Left-right symmetry of zebrafish embryos requires somite surface tension.

The body axis of vertebrate embryos is periodically segmented into bilaterally symmetric pairs of somites1,2. The anteroposterior length of somites, their position and left-right symmetry are thought to be molecularly determined before somite morphogenesis3,4. Here we show that, in zebrafish embryos, initial somite anteroposterior lengths and positions are imprecise and, consequently, many somite pairs form left-right asymmetrically. Notably, these imprecisions are not left unchecked and we find that anteroposterior lengths adjust within an hour after somite formation, thereby increasing morphological symmetry. We find that anteroposterior length adjustments result entirely from changes in somite shape without change in somite volume, with changes in anteroposterior length being compensated by corresponding changes in mediolateral length. The anteroposterior adjustment mechanism is facilitated by somite surface tension, which we show by comparing in vivo experiments and in vitro single-somite explant cultures using a mechanical model. Length adjustment is inhibited by perturbation of molecules involved in surface tension, such as integrin and fibronectin. By contrast, the adjustment mechanism is unaffected by perturbations to the segmentation clock, therefore revealing a distinct process that influences morphological segment lengths. We propose that tissue surface tension provides a general mechanism to adjust shapes and ensure precision and symmetry of tissues in developing embryos.

Efficacy of Oral SERDs in the treatment of ER+, HER2 - metastatic breast cancer, a stratified analysis of the ESR1 wild type and mutant subgroups.

BACKGROUND: Oral SERDs are a novel drug class that have been developed to counteract resistance due to ESR1 mutations. Several SERDs have emerged from phase 2 and 3 trials, with the FDA limiting approval for Elacestrant to patients with ESR1mt tumours despite PFS benefit in the overall population. However, questions remain on whether patients with ESR1wt tumours stand to benefit from oral SERDs. PATIENTS AND METHODS: Manuscripts and conference presentations of Randomised Controlled Trials were extracted after a systematic search of Embase, PubMed and Cochrane from inception until January 21,2023. RCTs investigating the efficacy of oral SERDs versus endocrine therapy for ER positive, HER2 negative advanced breast cancer, and which reported the Kaplan Meier (KM) curves of PFS in the overall and ESR1 mutant (ESR1mt) population were selected. A graphical reconstructive algorithm was applied to estimate time-to-event outcomes from reported KM curves in all overall and ESR1mt cohorts. A bipartite matching algorithm, KMSubtraction, was used to derive survival data for unreported (ESR1wt) subgroups. An individual patient data (IPD) meta-analysis was then pursued, pooling data by ESR1 mutation status in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Cochrane Guidelines for IPD. RESULTS: The randomized clinical trials ACELERA, AMEERA-3, EMERALD and SERENA-2 were included, totalling 1290 patients. In the pooled analysis of the overall cohort, PFS benefit was observed with oral SERDs when compared with treatment of physicians choice (TPC) (HR 0.783, 95%CI 0.681-0.900, p<0.001). In the ESR1mt subgroup, oral SERDs demonstrated improved PFS (HR 0.557, 95%CI 0.440-0.705, p<0.001) compared to TPC. In the ESR1wt subgroup, oral SERDs demonstrated no significant PFS benefit (HR 0.944, 95%CI 0.783-1.138, p=0.543) when compared to TPC. CONCLUSIONS: The results of this IPD meta-analysis suggests that PFS benefit in the overall population is mainly driven by the ESR1mt subgroup.

Epigenomic promoter alterations predict for benefit from immune checkpoint inhibition in metastatic gastric cancer.

BACKGROUND: Utilization of alternative transcription start sites through alterations in epigenetic promoter regions causes reduced expression of immunogenic N-terminal peptides, which may facilitate immune evasion in early gastric cancer. We hypothesized that tumors with high alternate promoter utilization would be resistant to immune checkpoint inhibition in metastatic gastric cancer. PATIENTS AND METHODS: Two cohorts of patients with metastatic gastric cancer treated with immunotherapy were analyzed. The first cohort (N = 24) included patients treated with either nivolumab or pembrolizumab. Alternate promoter utilization was measured using the NanoString® (NanoString Technologies, Seattle, WA, USA) platform on archival tissue samples. The second cohort was a phase II clinical trial of patients uniformly treated with pembrolizumab (N = 37). Fresh tumor biopsies were obtained, and transcriptomic analysis was carried out on RNAseq data. Alternate promoter utilization was correlated to T-cell cytolytic activity, objective response rate and survival. RESULTS: In the first cohort 8 of 24 (33%) tumors were identified to have high alternate promoter utilization (APhigh), and this was used to define the APhigh tertile of the second cohort (13 APhigh of 37). APhigh tumors exhibited decreased markers of T-cell cytolytic activity and lower response rates (8% versus 42%, P = 0.03). Median progression-free survival was lower in the APhigh group (55 versus 180 days, P = 0.0076). In multivariate analysis, alternative promoter utilization was an independent predictor of immunotherapy survival [hazard ratio 0.29, 95% confidence interval 0.099-0.85, P = 0.024). Analyzing tumoral evolution through paired pre-treatment and post-treatment biopsies, we observed consistent shifts in alternative promoter utilization rate associated with clinical response. CONCLUSION: A substantial proportion of metastatic gastric cancers utilize alternate promoters as a mechanism of immune evasion, and these tumors may be resistant to anti-PD1 immune checkpoint inhibition. Alternate promoter utilization is thus a potential mechanism of resistance to immune checkpoint inhibition, and a novel predictive biomarker for immunotherapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT#02589496.

Vistusertib (dual m-TORC1/2 inhibitor) in combination with paclitaxel in patients with high-grade serous ovarian and squamous non-small-cell lung cancer.

Background: We have previously shown that raised p-S6K levels correlate with resistance to chemotherapy in ovarian cancer. We hypothesised that inhibiting p-S6K signalling with the dual m-TORC1/2 inhibitor in patients receiving weekly paclitaxel could improve outcomes in such patients. Patients and methods: In dose escalation, weekly paclitaxel (80 mg/m2) was given 6/7 weeks in combination with two intermittent schedules of vistusertib (dosing starting on the day of paclitaxel): schedule A, vistusertib dosed bd for 3 consecutive days per week (3/7 days) and schedule B, vistusertib dosed bd for 2 consecutive days per week (2/7 days). After establishing a recommended phase II dose (RP2D), expansion cohorts in high-grade serous ovarian cancer (HGSOC) and squamous non-small-cell lung cancer (sqNSCLC) were explored in 25 and 40 patients, respectively. Results: The dose-escalation arms comprised 22 patients with advanced solid tumours. The dose-limiting toxicities were fatigue and mucositis in schedule A and rash in schedule B. On the basis of toxicity and pharmacokinetic (PK) and pharmacodynamic (PD) evaluations, the RP2D was established as 80 mg/m2 paclitaxel with 50 mg vistusertib bd 3/7 days for 6/7 weeks. In the HGSOC expansion, RECIST and GCIG CA125 response rates were 13/25 (52%) and 16/25 (64%), respectively, with median progression-free survival (mPFS) of 5.8 months (95% CI: 3.28-18.54). The RP2D was not well tolerated in the SqNSCLC expansion, but toxicities were manageable after the daily vistusertib dose was reduced to 25 mg bd for the following 23 patients. The RECIST response rate in this group was 8/23 (35%), and the mPFS was 5.8 months (95% CI: 2.76-21.25). Discussion: In this phase I trial, we report a highly active and well-tolerated combination of vistusertib, administered as an intermittent schedule with weekly paclitaxel, in patients with HGSOC and SqNSCLC. Clinical trial registration: ClinicialTrials.gov identifier: CNCT02193633.

Highly-Efficient Guiding of Motile Microtubules on Non-Topographical Motor Patterns.

Molecular motors, highly efficient biological nanomachines, hold the potential to be employed for a wide range of nanotechnological applications. Toward this end, kinesin, dynein, or myosin motor proteins are commonly surface-immobilized within engineered environments in order to transport cargo attached to cytoskeletal filaments. Being able to flexibly control the direction of filament motion, and in particular on planar, non-topographical surfaces, has, however, remained challenging. Here, we demonstrate the applicability of a UV-laser-based ablation technique to programmably generate highly localized patterns of functional kinesin-1 motors with different shapes and sizes on PLL-g-PEG-coated polystyrene surfaces. Straight and curved motor tracks with widths of less than 500 nm could be generated in a highly reproducible manner and proved to reliably guide gliding microtubules. Though dependent on track curvature, the characteristic travel lengths of the microtubules on the tracks significantly exceeded earlier predictions. Moreover, we experimentally verified the performance of complex kinesin-1 patterns, recently designed by evolutionary algorithms for controlling the global directionality of microtubule motion on large-area substrates.

Asymmetric Flows in the Intercellular Membrane during Cytokinesis.

Eukaryotic cells undergo shape changes during their division and growth. This involves flow of material both in the cell membrane and in the cytoskeletal layer beneath the membrane. Such flows result in redistribution of phospholipid at the cell surface and actomyosin in the cortex. Here we focus on the growth of the intercellular surface during cell division in a Caenorhabditis elegans embryo. The growth of this surface leads to the formation of a double-layer of separating membranes between the two daughter cells. The division plane typically has a circular periphery and the growth starts from the periphery as a membrane invagination, which grows radially inward like the shutter of a camera. The growth is typically not concentric, in the sense that the closing internal ring is located off-center. Cytoskeletal proteins anillin and septin have been found to be responsible for initiating and maintaining the asymmetry of ring closure but the role of possible asymmetry in the material flow into the growing membrane has not been investigated yet. Motivated by experimental evidence of such flow asymmetry, here we explore the patterns of internal ring closure in the growing membrane in response to asymmetric boundary fluxes. We highlight the importance of the flow asymmetry by showing that many of the asymmetric growth patterns observed experimentally can be reproduced by our model, which incorporates the viscous nature of the membrane and contractility of the associated cortex.

Modular pump head design of diffused, metal, and hybrid pump geometry for diode-side-pumped high power Nd:YAG laser.

In this paper, we present a comparative study on pump heads for a high power diode-side-pumped Nd:YAG laser. The pump head is a modular type, which is in the form of discs, with each disc holding three pump diodes kept at 120° with respect to each other. Unabsorbed pump light from the active medium is reflected by reflectors mounted adjacent to the pump diodes. The performance of a high power pump head made of modular discs mounted with specular or diffused type reflectors was studied. Hybrid pump geometry was also investigated, where the pump head is made up of discs loaded with metal and diffused reflectors, alternately. The discs are loaded around the active medium in such a way that successive discs are rotated by sixty degrees with respect to each other. Fluorescence profiles, thermal lensing, laser output power, and M2 values were studied for pump heads made up of metal, diffused, and hybrid type reflectors. All of the pump heads were studied for three different resonator lengths to maximize the output power with the best beam quality. The experimental results show that the diffused reflector-based geometry in a sixty degree rotated configuration produced the maximum output power and best beam quality in terms of the M2 value.

Differential bleaching of corals based on El Niño type and intensity in the Andaman Sea, southeast Bay of Bengal.

The Andaman coral reef region experienced mass bleaching events during 1998 and 2010. The purpose of this study is to investigate the role of the El Niño in the coral reef bleaching events of the Andaman region. Both Niño 3.4 and 3 indices were examined to find out the relationship between the mass bleaching events and El Niño, and correlated with sea surface temperature (SST) anomalies in the Andaman Sea. The result shows that abnormal warming and mass bleaching events in the Andaman Sea were seen only during strong El Niño years of 1997-1998 and 2009-2010. The Andaman Sea SST was more elevated and associated with El Niño Modoki (central Pacific El Niño) than conventional El Niño (eastern Pacific El Niño) occurrences. It is suggested that the development of hot spot patterns around the Andaman Islands during May 1998 and April-May 2010 may be attributed to zonal shifts in the Walker circulation driven by El Niño during the corresponding period.

Modular pump geometry for diode side-pumped high-power Nd:YAG rod laser.

In this paper, we present a modular design configuration to side-pump an Nd:YAG rod of a diode-pumped high-power CW laser. Independent modules in the form of discs are loaded with three-diode linear bar arrays at 120° with respect to each other and are assembled along the length of the rod. By keeping successive discs at three different angular separations (the minimum, intermediate, and maximum), helical, 60° rotated, and linear geometries, respectively, were created. Parameters like thermal lensing, fluorescence profile, laser beam profile, and beam quality factor (M2) were studied to compare the performances of different geometries. The results indicate that the 60° rotated configuration provides the best performance when compared with rest of the schemes. To the best of our knowledge, this is the first time that such novel modular-type pump geometries with a provision for the angular separation of pump diodes have been tried.

Male Partner Involvement in Birth Preparedness, Complication Readiness and Obstetric Emergencies in Central Rural India: A Cross-Sectional Study.

BACKGROUND AND OBJECTIVES: Childbirth is mainly thought to be a woman's concern, and mortality can be prevented by making a birth plan constituting birth preparedness and complication readiness with the entire family as one unit. Indian National Plans aim to increase male involvement, but the policies lack directions and monitoring systems; hence, it becomes important to address this issue. METHODOLOGY:  A cross-sectional study conducted in a rural hospital and a community-based setup included 350 male participants, consisting of new fathers or expecting fathers, who were interviewed with the help of a questionnaire. RESULTS: Only 28.29% of male participants were well involved in the process of birth preparedness and complication readiness. 83% of the husbands accompanied their respective wives during ANC visits (mean number of visits: 5.76). 33% of males were aware of various danger signs and complications related to pregnancy. The males with better education (p-value < 0.005) and economic status (p-value < 0.0001) had better birth preparedness. Several variables in the study were positively correlated with the amount of money saved.  Interpretation and conclusion: Male involvement during pregnancy significantly impacts maternal and child health outcomes. However, this study highlights a lack of awareness and involvement among males. We strongly recommend enhancing existing maternal and child health (MCH) programs to include components focused on male partner engagement in birth preparedness, complication readiness, and obstetric emergencies.

Pediatric isolated bilateral iliac aneurysm.

Aneurysms are rare in children. Isolated iliac artery aneurysms are very rare, especially bilateral aneurysms. Pediatric aneurysms are usually secondary to connective tissue disorders, arteritis, or mycotic causes. We present a case of a 3-year-old child with bilateral idiopathic common iliac aneurysms that were successfully repaired with autogenous vein grafts.

Clinical Utility of Soluble Lectin Type Oxidized Low-Density Lipoprotein Receptor as a Biomarker for Myocardial Infarction and Stable Angina.

Background and objectives Endothelial soluble lectin-type oxidized low-density lipoprotein receptor 1 (sLOX-1) recognizes oxidized low-density lipoprotein (LDL) and triggers downstream signaling leading to atherosclerosis. The objective of this study was to demonstrate the utility of sLOX-1 as a biomarker for detecting acute myocardial infarction (MI) and stable angina (SA) and to develop a diagnostic algorithm for distinguishing coronary vasospasm from coronary plaque rupture. Methods We enrolled 62 patients who underwent diagnostic coronary angiography (CAG) and 30 healthy controls (21 men and nine women) and measured sLOX-1, troponin I, and cardiac myosin-binding protein C (c-MyBPC) using commercial kits. Results Patients with MI exhibited higher sLOX-1 levels (301.55 ± 196.16 pg/ml) than patients with stable angina (220.76 ± 103.65 pg/ml) and healthy controls (121.14 ± 77.10, F: 10.55, p<0.001). Although higher troponin I levels were detected in MI patients (263.00 ± 493.00 vs. 3.19 ± 2.15 ng/ml, p=0.0019), no significant elevation was observed in SA patients (1.91 ± 0.79 ng/ml). Plasma sLOX-1 levels showed a positive association with age (r=0.37, p=0.003), but not with gender (r=0.04, p=0.75). Troponin I showed no association with age (r=0.12, p=0.36) or gender (r=0.06, p=0.62). Receiver operating characteristic (ROC) curves revealed that among the three biomarkers, troponin-I showed a higher area under the curve (AUC) (AUC: 0.941), followed by sLOX-1 (AUC: 0.888), while c-MyBPC showed no clinical utility in the detection of MI (AUC: 0.666). Conclusions A marked elevation of sLOX-1 can detect MI and differentiate the presence or absence of plaque rupture, along with diagnosing stable angina.

Melanin pigments from sediment-associated Nocardiopsis sp. marine actinobacterium and antibacterial potential.

To extract the melanin pigment from marine microbes and their biological potential, the present study was done. Isolation and identification of the melanin-producing Nocardiopsis sp. were obtained from the sediment samples. Zone of inhibition and minimal inhibitory concentration test was performed using melanin. Melanin was extracted from sediment-associated marine Nocardiopsis sp. In the present study, marine actinobacterium was identified by the conventional method, and the isolate was identified as Nocardiopsis sp. Melanin was extracted, and antibacterial activities were performed against different pathogens and the highest zone of inhibition is more in the E. coli while related to another two species. From previous observation done by Fu et al., they have said that marine actinobacteria have the ability of antimicrobial activity, which is very much helpful in producing the potential antimicrobial drugs this was similar to our study that marine actinobacteria have the capability to produce melanin pigment, and at the same time, it helps as to show the antibacterial activity. We concluded that melanin is produced by the Nocardiopsis sp. We also found that melanin extracted from the Nocardiopsis sp. of marine actinobacterium also has an antibacterial effect.

Preparation of Single-Somite Explants from Zebrafish Embryos.

The body axis of vertebrate embryos is periodically subdivided into 3D multicellular units called somites. While genetic oscillations and molecular prepatterns determine the initial length-scale of somites, mechanical processes have been implicated in setting their final size and shape. To better understand the intrinsic material properties of somites, a method is developed to culture single-somite explant from zebrafish embryos. Single somites are isolated by first removing the skin of embryos, followed by yolk removal and sequential excision of neighboring tissues. Using transgenic embryos, the distribution of various sub-cellular structures can be observed by fluorescent time-lapse microscopy. Dynamics of explanted somites can be followed for several hours, thus providing an experimental framework for studying tissue-scale shape changes at single-cell resolution. This approach enables direct mechanical manipulation of somites, allowing for dissection of the material properties of the tissue. Finally, the technique outlined here can be readily extended for explanting other tissues such as the notochord, neural plate, and lateral plate mesoderm.

Hand2 delineates mesothelium progenitors and is reactivated in mesothelioma.

The mesothelium lines body cavities and surrounds internal organs, widely contributing to homeostasis and regeneration. Mesothelium disruptions cause visceral anomalies and mesothelioma tumors. Nonetheless, the embryonic emergence of mesothelia remains incompletely understood. Here, we track mesothelial origins in the lateral plate mesoderm (LPM) using zebrafish. Single-cell transcriptomics uncovers a post-gastrulation gene expression signature centered on hand2 in distinct LPM progenitor cells. We map mesothelial progenitors to lateral-most, hand2-expressing LPM and confirm conservation in mouse. Time-lapse imaging of zebrafish hand2 reporter embryos captures mesothelium formation including pericardium, visceral, and parietal peritoneum. We find primordial germ cells migrate with the forming mesothelium as ventral migration boundary. Functionally, hand2 loss disrupts mesothelium formation with reduced progenitor cells and perturbed migration. In mouse and human mesothelioma, we document expression of LPM-associated transcription factors including Hand2, suggesting re-initiation of a developmental program. Our data connects mesothelium development to Hand2, expanding our understanding of mesothelial pathologies.

A Survey on Security and Privacy Issues in Contact Tracing Application of Covid-19.

In response to the coronavirus (COVID-19) pandemic, Government and public health authorities around the world are developing contact tracing apps as a way to trace and slow the unfold of the virus. There is major divergence among nations, however, between a "privacy-first" approach that protects citizens' information at the price of very restricted access for public health authorities and a "data-first" approach that stores massive amounts of knowledge that, whereas of immeasurable price to epidemiologists. Contact tracing apps work by gathering information from people who have tested positive for the virus and so locating and notifying individuals with whom those people are in shut contact, oftentimes by use of GPS, Bluetooth, or wireless technology. All of the user's information is employed and picked up, the study found that users' information would be created anonymous, encrypted, secured, and can be transmitted on-line and stored solely in an aggregated format. Contact tracing apps use either a centralized or a decentralized approach to work the user's information. Apps that use a centralized approach have high privacy risks. In this paper, the researcher's contributions related to the security and privacy of Contact tracing apps have been discussed and, later research gaps have been identified with proposed solutions.

Is investigation of patients with haemoptysis and normal chest radiograph justified?

BACKGROUND: Haemoptysis is a common clinical symptom. A small proportion of patients present with haemoptysis and normal chest radiograph. The investigation strategy for this group of patients is unclear. The aim of this study is to see whether further investigations for this group of patients are justified. METHODS: A retrospective analysis was conducted of consecutive patients presenting with haemoptysis and normal chest radiograph over a period of 56 months irrespective of their smoking status. These patients were investigated by CT of the thorax and fibreoptic bronchoscopy. RESULTS: 275 episodes of haemoptysis with normal chest radiograph were investigated further in 270 patients (60% males). The median age was 60 years. Twenty-six patients were diagnosed to have respiratory tract malignancies (larynx, 1; trachea, 1; lung, 22; carcinoid, 1; and leiomyoma, 1). Eight (31%) of the 26 patients with respiratory tract malignancy had radical treatment. Fibreoptic bronchoscopy was diagnostic of cancer in 14 (54%) of the 26 patients with malignancy. CT of the thorax was suggestive of cancer in 24 (96%) of the 25 patients with malignancy. CONCLUSION: It is concluded that further investigation of haemoptysis in smokers is justified regardless of the amount or frequency of haemoptysis based on a 9.6% rate of malignancy in this consecutive series. It is recommended that these patients are investigated with CT of the thorax followed by fibreoptic bronchoscopy.