Adhesion of a nematic elastomer cylinder.

Reversible dry adhesion is exploited by lizards and insects in nature, and is of interest to robotics and bio-medicine. In this paper, we use numerical simulation to study how the soft elasticity of liquid crystal elastomers can affect its adhesion and provide a technological opportunity. Liquid crystal elastomers are cross-linked elastomer networks with liquid crystal mesogens incorporated into the main or side chain. Polydomain liquid crystalline (nematic) elastomers exhibit unusual mechanical properties like soft elasticity, where the material deforms at nearly constant stress, due to the reorientation of mesogens. Our study reveals that the soft elasticity of nematic elastomers dramatically affects the interfacial stress distribution at the interface of a nematic elastomer cylinder adhered to a rigid substrate. The stress near the edge of the nematic cylinder under tensile load deviates from the singular behavior predicted for linear elastic materials, and the maximum normal stress reduces dramatically. This suggests that nematic elastomers should display extremely high, but controllable adhesion, consistent with the available experimental observations.

Network-informed discovery of multidrug combinations for ERα+/HER2-/PI3Kα-mutant breast cancer.

Breast cancer is a persistent threat to women worldwide. A large proportion of breast cancers are dependent on the estrogen receptor α (ERα) for tumor progression. Therefore, targeting ERα with antagonists, such as tamoxifen, or estrogen deprivation by aromatase inhibitors remain standard therapies for ERα + breast cancer. The clinical benefits of monotherapy are often counterbalanced by off-target toxicity and development of resistance. Combinations of more than two drugs might be of great therapeutic value to prevent resistance, and to reduce doses, and hence, decrease toxicity. We mined data from the literature and public repositories to construct a network of potential drug targets for synergistic multidrug combinations. With 9 drugs, we performed a phenotypic combinatorial screen with ERα + breast cancer cell lines. We identified two optimized low-dose combinations of 3 and 4 drugs of high therapeutic relevance to the frequent ERα + /HER2-/PI3Kα-mutant subtype of breast cancer. The 3-drug combination targets ERα in combination with PI3Kα and cyclin-dependent kinase inhibitor 1 (p21). In addition, the 4-drug combination contains an inhibitor for poly (ADP-ribose) polymerase 1 (PARP1), which showed benefits in long-term treatments. Moreover, we validated the efficacy of the combinations in tamoxifen-resistant cell lines, patient-derived organoids, and xenograft experiments. Thus, we propose multidrug combinations that have the potential to overcome the standard issues of current monotherapies.

A nonlinear beam model of photomotile structures.

Actuation remains a significant challenge in soft robotics. Actuation by light has important advantages: Objects can be actuated from a distance, distinct frequencies can be used to actuate and control distinct modes with minimal interference, and significant power can be transmitted over long distances through corrosion-free, lightweight fiber optic cables. Photochemical processes that directly convert photons to configurational changes are particularly attractive for actuation. Various works have reported light-induced actuation with liquid crystal elastomers combined with azobenzene photochromes. We present a simple modeling framework and a series of examples that study actuation by light. Of particular interest is the generation of cyclic or periodic motion under steady illumination. We show that this emerges as a result of a coupling between light absorption and deformation. As the structure absorbs light and deforms, the conditions of illumination change, and this, in turn, changes the nature of further deformation. This coupling can be exploited in either closed structures or with structural instabilities to generate cyclic motion.

Treatment of Keloids with Surgery and Immediate Postoperative Radiotherapy: Knowledge Gained Over 17 Years.

Background The treatment of keloidal scars with radiotherapy has been practiced for more than a century. Radiotherapy post-surgery has been deemed necessary and effective in preventing recurrence but still, no clear guidelines exist as to the best modality of radiotherapy, the ideal dose, and the time it should be given for keloidal scars. The purpose of this study is to confirm the effectiveness of this treatment and address these issues. Methods Since 2004, 120 patients presenting with keloidal scars were seen by the author. Out of them, 50 were managed with surgery followed by HDR brachytherapy/electron beam radiotherapy delivering 2000 rads to the scar within 24 hours of surgery. Patients were followed up for at least 18 months to assess the scar status and the recurrence of keloids. Recurrence was defined as the appearance of a nodule or an obvious return of the keloid within 1 year of treatment. Results Three patients developed a nodule in the scar, which was deemed a recurrence, making an incidence of 6%. There was no major problem after immediate postoperative radiotherapy. Five patients had delayed healing at 2 weeks and a hypertrophic scar was noted in five patients at 4 weeks that settled with conservative measures. Conclusion Treating the vexing problem of keloids with surgery and immediate postoperative radiotherapy is safe and effective. We recommend that this be adopted as the standard treatment in keloid management.

The Hsp70-Hsp90 go-between Hop/Stip1/Sti1 is a proteostatic switch and may be a drug target in cancer and neurodegeneration.

The Hsp70 and Hsp90 molecular chaperone systems are critical regulators of protein homeostasis (proteostasis) in eukaryotes under normal and stressed conditions. The Hsp70 and Hsp90 systems physically and functionally interact to ensure cellular proteostasis. Co-chaperones interact with Hsp70 and Hsp90 to regulate and to promote their molecular chaperone functions. Mammalian Hop, also called Stip1, and its budding yeast ortholog Sti1 are eukaryote-specific co-chaperones, which have been thought to be essential for substrate ("client") transfer from Hsp70 to Hsp90. Substrate transfer is facilitated by the ability of Hop to interact simultaneously with Hsp70 and Hsp90 as part of a ternary complex. Intriguingly, in prokaryotes, which lack a Hop ortholog, the Hsp70 and Hsp90 orthologs interact directly. Recent evidence shows that eukaryotic Hsp70 and Hsp90 can also form a prokaryote-like binary chaperone complex in the absence of Hop, and that this binary complex displays enhanced protein folding and anti-aggregation activities. The canonical Hsp70-Hop-Hsp90 ternary chaperone complex is essential for optimal maturation and stability of a small subset of clients, including the glucocorticoid receptor, the tyrosine kinase v-Src, and the 26S/30S proteasome. Whereas many cancers have increased levels of Hop, the levels of Hop decrease in the aging human brain. Since Hop is not essential in all eukaryotic cells and organisms, tuning Hop levels or activity might be beneficial for the treatment of cancer and neurodegeneration.

Metamaterials with engineered failure load and stiffness.

Architected materials or metamaterials have proved to be a very effective way of making materials with unusual mechanical properties. For example, by designing the mesoscale geometry of architected materials, it is possible to obtain extremely high stiffness-to-weight ratio or unusual Poisson's ratio. However, much of this work has focused on designing properties like stiffness and density, and much remains unknown about the critical load to failure. This is the focus of the current work. We show that the addition of local internal prestress in selected regions of architected materials enables the design of materials where the critical load to failure can be optimized independently from the density and/or quasistatic stiffness. We propose a method to optimize the specific load to failure and specific stiffness using sensitivity analysis and derive the maximum bounds on the attainable properties. We demonstrate the method in a 2D triangular lattice and a 3D octahedral truss, showing excellent agreement between experimental and theoretical results. The method can be used to design materials with predetermined fracture load, failure location, and fracture paths.

Personal protective equipment use in laparoscopy during COVID-19.

COVID-19 pandemic mandates all the laparoscopic surgeons to don the personal protective equipment (PPE) to prevent getting infected in the operation theatre. PPE has few inherent problems which makes the surgery extremely challenging for all the surgeons. Dehydration and profuse sweating along with breathing difficulty due to N95 mask with PPE increases the chances of committing surgical error during laparoscopy.

Patterning nonisometric origami in nematic elastomer sheets.

Nematic elastomers dramatically change their shape in response to diverse stimuli including light and heat. In this paper, we provide a systematic framework for the design of complex three dimensional shapes through the actuation of heterogeneously patterned nematic elastomer sheets. These sheets are composed of nonisometric origami building blocks which, when appropriately linked together, can actuate into a diverse array of three dimensional faceted shapes. We demonstrate both theoretically and experimentally that the nonisometric origami building blocks actuate in the predicted manner, and that the integration of multiple building blocks leads to complex, yet predictable and robust, shapes. We then show that this experimentally realized functionality enables a rich design landscape for actuation using nematic elastomers. We highlight this landscape through examples, which utilize large arrays of these building blocks to realize a desired three dimensional origami shape. In combination, these results amount to an engineering design principle, which provides a template for the programming of arbitrarily complex three dimensional shapes on demand.

A Glycomic Approach Towards Identification of Signature Molecules in CD34+ Haematopoietic Stem Cells from Umbilical Cord Blood.

Umbilical cord blood (UCB) is a powerful storehouse for normal CD34+ haematopoietic stem cells (HSCs), often used for allogeneic bone marrow (BM) transplantation in malignant and non-malignant diseases. The glycomic especially the sialoglycomic aspect of these HSCs has been unravelled in this study. Cell surface expression of the glycans with the related enzymatic activities has been compared with the BM of childhood acute lymphoblastic leukaemia, a common BM-associated malignancy. An enhanced cell surface expression of α2,3-linked sialic acid, P- and E-selectins, and intercellular adhesion molecule along with reduced expression of L-selectin distinguishes CD34+ HSCs of UCB from leukaemic samples. More importantly, high expression of O-acetylated sialoglycoproteins, a hallmark of lymphoblasts, is drastically reduced in the CD34+ HSCs of UCB and is substantiated by the low activity of sialylate-O-acetyltransferase and high sialidase activity. In contrast, a significant variation is evident in the expression of sialic acid, α2,6-linked sialic acids, and the sialyltransferase activity. Taken together, these studies indicate a few signature molecules, forming a unique glycomic template, which may be a potential indicator, reassuring the normal profile of these stem cells, to be used for future transplantation.

Exceptional Resilience of Small-Scale Au30Cu25Zn45 under Cyclic Stress-Induced Phase Transformation.

Shape memory alloys that produce and recover from large deformation driven by martensitic transformation are widely exploited in biomedical devices and microactuators. Generally their actuation work degrades significantly within first a few cycles and is reduced at smaller dimensions. Further, alloys exhibiting unprecedented reversibility have relatively small superelastic strain, 0.7%. These raise the questions of whether high reversibility is necessarily accompanied by small work and strain and whether high work and strain is necessarily diminished at small scale. Here we conclusively demonstrate that these are not true by showing that Au30Cu25Zn45 pillars exhibit 12 MJ m-3 work and 3.5% superelastic strain even after 100 000 phase transformation cycles. Our findings confirm that the lattice compatibility dominates the mechanical behavior of phase-changing materials at nano to micron scales and points a way for smart microactuators design having the mutual benefits of high actuation work and long lifetime.

Length scales and pinning of interfaces.

The pinning of interfaces and free discontinuities by defects and heterogeneities plays an important role in a variety of phenomena, including grain growth, martensitic phase transitions, ferroelectricity, dislocations and fracture. We explore the role of length scale on the pinning of interfaces and show that the width of the interface relative to the length scale of the heterogeneity can have a profound effect on the pinning behaviour, and ultimately on hysteresis. When the heterogeneity is large, the pinning is strong and can lead to stick-slip behaviour as predicted by various models in the literature. However, when the heterogeneity is small, we find that the interface may not be pinned in a significant manner. This shows that a potential route to making materials with low hysteresis is to introduce heterogeneities at a length scale that is small compared with the width of the phase boundary. Finally, the intermediate setting where the length scale of the heterogeneity is comparable to that of the interface width is characterized by complex interactions, thereby giving rise to a non-monotone relationship between the relative heterogeneity size and the critical depinning stress.

Critical stoichiometric ratio of CD4(+) CD25(+) FoxP3(+) regulatory T cells and CD4(+) CD25(-) responder T cells influence immunosuppression in patients with B-cell acute lymphoblastic leukaemia.

Regulatory T (Treg) cells act to suppress activation of the immune system and thereby maintain immunological homeostasis and tolerance to self-antigens. The frequency and suppressing activity of Treg cells in general are high in different malignancies. We wanted to identify the role and regulation of CD4(+)  CD25(+)  FoxP3(+) Treg cells in B-cell acute lymphoblastic leukaemia (B-ALL). We have included patients at diagnosis (n = 54), patients in clinical remission (n = 32) and normal healthy individuals (n = 35). These diagnosed patients demonstrated a lower number of CD4(+)  CD25(+) cells co-expressing a higher level of FoxP3, interleukin-10, transforming growth factor-ß and CD152/CTLA-4 than the normal population. Treg cells from patients showed a higher suppressive capability on CD4(+)  CD25(-) responder T (Tresp) cells than normal. The frequency and immunosuppressive potential of CD4(+)  CD25(+)  FoxP3(+) Treg cells became high with the progression of malignancy in B-ALL. Relative distribution of Tresp and Treg cells was only ~5 : 1 in B-ALL but ~35 : 1 in normal healthy individuals, further confirming the elevated immunosuppression in patients. A co-culture study at these definite ex vivo ratios, indicated that Treg cells from B-ALL patients exhibited higher immunosuppression than Treg cells from normal healthy individuals. After chemotherapy using the MCP841 protocol, the frequency of CD4(+)  CD25(+) cells was gradually enhanced with the reduction of FoxP3, interleukin-10 positivity corresponded with disease presentation, indicating reduced immunosuppression. Taken together, our study indicated that the CD4(+)  CD25(+)  FoxP3(+) Treg cells played an important role in immunosuppression, resulting in a positive disease-correlation in these patients. To the best of our knowledge, this is the first detailed report on the frequency, regulation and functionality of Treg cells in B-ALL.

Mahanine synergistically enhances cytotoxicity of 5-fluorouracil through ROS-mediated activation of PTEN and p53/p73 in colon carcinoma.

5-Fluorouracil (5-FU) alone or in combination with other drugs is the main basis of chemotherapeutic treatment in colorectal cancer although patients with microsatellite instability generally show resistance to 5-FU treatment. The present investigation is focussed on the mechanistic insight of a pure herbal carbazole alkaloid, mahanine, as a single or in combination with 5-FU in colon cancer. We demonstrated that mahanine-induced apoptosis involved reactive oxygen species (ROS)-mediated nuclear accumulation of PTEN and its interaction with p53/p73. Mahanine and 5-FU in combination exerted synergistic inhibitory effect on cell viability. This combination also enhanced ROS production, increased tumour suppressor proteins and suppressed chemo-migration. Taken together, our results revealed that mahanine can be a potential chemotherapeutic agent with efficacy to reduce the concentration of toxic 5-FU in colon cancer.

Credit hours and continuing medical education (CME) programmes.

Continuing medical education (CME) credits has been mandated by the National Medical Commission for registered medical practitioners in India as a part of continuing professional development and a minimum of 30 credits in 5 years is required for the renewal of the medical license. Undoubtedly, credit hours for CME attendance is an essential yardstick for professional and career growth, the modus operandi adopted to grant these credit hours needs a serious look. Targeted learning with adequate feedback either with a post CME examination or questionnaire should become the norm and every publication in high impact indexed journal deserve a higher credit point than the rest of the publications.

Navigating the disappointment of manuscript rejection: An author's dialogue with a reviewer and editor of tropical doctor (TD).

With the majority of medical journals having a rejection rate of >80% of submitted manuscripts, it does come as a shock and as grief to the author who great expectations before submission. Though the majority of literature available does mention how to overcome the lacunae in the manuscript before considering resubmission in another journal, none addresses the mental agony and setback the author faces and the way to overcome this setback. Every author should develop immunity and also be adequately mentally prepared to overcome this misery.

Recent advances in the diagnosis and treatment of complex anal fistula.

Anal fistula can be a challenging condition to manage, with complex fistulas presenting even greater difficulties. The primary concerns in treating this condition are a risk of damage to the anal sphincters, which can compromise fecal continence, and refractoriness to treatment, as evidenced by a high recurrence rate. Furthermore, the treatment of complex anal fistula involves several additional challenges. Satisfactory solutions to many of these obstacles remain elusive, and no consensus has been established regarding the available treatment options. In summary, complex anal fistula has no established gold-standard treatment, and the quest for effective therapies continues. This review discusses and highlights groundbreaking advances in the management of complex anal fistula over the past decade.