First person – Ahsan Javed

The Faculty of Law of the University of Helsinki is committed to diverse and internationally collaborative approaches to studying various legal systems in the context of comparative law, and UHLS and the Law Faculty of the National Research University, Higher School of Economics have developed an ongoing program to undertake this effort. The original annual conference series on the Development of Russian Law was launched in 2008 as an initiative to further knowledge and critical thinking about Russian law during its period of transition and modernization. The conference is held annually and brings together legal practitioners and scholars from Russia, Finland and elsewhere to discuss important matters of Russian law, legal reform, and legal practice. Prior years’ Conference themes have included discussions of legal reforms, the justice system, the Russian legal profession, human rights, civil and business law, legal policy, rule-of-law and market economy. This year’s program was designed to attract law faculty, scholars from different disciplines, and also practicing lawyers, to address a wide range of topics grouped around the general theme of how the phenomenon and challenges of globalization affect Russian legal system development. The call for papers included: (i) Relationships between Russian domestic and international law, (ii) The impacts of international legal institutions on the development of Russian law(s), (iii) Globalization in the field of business law, (iv) Global law & Russian legal theory, (v) Regional models of legal cooperation and Russia’s participation, (vi) Transnational legal problems in areas such as constitutionalism and rule-of-law, (vii) Theoretical and applied implications of the concept of global transplants, and (viii) A global human rights agenda, including Russia’s place in this agenda. This was a very ambitious and multi-faceted undertaking. Through a process of careful evaluation, the Conference organizers produced a very diverse and challenging program, consisting of 8 Sessions, (7 panels and one round-table devoted to specific Session themes), along with a general Round-table discussion on the subject of Russian-Finnish legal cooperation partnering.1 The two-day Symposium, October 6–7, was preceded by a Wednesday afternoon PhD student seminar. At this seminar, there were presentations by Dr. Ari Hirvonen (University of Helsinki) on Finnish doctoral education in law and Dr. Svetlana Vasilieva (Higher School of Economics, Moscow, Russia) on Russian PhD education in law, followed by presentations by PhD students of their works-in-progress.2 Professor Pia Letto-Vanamo, Director of the Doctoral School at the University of Helsinki, then delivered the Keynote Lecture – Methodological Challenges of Legal Research, followed by a Reception for participants. In this lecture, she highlighted how global agenda influences national legal issues and what it is to practice good lawyering.

We welcome you to the fourteenth annual International Computing Education Research Conference, ICER 2018, sponsored by the ACM Special Interest Group on Computer Science Education (SIGCSE). Espoo, Finland is the host city for this year's conference, with sessions taking place on the Aalto University campus. ICER stands as the premier ACM forum for dissemination and discussion of the latest findings in computing education research across the globe. ICER research papers represent significant, rigorous contributions to the field. One hundred twenty-five research papers were submitted, with twenty-eight papers accepted for publication (a 22% acceptance rate) in the conference proceedings in the ACM Digital Library. All papers were double-blind peer reviewed by three members of the program committee. In addition, each paper received a meta-review by a member of the senior program committee, with the two Program Co-Chairs making final acceptance decisions. In addition to the research paper presentations, ICER includes Lightning Talk and Poster sessions as a way for ICER attendees to present early results, gain feedback from conference attendees, find collaborators on a topic, and/or spark discussion among conference participants. The conference also serves a vital mentoring and advising role for upcoming discipline-based computing education researchers through the Doctoral Consortium. The Work in Progress workshop is a dedicated one-day workshop for ICER attendees to provide and receive friendly, constructive feedback on research during formative stages of development. Associated co-located workshops with external sponsorship at ICER 2018 include Building Your Team of Change Champions and Computing Science Educational Infrastructure: Crossing the Borders. We are honored to welcome Kirsti Lonka, the Professor of Educational Psychology in the Faculty of Education at the University of Helsinki, Finland to present the ICER 2018 keynote address. For the past 30 years, she has been investigating various aspects of learning in higher education, medical education, teacher education, and postgraduate education (PhD students). In the area of academic writing, her work has focused around conceptions of writing, note taking, process writing, portfolios and writing across curriculum (writing as a learning tool). Professor Lonka's keynote, Growing minds - 21st century competences and digitalization among Finnish youth?, discusses her recent research concerning the digital technology background among Finnish school children and its relation to their activities and attitudes. The keynote addresses the intensive reforms, both in research-based teacher education and at school that are going on in Finland. In addition to the new Finnish curricula, the latest developments in education, innovative pedagogical methods, technologies in education and new learning environments will be presented.

Notes on Contributors

Pressure and shear stress‐induced stretch of tubular epithelial cells is relevant to both physiological and diseased kidney. Piezo1 is a mechanically‐activated cation channel stimulated by membrane tension and stretch; it is highly expressed in the inner medulla of the kidney. Aquaporin‐2 (AQP2) is located in the principal cells of the collecting ducts in the kidney, which is a key aquaporin determining final urine output. The current study aims to investigate whether activation of Piezo1 induces AQP2 expression in the collecting duct principal cells. In human kidney biopsy specimen, Piezo1 was found expressed mainly in the collecting ducts where it co‐localized with AQP2. Upon treating primary cultured rat inner medullary collecting duct (IMCD) cells with Piezo1 activator Yoda1 (0.01μM to 1μM), the protein expression of AQP2 was markedly increased. Activation of Piezo1 by Yoda1 was also associated with intracellular F‐actin depolymerization and dramatically increased accumulation of AQP2 on the apical plasma membrane of IMCD cells. Upregulation of AQP2 protein was also observed when Piezo1 was stimulated with mechanical cyclic tensile strain at 5% elongation, 1Hz for 3hour in IMCD cells, which was markedly inhibited by GsMTx4 (0.1μM to 5μM), a Piezo1 antagonist. Both stretch and Yoda1 treatment induced elevation of intracellular calcium levels and upregulation of calpain2 protein expression (calcium‐activated non‐lysosomal thiol‐proteases) as well as phosphorylation of Akt protein in rat IMCD cells. Dehydration for 24h (which is presumably leading to the swelling of principal cells, Chou CL, Am J Physiol Renal Physiol, 2008) in mice was associated with increased levels of piezo1 mRNA and protein expression in the kidney inner medulla. In conclusion, activation of Piezo1 by mechanical stretch or activators increased protein expression and intracellular trafficking of AQP2 in rat IMCD cells, which was associated with F‐actin depolymerizing and elevated intracellular calcium levels. These studies indicate that piezo1 may play a functional role in the regulation of urinary osmolarity in pressure‐induced stretch of principal cells relevant to both physiological and pathophysiological conditions.

In this occasional series we record the views and personal experiences of people who have specially contributed to the evolution of ideas in the journal's field of interest. Juha Partanen is a Finnish social researcher with strong international interests. His work has often focused on drinking and drinking problems but he has also been concerned with wider issues. For many years he has worked at the Finnish Social Research Institute for Alcohol Studies and was, for a time, its Director.

Buruli ulcer (BU) is a neglected tropical disease of the skin and subcutaneous tissue caused by Mycobacterium ulcerans. The disease has been reported from over 30 countries with most cases coming from West Africa. While it is commonly accepted that BU is not acquired by human-to-human transmission both the environmental reservoir of the pathogen and the mode of transmission to humans remain to be identified. Clinically BU presents with a wide range of forms which includes non-ulcerative lesions and ulcers with undermined edges. Much of the pathology of a M. ulcerans infection is believed to be caused by its unique ability to produce the macrolide toxin called mycolactone which causes tissue necrosis and local immunosuppression. BU can be diagnosed by microscopy, polymerase chain reaction (PCR), culturing and histology, however due to lack of access to laboratory facilities, cases are often diagnosed based on clinical symptoms only. Historically, BU was treated using wide scale excision, but since 2004 the WHO recommends the use of streptomycin and rifampicin daily for 8 weeks to treat the infection. In the framework of this PhD thesis we have established a new BU field research site in the Mape Basin of Cameroon and studied various aspects of BU epidemiology, differential diagnosis and transmission at this location. As a basis for our research, we conducted an exhaustive house-by-house survey for BU, leprosy and yaws in the Bankim Health District. Following the survey we closely monitored and studied all BU cases detected in the region. By supporting local laboratory diagnosis with real time-PCR (RT-PCR) and culturing, we were able to identify and describe a case of cutaneous tuberculosis which was initially diagnosed as BU. This patient highlighted the importance of further support to improve clinical differential diagnosis of BU in remote endemic areas. Eighty-eight of all the RT-PCR confirmed BU cases identified in the Mape Basin in the course of our research were studied in detail. By mapping the patients’ homes we were able to describe the distribution of BU in the area and to identify highly endemic communities. Based on the population age data collected in the survey we were also able to compute the age adjusted cumulative incidence rate of BU, revealing that children below the age of five were underrepresented among cases of BU. By analysing serological responses of patients and community members from BU endemic areas in the Mape Basin and Ghana against an immunodominant antigen of M. ulcerans, we have observed a similar late onset of seroconversion, indicating that BU transmission intensifies when preschool children start moving further away from home. To identify potential sites of M. ulcerans transmission, we screened sites of environmental contact at the homes and farms of laboratory confirmed BU patients for the presence of M. ulcerans DNA. In this analysis we identified three RT-PCR positive permanent village water sites and by studying one of these sites longitudinally in great detail we obtained evidence that M. ulcerans can persist in underwater detritus. This niche of M. ulcerans may represent an environmental reservoir and a source of infection of the pathogen. To further elucidate BU transmission pathways we have generated a set of clinical isolates of M. ulcerans from the Mape Basin for a phylogeographic analysis of the distribution of the currently circulating haplotypes of M. ulcerans based on whole genome sequencing. By the routine culturing from clinical specimens and the evaluation of different transport media and decontamination methods we were further able to develop an optimized protocol for the primary isolation of M. ulcerans after long term storage of samples. Our interdisciplinary research approach including biomedical and social science research elements, including future behavioural studies in young children, may eventually help to elucidate transmission and to improve control of BU.

Tight junctions (TJs) control the transport of substances across epithelial tissue barriers, but how the TJ barrier is regulated is not well understood. In my PhD thesis, I characterized the function of ARHGAP12, a Rho GTPase Activating Protein associated with TJs. Using biochemical, biophysical, and cell biological approaches, I show that the tandem WW domain of ARHGAP12 interacts directly and specifically with PPxR motifs in the proline-rich domain of the actin nucleation promoting factor N-WASP. This interaction suppresses N-WASP oligomerization and attenuates actin polymerization mediated by Arp2/3 complex, providing novel mechanistic insight into how the actin cytoskeleton is regulated at epithelial TJs. With the aim of visualizing the native architecture of epithelial TJs and the associated cytoskeleton, I established and optimized conditions for cryo-correlative light and electron microscopy, which combines cryo-focused ion beam milling and cryo-electron tomography. Junctional assemblies and associated cytoskeletal filaments were successfully visualized.

The biology and physical properties of the uniquely human skin cream 'vernix caseosa' are discussed. This material coats the foetal skin surface during the last trimester of gestation and provides multiple beneficial functions for the foetus and newborn infant. Vernix has a complex structure similar to stratum corneum but lacks lipid lamellae and is more plastic due to the absence of desmosomal constraints. In utero, vernix is made in part by foetal sebaceous glands, interacts with pulmonary surfactant, detaches into the amniotic fluid, and is swallowed by the foetus. At the time of birth, vernix has a remarkably constant water content approximating 80%. Postnatally, vernix is simultaneously a cleanser, a moisturizer, an anti-infective, and an anti-oxidant. Vernix facilitates acid mantle development and supports normal bacterial colonization. Its hydrated cellular structure and unusual lipid composition provide a 'best' solution for the needs of the foetus and newborn, not least of which is the attraction of caregivers. Vernix is an important natural biomaterial of potential interest to cosmetic scientists, and other disciplines involved in product development and therapies targeting the complex interface between the stratum corneum and a changing terrestrial environment.

Previous studies have shown that high concentrations of ethanol (>/=40%) cause functional damage of the gastrointestinal epithelial barrier by direct cytotoxic effect on the epithelial cells. The effects of lower noncytotoxic doses of ethanol on epithelial barrier function are unknown. A major function of gastrointestinal epithelial cells is to provide a barrier against the hostile substances in the gastrointestinal lumen. The apicolaterally located tight junctions (TJs) form a paracellular seal between the lateral membranes of adjacent cells and act as a paracellular barrier. In this study, we investigated the effects of lower doses of ethanol on intestinal epithelial TJ barrier function using filter-grown Caco-2 intestinal epithelial monolayers. The Caco-2 TJ barrier function was assessed by measuring epithelial resistance or paracellular permeability of the filter-grown monolayers. Ethanol (0, 1, 2.5, 5, 7.5, and 10%) produced a dose-related drop in Caco-2 epithelial resistance and increase in paracellular permeability. Ethanol also produced a progressive disruption of TJ protein (ZO-1) with separation of ZO-1 proteins from the cellular junctions and formation of large gaps between the adjacent cells. Ethanol, at the doses used (</=10%), did not cause cytotoxicity (lactate dehydrogenase release) to the Caco-2 cells. Ethanol produced a disassembly and displacement of perijunctional actin and myosin filaments from the perijunctional areas. On ethanol removal, actin and myosin filaments rapidly reassembled at the cellular borders. Ethanol stimulated the Caco-2 myosin light chain kinase (MLCK) activity but did not affect the MLCK protein levels. Specific MLCK inhibitor ML-7 inhibited both ethanol increases in MLCK activity and TJ permeability without affecting the MLCK protein levels. Consistent with these findings, metabolic inhibitors sodium azide and 2,4-dinitrophenol significantly prevented ethanol-induced increase in Caco-2 TJ permeability, whereas cycloheximide or actinomycin D had no effect. The results of this study indicate that ethanol at low noncytotoxic doses causes a functional and structural opening of the Caco-2 intestinal epithelial TJ barrier by activating MLCK.

The epithelial barrier is a critical component of innate immunity and provides protection against microbial invasion. Claudin-1, a tight junction protein, is known to contribute to the epithelial cell barrier. An experimentally induced rat periodontal disease model was used to study the effects of lipopolysaccharide (LPS) on the expression of tight junction-associated molecule genes in the junctional epithelium. LPS was applied for 8 wk in the gingival sulcus, and junctional epithelium was collected by laser-capture microdissection and subjected to microarray analysis. Microarray analysis identified that expression of the claudin-1 gene was decreased in the epithelium by chronic LPS challenge. Immunohistochemical analysis confirmed the expression of claudin-1 protein in junctional epithelium and that 8 wk of chronic LPS topical application significantly reduced claudin-1 expression. The effect of LPS on claudin-1 protein expression was validated using a porcine junctional epithelial cell culture Transwell model. The epithelial barrier, as measured using transmembrane resistance, was significantly reduced after 3 wk of LPS challenge and this was associated with a decreased level of expression of claudin-1 protein. These results confirm that the initiation of experimental periodontal disease is associated with reduction in the expression of claudin-1 gene and protein. This decreased level of a critical tight junction protein may result in the disruption of barrier function and may play an important role in the initiation of periodontal disease.

Transient opening of tricellular vertices controls paracellular transport through the follicle epithelium during Drosophila oogenesis.

Objective To investigate the effect of fusidic acid cream on inflammatory reaction caused by skin barrier damage.Methods Eight male SKH-1 hairless mice were included in this study.The back of each of these mice were equally divided into six regions measuring 1 cm × 2 cm in size,which were then assigned into six groups:blank control group remaining untreated,barrier-impaired group,barrier-impaired and fusidic acid-treated group,barrier-impaired and vehicle-treated group,barrier-unimpaired and fusidic acid-treated group,barrierunimpaired and vehicle-treated group.Stratum corneum was removed by adhesive tape stripping to establish an animal model of acute skin barrier damage in the corresponding skin regions of these mice,and fusidic acid cream or vehicle was topically applied to the corresponding regions once.Twelve hours later,skin surface swab samples were collected from the back of these mice followed by bacterial culture and colony counting.Mice were then sacrificed,and skin tissue specimens were resected from these mice,and subjected to real-time fluorescence-based quantitative PCR for the measurement of the mRNA expressions of myeloid differentiation factor 88 (MyD88),interleukin-1α (IL-1α),IL-6,epidermal antibacterial peptides S100a8 and S100a9.Statistical analysis was carried out by repeated-measures analysis of variance (ANOVA) and least significant difference (LSD) test.Results The mRNA expressions of MyD88,IL-1α,IL-6,S100a8 and S100a9 were all significantly higher in the barrier-impaired group than in the blank control group (all P ＜ 0.05).Specifically,the mRNA expression level of MyD88 in the barrier-impaired group was 8 times that in the blank control group (8.3 ± 3.0 vs.0.8 ± 0.4).Compared with the barrier-impaired group,the barrier-impaired and fusidic acid-treated group showed a significant decrease in the mRNA expressions of IL-1α (2.8 ± 0.3 vs.20.1 ± 10.0,F =47.11,P ＜ 0.01),IL-6 (1.6 ± 2.3 vs.9.4 ± 4.0,F =16.18,P＜ 0.01),S100a8 (1.5 ± 1.4 vs.5.0 ± 1.6,F=59.71,P＜ 0.05) and S100a9 (1.2 ± 0.7 vs.3.4 ± 1.6,F=21.94,P ＜ 0.05).Conlusions Fusidic acid cream could attenuate the inflammatory reaction caused by acute skin barrier damage,which might partly explain its action mechanism in the treatment of inflammatory skin diseases. Key words: Fusidic acid; Skin barrier; Myeloid differentiation factor 88; Interleukins

ABSTRACTThe epithelium has many critical roles in homeostasis, including an essential responsibility in establishing tissue barriers. In addition to the fundamental role in separating internal from external environment, epithelial barriers maintain nutrient, fluid, electrolyte and metabolic waste balance in multiple organs. While, by definition, barrier function is conserved, the structure of the epithelium varies across organs. For example, the skin barrier is a squamous layer of cells with distinct structural features, while the lung barrier is composed of a very thin single cell to minimize diffusion space. With the increased focus on age-dependent alterations in organ structure and function, there is an emerging interest in the impact of age on epithelial barriers. This review will focus on the impact of aging on the epithelial barrier of several organs, including the skin, lung, gastrointestinal tract and the kidney, at a structural and functional level.

Objective To evaluate the effect of salicylic acid on skin barrier function and the efficacy of salicylic acid combined with flumetasone ointment for the treatment of atopic dermatitis (AD).Methods Sixtyfour patients with AD (including 31 males and 33 females) aged 18 to 58 years were recruited into the present study.Four lesional areas of similar size and severity were selected at the similar body sites of both sides of each patient,and randomly classified into four groups to be topically treated with compound flumetasone ointment (containing 0.02％ flumetasone and 3％ salicylic acid,compound flumetasone group),flumetasone 0.02％ ointment (flumetasone group),salicylic acid 3％ ointment (salicylic acid group) and vehicle (control group),respectively;two normal skin areas were chosen from apparently normal skin on the similar body sites of both sides of each patient and topically treated with salicylic acid 3％ ointment (salicylic acid group) and vehicle (control group) respectively.All of these preparations were applied twice a day for 3 weeks.Transepidermal water loss (TEWL) was measured by a Tewameter MPA580 (Courage & Khazaka,Germany) at the baseline as well as on week 1,2 and 3 after initiation of treatment.Symptom and sign scores were evaluated before and after the treatment.Meanwhile,two normal skin areas were selected on bilateral forearm of 30 healthy controls and treated with 3％ salicylic acid ointment (salicylic acid group) and vehicle (control group) respectively twice a day for 3 weeks,and TEWL was measured before treatment as well as on week 1 and 3 after initiation of treatment.Results In the healthy controls,TEWL value showed no significant difference between the salicylic acid group and control group at any of these time points.As far as the lesional skin was concerned,no statistical difference was observed in TEWL value at the baseline between the four groups ((34.26 ± 20.82) vs.(33.02 ±16.71) vs.(34.16 ± 18.03) vs.(33.81 ± 17.11) g· m-2· h-1,P ＞ 0.05),but significant difference was noted after treatment (repeated measurement data analysis of variance,F =39.57,P ＜0.01),with the TEWL value being (22.38 ± 16.16),(17.04 ± 12.74),and (15.34 ± 13.13) g·m-2·h-1 respectively in the compound flumetasone group on week 1,2 and 3,(24.63 ± 17.08),(20.37 ± 9.53),(19.06 ± 9.17) g·m-2·h-1 respectively in the flumetasone group,(26.49 ± 8.59),(21.91 ± 8.46),(21.20 ± 9.38) g·m-2·h-1 respectively in the salicylic acid group,and (29.80 ± 12.48),(26.16 ± 8.31),(25.52 ± 6.05) g·m-2·h-1 respectively in the control group.In detail,the decrease in TEWL value was stronger in the compound flumetasone group than in the flumetasone group on week 1,2,and 3 (all P ＜0.05),in the salicylic acid group than in the control group (P ＜0.05 or 0.01),but similar between the flumetasone group and salicylic acid group.In non-lesional skin,the salicylic acid group showed a more intense decrease in TEWL value compared with the control group on week 2 and 3 (both P ＜0.05).Both the cure rate and response rate were significantly higher in the compound flumetasone group than in the flumetasone group (53.1％ vs.34.4％,x2 =4.57,P＜0.05;83.1％ vs.64.1％,x2 =6.90,P＜0.01).Conclusions The salicylic acid 3％ ointment shows a reparative effect on skin barrier in patients with AD,and the compound flumetasone ointment is superior to the flumetasone ointment in the treatment of AD. Key words: Dermatitis, atopic; Skin barrier; Salicylic acid; Flumethasone

Interleukin (IL)-15 is able to regulate tight junction formation in intestinal epithelial cells. However, the mechanisms that regulate the intestinal barrier function in response to IL-15 and the involved subunits of the IL-15 ligand-receptor system are unknown. We determined the IL-2Rbeta subunit and IL-15-dependent regulation of tight junction-associated proteins in the human intestinal epithelial cell line T-84. The IL-2Rbeta subunit was expressed and induced signal transduction in caveolin enriched rafts in intestinal epithelial cells. IL-15-mediated tightening of intestinal epithelial monolayers correlated with the enhanced recruitment of tight junction proteins into Triton X-100-insoluble protein fractions. IL-15-mediated up-regulation of ZO-1 and ZO-2 expression was independent of the IL-2Rbeta subunit, whereas the phosphorylation of occludin and enhanced membrane association of claudin-1 and claudin-2 by IL-15 required the presence of the IL-2Rbeta subunit. Recruitment of claudins and hyperphosphorylated occludin into tight junctions resulted in a more marked induction of tight junction formation in intestinal epithelial cells than the up-regulation of ZO-1 and ZO-2 by itself. The regulation of the intestinal epithelial barrier function by IL-15 involves IL-2Rbeta-dependent and -independent signaling pathways leading to the recruitment of claudins, hyperphosphorylated occludin, ZO-1, and ZO-2 into the tight junctional protein complex.