated in diabetic mice compared to wild type, indicative of delayed regeneration (significant interaction [P<0.05]). The * indicates significant differences detected by post-hoc testing (P<0.05). Conversely, (F) Akita soleus (SOL) demonstrates no impairment in establishing Myh3 expression following injury and does not continue to significantly overexpress Myh3 at 10 days post-injury. (G) Representative image of regenerating regions of muscles at 5 days post-injury stained for Myh3 (red) and laminin (green). Inset (derived from TA muscles) is provided without green channel to clearly demonstrate Myh3 stain morphology. Scale bar represents 50 um in panels C and G. (H) MMP-9 immunobloting on uninjured and regenerating (2 days post-injury) TA, GAS and SOL muscles from WT and Akita mice demonstrate the intrinisic differences between muscles in pro-MMP-9 expression (main effect of muscle group; P<0.05), but no differences between WT and Akita mice. MMP-9 content is relative to beta-actin loading controls and representative MMP-9 blots are included.</p