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IntroductionAchieving parenthood is challenging in individuals receiving renal replacement therapy (RRT; dialysis or kidney transplantation) for end-stage kidney disease. Decision-making regarding parenthood in RRT recipients should be underpinned by robust data, yet there is limited data on parental factors that drive adverse health outcomes. Therefore, we aim to investigate the perinatal risks and outcomes in parents receiving RRT.Methods and analysisThis is a multijurisdictional probabilistic data linkage study of perinatal, hospital, birth, death and renal registers from 1991 to 2013 from New South Wales, Western Australia, South Australia and the Australian Capital Territory. This study includes all babies born ≥20 weeks’ gestation or 400 g birth weight captured through mandated data collection in the perinatal data sets. Through linkage with the Australian and New Zealand Dialysis and Transplant (ANZDATA) registry, babies exposed to RRT (and their parents) will be compared with babies who have not been exposed to RRT (and their parents) to determine obstetric and fetal outcomes, birth rates and fertility rates. One of the novel aspects of this study is the method that will be used to link fathers receiving RRT to the mothers and their babies within the perinatal data sets, using the birth register, enabling the identification of family units. The linked data set will be used to validate the parenthood events directly reported to ANZDATA.Ethics and disseminationEthics approval was obtained from Human Research Ethics Committees (HREC) and Aboriginal HREC in each jurisdiction. Findings of this study will be disseminated at scientific conferences and in peer-reviewed journals in tabular and aggregated forms. De-identified data will be presented and individual patients will not be identified. We will aim to present findings to relevant stakeholders (eg, patients, clinicians and policymakers) to maximise translational impact of research findings.

This work reports engineered toehold RNA–based biosensors for COVID-19 diagnostics, with a simple color or luminescence readout that makes it easily deployable in both well-equipped labs as well as low resource settings., The continued resurgence of the COVID-19 pandemic with multiple variants underlines the need for diagnostics that are adaptable to the virus. We have developed toehold RNA–based sensors across the SARS-CoV-2 genome for direct and ultrasensitive detection of the virus and its prominent variants. Here, isothermal amplification of a fragment of SARS-CoV-2 RNA coupled with activation of our biosensors leads to a conformational switch in the sensor. This leads to translation of a reporter protein, for example, LacZ or nano-lantern that is easily detected using color/luminescence. By optimizing RNA amplification and biosensor design, we have generated a highly sensitive diagnostic assay that is capable of detecting as low as 100 copies of viral RNA with development of bright color. This is easily visualized by the human eye and quantifiable using spectrophotometry. Finally, this PHAsed NASBA-Translation Optical Method (PHANTOM) using our engineered RNA biosensors efficiently detects viral RNA in patient samples. This work presents a powerful and universally accessible strategy for detecting COVID-19 and variants. This strategy is adaptable to further viral evolution and brings RNA bioengineering center-stage.

Bright, sensitive fluorescent probes that respond to changes in the cellular microenvironment are extremely valuable for imaging cellular dynamics. We report a simple, one-step synthesis of a new hemicaynine (HC-1) dye as a sensitive, red-emitting (λmax-610 nm) fluorogenic probe for micro-viscosity and local order in diverse environments, including live cells. HC-1 responds to increasing micro-viscosity through changes in fluorescence intensity and lifetime, and is sensitive enough to report dynamic micellar self-assembly. While HC-1 shows properties of a molecular ‘rotor’, time-dependent density functional theoretical analysis reveals that in HC-1, an inhibition of photo-isomerization in viscous environment is the likely cause of fluorescence enhancement. HC-1 localizes to mitochondria in live cells and responds to mitochondrial ordering through a significant increase in fluorescence. Strikingly, we show that HC-1 is also a sensitive probe for the spatial heterogeneity of mitochondrial organization in embryonic stem cells as well as dynamic remodeling of the mitochondria in early-differentiated cells.

Dopaminergic drugs have been used as the first-line treatment for restless legs syndrome (RLS) for many years and are considered to be, at least over the short-term, effective and safe. However, the main long-term complication of dopaminergic treatment is augmentation, which is an overall increase in symptom severity and intensity, with symptoms starting earlier in the afternoon and expanding to previously unaffected parts of the body. Augmentation is a common complication, with prevalence rates of nearly 50%, and is a common cause of treatment failure. Furthermore, augmentation occurs almost exclusively during treatment with dopaminergic drugs. Due to its frequency, there is a strong clinical need for treatment alternatives to dopaminergic drugs. Moreover, recent treatment guidelines recommend that treatment be initiated, whenever possible, with non-dopaminergic drugs (ie, α2δ ligands). Alternative treatments such as intravenous iron preparations directly address iron deficiency, as well as the consequences of iron deficiency in regard to glutamate and adenosine. This article also reviews current knowledge supporting an involvement of glutamatergic and adenosinergic neurotransmission in the pathophysiology of RLS, and explores the potential development of drugs acting on both systems.

Purpose The purpose of this paper is to examine the relationship between protean career attitude (PCA) and proactive work behaviors (PWB) and with the theoretical underpinning of self-determination theory to ascertain if passion for work acts as a mediator for PCA and PWB. Design/methodology/approach A survey of 255 millennial employees working in diverse industries in India (such as information technology, banking and education) was conducted. Regression analysis was used to measure the direct effects of the hypothesized relationships. Sobel test and bootstrapping analysis were used to measure the indirect effects of the hypothesized relationship. Findings PCA assists in fostering passion for work. Passion for work is positively related with PWB and fully mediates the relationship between PCA and PWB. Practical implications Employers should provide flexibility in work design and autonomy in career decisions. Also, Human resource managers should provide career growth opportunities to retain millennial talent. Originality/value This study bridges the knowledge gap between different domains of knowledge including PCA, passion for work and PWB. This study is one of the rare attempts to understand the relationship between PCA and PWB through the lens of passion for work. It also bridges the gap relating to its context. With an increasing number of millennials in workforce in India, an understanding of their career attitudes and outcome behaviors has become a significant concern. The results of the present study underpin career motivation theory, self-determination theory and generational cohort theory.

Identifying key cellular events that facilitate stem cell function and tissue organization is crucial for understanding the process of regeneration. Planarians are powerful model system to study regeneration and stem cell (neoblast) function. Here, using planaria, we show that the initial events of regeneration, such as epithelialization and epidermal organization are critically regulated by a novel cytoplasmic poly A-binding protein, SMED-PABPC2. Knockdown of smed-pabpc2 leads to defects in epidermal lineage specification, disorganization of epidermis and ECM, and deregulated wound healing, resulting in the selective failure of neoblast proliferation near the wound region. Polysome profiling suggests that epidermal lineage transcripts, including zfp-1, are translationally regulated by SMED-PABPC2. Together, our results uncover a novel role for SMED-PABPC2 in the maintenance of epidermal and ECM integrity, critical for wound healing and subsequent processes for regeneration., Summary: PABPC2 plays a crucial role in the maintenance of epidermal and extracellular matrix integrity, which is essential for neoblast function and regeneration in planarians.

Cell behavior is controlled through spatio-temporally localized protein activity. Despite unique and often contradictory roles played by Src-family-kinases (SFKs) in regulating cell physiology, activity patterns of individual SFKs have remained elusive. Here, we report a biosensor for specifically visualizing active conformation of SFK-Fyn in live cells. We deployed combinatorial library screening to isolate a binding-protein (F29) targeting activated Fyn. Nuclear-magnetic-resonance (NMR) analysis provides the structural basis of F29 specificity for Fyn over homologous SFKs. Using F29, we engineered a sensitive, minimally-perturbing fluorescence-resonance-energy-transfer (FRET) biosensor (FynSensor) that reveals cellular Fyn activity to be spatially localized, pulsatile and sensitive to adhesion/integrin signaling. Strikingly, growth factor stimulation further enhanced Fyn activity in pre-activated intracellular zones. However, inhibition of focal-adhesion-kinase activity not only attenuates Fyn activity, but abolishes growth-factor modulation. FynSensor imaging uncovers spatially-organized, sensitized signaling clusters, direct crosstalk between integrin and growth-factor-signaling, and clarifies how compartmentalized Src-kinase activity may drive cell fate.

Cell behavior is controlled through spatio-temporally localized protein activity. Despite unique and often contradictory roles played by Src-family-kinases (SFKs) in regulating cell physiology, activity patterns of individual SFKs have remained elusive. Here, we report a biosensor for specifically visualizing active conformation of SFK-Fyn in live cells. We deployed combinatorial library screening to isolate a binding-protein (F29) targeting activated Fyn. Nuclear-magnetic-resonance (NMR) analysis provides the structural basis of F29 specificity for Fyn over homologous SFKs. Using F29, we engineered a sensitive, minimally-perturbing fluorescence-resonance-energy-transfer (FRET) biosensor (FynSensor) that reveals cellular Fyn activity to be spatially localized, pulsatile and sensitive to adhesion/integrin signaling. Strikingly, growth factor stimulation further enhanced Fyn activity in pre-activated intracellular zones. However, inhibition of focal-adhesion-kinase activity not only attenuates Fyn activity, but abolishes growth-factor modulation. FynSensor imaging uncovers spatially organized, sensitized signaling clusters, direct crosstalk between integrin and growth-factor-signaling, and clarifies how compartmentalized Src-kinase activity may drive cell fate., eLife digest Cells contain networks of signaling proteins that can respond to a variety of cues from the surrounding environment. Often the cell’s response to these cues is not just controlled by the level of protein, but by changing the activity of signaling proteins. For example, a signaling protein in humans and other mammals known as Fyn regulates a number of different processes, including when a cell grows, dies, or develops a specialist role. Defects in the activity of Fyn are associated with several diseases in humans including cancer and Alzheimer’s disease. However, it remains unclear how Fyn contributes to these diseases, or how the protein is able to precisely coordinate responses to multiple different cues in healthy individuals. This is largely because there are no readily available tools that are able to specifically detect where and when this protein is active in cells. Researchers often use fluorescent proteins called biosensors as tools to detect where specific proteins are located in living cells over time. Now, Mukherjee, Singh et al. have developed a new biosensor named FynSensor to monitor the active form of Fyn in mammalian cells. Microscopy imaging of FynSensor in several different cell types showed that although Fyn was present everywhere, it was only active in certain areas. In these areas the protein switched between an active and inactive state, with clear ‘pulses’ of signaling activity lasting a couple of minutes in response to specific cues. These areas of high Fyn activity behaved like signaling hubs in which several different cues integrate together before Fyn triggers an appropriate cell response. These results shed light on how Fyn is able to precisely control many different processes in cells. In the future, FynSensor could be used to rapidly screen for drug-like molecules to treat cancer, Alzheimer’s disease and other conditions linked with defects in Fyn activity. Furthermore, the FynSensor could be adapted to allow researchers to study other signaling proteins in humans and other animals.

Importance Blood biomarkers able to diagnose Alzheimer disease (AD) at the preclinical stage would enable trial enrollment when the disease is potentially reversible. Plasma neuronal-enriched extracellular vesicles (nEVs) of patients with AD were reported to exhibit elevated levels of phosphorylated (p) tau, Aβ42, and phosphorylated insulin receptor substrate 1 (IRS-1). Objective To validate nEV biomarkers as AD predictors. Design, Setting, Participants This case-control study included longitudinal plasma samples from cognitively normal participants in the Baltimore Longitudinal Study of Aging (BLSA) cohort who developed AD up to January 2015 and age- and sex-matched controls who remained cognitively normal over a similar length of follow-up. Repeated samples were blindly analyzed over 1 year from participants with clinical AD and controls from the Johns Hopkins Alzheimer Disease Research Center (JHADRC). Data were collected from September 2016 to January 2018. Analyses were conducted in March 2019. Main Outcomes and Measures Neuronal-enriched extracellular vesicles were immunoprecipitated; tau, Aβ42, and IRS-1 biomarkers were quantified by immunoassays; and nEV concentration and diameter were determined by nanoparticle tracking analysis. Levels and longitudinal trajectories of nEV biomarkers between participants with future AD and control participants were compared. Results Overall, 887 longitudinal plasma samples from 128 BLSA participants who eventually developed AD and 222 age and sex-matched controls who remained cognitively normal were analyzed. Participants were followed up (from earliest sample to AD symptom onset) for a mean (SD) of 3.5 (2.31) years (range, 0-9.73 years). Overall, 161 participants were included in the training set, and 80 were in the test set. Participants in the BLSA cohort with future AD (mean [SD] age, 79.09 [7.02] years; 68 women [53.13%]) had longitudinally higher p-tau181, p-tau231, pSer312-IRS-1, pY-IRS-1, and nEV diameter than controls (mean [SD] age, 76.2 [7.36] years; 110 women [50.45%]) but had similar Aβ42, total tau, TSG101, and nEV concentration. In the training BLSA set, a model combining preclinical longitudinal data achieved 89.6% area under curve (AUC), 81.8% sensitivity, and 85.8% specificity for predicting AD. The model was validated in the test BLSA set (80% AUC, 55.6% sensitivity, 88.7% specificity). Preclinical levels of nEV biomarkers were associated with cognitive performance. In addition, 128 repeated samples over 1 year from 64 JHADRC participants with clinical AD and controls were analyzed. In the JHADRC cohort (35 participants with AD: mean [SD] age, 74.03 [8.73] years; 18 women [51.43%] and 29 controls: mean [SD] age, 72.14 [7.86] years; 23 women [79.31%]), nEV biomarkers achieved discrimination with 98.9% AUC, 100% sensitivity, and 94.7% specificity in the training set and 76.7% AUC, 91.7% sensitivity, and 60% specificity in the test set. Conclusions and Relevance We validated nEV biomarker candidates and further demonstrated that their preclinical longitudinal trajectories can predict AD diagnosis. These findings motivate further development of nEV biomarkers toward a clinical blood test for AD.

In Kenya&rsquo, s capital city, Nairobi, streets are regularly gridlocked. While it is clear that roads are congested at peak hours, it is not known which commuters are experiencing that congestion or what their commute times actually are. Even less is known about commuting patterns in other Kenyan cities. This paper contributes new evidence on commuting from a survey of 14,580 households, conducted in 15 Kenyan cities in 2013. Walking and matatus&mdash, privately-operated paratransit&mdash, account for 89% of all adult commuting in urban Kenya. As cities increase in size, the proportion relying on walking falls and matatu use increases. Within a city, commuters with higher income and education, and those living further from the city center, are more likely to use matatus rather than walk. Commute times are surprisingly short. In smaller Kenyan cities the median commute time is just 20 min. In Nairobi, the median commute time is 30 min, and only 5% of those surveyed reported commuting an hour or longer. These data paint a remarkably sustainable picture of urban travel patterns in Kenya. As incomes, education levels, and demand for motorized travel rise, the challenge will be to expand and improve the system while maintaining its sustainability.

Transfer RNA (tRNA)‐derived small RNAs (tsRNAs) have recently emerged as important regulators of protein translation and shown to have diverse biological functions. However, the underlying cellular and molecular mechanisms of tsRNA function in the context of dynamic cell‐state transitions remain unclear. Expression analysis of tsRNAs in distinct heterologous cell and tissue models of stem vs. differentiated states revealed a differentiation‐dependent enrichment of 5′‐tsRNAs. We report the identification of a set of 5′‐tsRNAs that is upregulated in differentiating mouse embryonic stem cells (mESCs). Notably, interactome studies with differentially enriched 5′‐tsRNAs revealed a switch in their association with “effector” RNPs and “target” mRNAs in different cell states. We demonstrate that specific 5′‐tsRNAs can preferentially interact with the RNA‐binding protein, Igf2bp1, in the RA‐induced differentiated state. This association influences the transcript stability and thereby translation of the pluripotency‐promoting factor, c‐Myc, thus providing a mechanistic basis for how 5′‐tsRNAs can modulate stem cell states in mESCs. Together our study highlights the role of 5′‐tsRNAs in defining distinct cell states.

Euchromatic histone methyltransferases (EHMTs), members of the KMT1 family, methylate histone and non‐histone proteins. Here, we uncover a novel role for EHMTs in regulating heterochromatin anchorage to the nuclear periphery (NP) via non‐histone methylation. We show that EHMTs methylate and stabilize LaminB1 (LMNB1), which associates with the H3K9me2‐marked peripheral heterochromatin. Loss of LMNB1 methylation or EHMTs abrogates heterochromatin anchorage at the NP. We further demonstrate that the loss of EHMTs induces many hallmarks of aging including global reduction of H3K27methyl marks and altered nuclear morphology. Consistent with this, we observe a gradual depletion of EHMTs, which correlates with loss of methylated LMNB1 and peripheral heterochromatin in aging human fibroblasts. Restoration of EHMT expression reverts peripheral heterochromatin defects in aged cells. Collectively, our work elucidates a new mechanism by which EHMTs regulate heterochromatin domain organization and reveals their impact on fundamental changes associated with the intrinsic aging process.

Summary FMRP is an RNA-binding protein that is known to localize in the cytoplasm and in the nucleus. Here, we have identified an interaction of FMRP with a specific set of C/D box snoRNAs in the nucleus. C/D box snoRNAs guide 2’O methylations of ribosomal RNA (rRNA) on defined sites, and this modification regulates rRNA folding and assembly of ribosomes. 2’O methylation of rRNA is partial on several sites in human embryonic stem cells, which results in ribosomes with differential methylation patterns. FMRP-snoRNA interaction affects rRNA methylation on several of these sites, and in the absence of FMRP, differential methylation pattern of rRNA is significantly altered. We found that FMRP recognizes ribosomes carrying specific methylation patterns on rRNA and the recognition of methylation pattern by FMRP may potentially determine the translation status of its target mRNAs. Thus, FMRP integrates its function in the nucleus and in the cytoplasm., Graphical Abstract, Highlights • FMRP binds to C/D Box snoRNAs in the nucleus • Differential 2’O-methylation on rRNA contributes to ribosome heterogeneity in a cell • 2’O-Methylation pattern on ribosomal RNA is altered in the absence of FMRP • FMRP recognizes 2’O-methylation on rRNA, which may determine interaction with ribosomes, Molecular Interaction; Stem Cells Research; Omics

This paper proposes a framework that examines three levels of access to infrastructure -- nominal, effective, and quality-adjusted access. Most conventional indicators measure nominal access --whether a household has physical access to a service in or near the house. By contrast, effective access incorporates functionality and use of service, and quality-adjusted access raises the bar by incorporating quality metrics. The paper illustrates the analytical utility of this conceptual framework by deploying data from a survey of 14,200 households in 15 Kenyan cities in 2012-13. First, the analysis finds that these cities fall far short of delivering universal access to basic infrastructure. Second, for most services there a large gap -- 3 to 41 percentage points—between nominal and effective access. When the bar is raised to include quality of service, the drop-off in the proportion of those with access is even more dramatic. These findings suggest that conventional nominal measures overreport the level of service in urban communities, and that current approaches to infrastructure delivery might be enhancing availability of a service without ensuring that the service is usable -- that is, functional, reliable and affordable. Third, there is an infrastructure access gap between nonpoor and poor households, as well as formal and informal settlements. Fourth, hedonic regression analysis reveals that four services -- electricity, water, toilets, and garbage collection—are associated with higher rents. The analysis has broader implications for understanding and measuring service access. It raises important questions as global discussions turn to indicators for the Sustainable Development Goals.

This paper proposes a framework that examines three levels of access to infrastructure -- nominal, effective, and quality-adjusted access. Most conventional indicators measure nominal access --whether a household has physical access to a service in or near the house. By contrast, effective access incorporates functionality and use of service, and quality-adjusted access raises the bar by incorporating quality metrics. The paper illustrates the analytical utility of this conceptual framework by deploying data from a survey of 14,200 households in 15 Kenyan cities in 2012-13. First, the analysis finds that these cities fall far short of delivering universal access to basic infrastructure. Second, for most services there a large gap -- 3 to 41 percentage points—between nominal and effective access. When the bar is raised to include quality of service, the drop-off in the proportion of those with access is even more dramatic. These findings suggest that conventional nominal measures overreport the level of service in urban communities, and that current approaches to infrastructure delivery might be enhancing availability of a service without ensuring that the service is usable -- that is, functional, reliable and affordable. Third, there is an infrastructure access gap between nonpoor and poor households, as well as formal and informal settlements. Fourth, hedonic regression analysis reveals that four services -- electricity, water, toilets, and garbage collection—are associated with higher rents. The analysis has broader implications for understanding and measuring service access. It raises important questions as global discussions turn to indicators for the Sustainable Development Goals.

Importance: Exenatide, a glucagon-like peptide 1 agonist used in type 2 diabetes, was recently found to have beneficial effects on motor function in a randomized, placebo-controlled trial in Parkinson disease (PD). Accumulating evidence suggests that impaired brain insulin and protein kinase B (Akt) signaling play a role in PD pathogenesis; however, exploring the extent to which drugs engage with putative mechnisms in vivo remains a challenge. Objective: To assess whether participants in the Exenatide-PD trial have augmented activity in brain insulin and Akt signaling pathways. Design, Setting, and Participants: Serum samples were collected from 60 participants in the single-center Exenatide-PD trial (June 18, 2014, to June 16, 2016), which compared patients with moderate PD randomized to 2 mg of exenatide once weekly or placebo for 48 weeks followed by a 12-week washout period. Serum extracellular vesicles, including exosomes, were extracted, precipitated, and enriched for neuronal source by anti–L1 cell adhesion molecule antibody absorption, and proteins of interest were evaluated using electrochemiluminescence assays. Statistical analysis was performed from May 1, 2017, to August 31, 2017. Main Outcomes and Measures: The main outcome was augmented brain insulin signaling that manifested as a change in tyrosine phosphorylated insulin receptor substrate 1 within neuronal extracellular vesicles at the end of 48 weeks of exenatide treatment. Additional outcome measures were changes in other insulin receptor substrate proteins and effects on protein expression in the Akt and mitogen-activated protein kinase pathways. Results: Sixty patients (mean [SD] age, 59.9 [8.4] years; 43 [72%] male) participated in the study: 31 in the exenatide group and 29 in the placebo group (data from 1 patient in the exenatide group were excluded). Patients treated with exenatide had augmented tyrosine phosphorylation of insulin receptor substrate 1 at 48 weeks (0.27 absorbance units [AU]; 95% CI, 0.09-0.44 AU; P = .003) and 60 weeks (0.23 AU; 95% CI, 0.05-0.41 AU; P = .01) compared with patients receiving placebo. Exenatide-treated patients had elevated expression of downstream substrates, including total Akt (0.35 U/mL; 95% CI, 0.16-0.53 U/mL; P

Background: Kidney transplantation facilitates pregnancy in women with end-stage kidney disease; however, the impact of pregnancy on short and longer-term graft function is uncertain. Methods: Obstetric, fetal, and graft outcomes for pregnancies from a large Australian transplant unit (1976-2015) were reviewed. Results: There were 56 pregnancies in 35 women with mean age at conception 30.4 ± 0.6 years and mean transplant-pregnancy interval 5.5 ± 0.5 years. The live birth rate was 78.9%. Preterm birth ( 110 μmol/L had increased risk of pre-eclampsia (OR 4.4; 95% CI 1.2-16.8; P =.03), but not preterm birth (OR 5.4; 95% CI 0.5-53; P =.04) or low birth-weight babies (OR 1.2; 95% CI 0.5-2.9; P =.04). Women with SCr > 140 μmol/L preconception had worst SCr trajectory, including higher rates of graft loss. Conclusions: Kidney transplantation pregnancies remain at high risk of obstetric complications, particularly pre-eclampsia. Prepregnancy graft function can be used to predict risk of adverse pregnancy outcomes and deterioration in graft function during and after delivery. Refereed/Peer-reviewed

Parkinson's disease is a multi-systems neurodegenerative disorder that is characterized by a combination of motor and non-motor symptoms. Non-motor symptoms of Parkinson's disease comprise a variety of cognitive, neuropsychiatric, autonomic, sensory, and sleep complaints. Although sleep disruption represents one of the most common non-motor symptom complaints among Parkinson's disease patients, recommendations regarding effective evaluation and management strategies for this specific population remain limited. This review gives an evidence based summary of the available treatment options and management strategies for the sleep complaints commonly encountered by patients with Parkinson's disease.

Accelerated lambing system is heavily reliant on reproductive technologies meant to enable off the season breeding in sheep. Therefore, the present study was programmed to assess the effect of breeding season (BS) on fertility of sheep following estrus synchronization (ES) and fixed time artificial insemination (FTAI). A total of 248 and 365 ewes were synchronized and inseminated during the BS (Febuary–March and July–September) and non-breeding season (NBS) respectively, during 2012–14. Synchronization of estrus was done by AVIKESIL-S, intra-vaginal progesterone sponges kept in situ in vagina for 12 days. 200 IU eCG was administered intramuscularly on 12th day after sponge withdrawal. FTAI was performed twice in ewes exhibiting signs of estrus at 48 and 56h after sponge removal, using liquid chilled semen of Patanwadi/Malpura rams containing 100 million sperm. Breeding season had no significant (p

Photo Dynamic Therapy (PDT) is regarded as an effective therapeutic approach for cancer, which employs light and photosensitizing chemical substances. The successful demonstration of this technique by Dougherty et al. paved a new way for tumor treatment. Since then the technique has been continuously evolving to keep up its promises in medical science. The basic idea of PDT is to administer photoactive small molecules within tumor cells. The photoactive molecules, well known as Photosensitizers (PS) absorb light from external light source depending on its absorption property and goes to excited state. In this excited state they react with molecular oxygen of the living tissues and forms reactive oxygen species (ROS). These ROS are very toxic to the cells as they instantly oxidize important biomolecules such as proteins and nucleic acids (DNA, RNA), which leads to the dysfunction of the cells and eventually results in the cell death. In this context, PS which absorb broad region of energy ranging to Near Infrared Region (NIR) is desired as NIR, with better penetration efficiency into deep tissues as compared to visible light. One single review would be inadequate to consolidate all aspects of PDT on its design and efficacy. Each step needs a lot of standardizations and efforts and every step is equally important. This review is an attempt to give a comprehensive overview about the recent advancement in NIR absorbing dyes such as BODIPYs, Keio Fluors, Aza-BODIPY, Chorin, Phthalocyanines, Cyanine dyes, and Nano particles based NIR photosensitizers and their potential in PDT. Herein, we have also given deep insights into the recent trends in this field which emphasizes the potential of this technique to become a first line of treatment for tumours of diverse range.

Background The US Kidney Donor Risk Index (KDRI) and the UK KDRI were developed to estimate the risk of graft failure following kidney transplantation. Neither score has been validated in the Australian and New Zealand (ANZ) population. Methods Using data from the Australia and New Zealand Organ Donor (ANZOD) and Dialysis and Transplant (ANZDATA) Registries, we included all adult deceased donor kidney-only transplants performed in ANZ from 2005 to 2016 (n = 6405). The KDRI was calculated using both the US donor-only and UK formulae. Three Cox models were constructed (Model 1: KDRI only; Model 2: Model 1 + transplant characteristics; Model 3: Model 2 + recipient characteristics) and compared using Harrell’s C-statistics for the outcomes of death-censored graft survival and overall graft survival. Results Both scores were strongly associated with death-censored and overall graft survival (P Conclusions The US and UK KDRI scores were moderately good at discriminating death-censored and overall graft survival in the ANZ population, with the US score performing slightly better in all models.

Study ObjectivesDetermine abnormalities in levels of iron-management proteins in neuronal origin-enriched extracellular vesicles (nEVs) in restless legs syndrome (RLS).MethodsWe used immunoprecipitation for neuronal marker L1CAM to isolate nEVs from the serum of 20 participants with RLS from a study including magnetic resonance imaging (MRI) determinations of iron deposition in the substantia nigra and hematologic parameters and 28 age- and sex-matched Controls.ResultsRLS compared with Control participants showed higher levels of nEV total ferritin but similar levels of transferrin receptor and ferroportin. Western blot analysis showed that heavy- but not light-chain ferritin was increased in nEVs of RLS compared with Control participants. In RLS but not Control participants, nEV total ferritin was positively correlated with systemic iron parameters; the two groups also differed in the relation of nEV total ferritin to MRI measures of iron deposition in substantia nigra.ConclusionsGiven the neuronal origin and diversity of EV cargo, nEVs provide an important platform for exploring the underlying pathophysiology and possible biomarkers of RLS.

Despite decades-long extensive research, probes that provide a comprehensive description of the lipid membrane microenvironment are still lacking. Here, a ``smart'' pyrene-terpyridine probe for multiparametric sensing of lipid membranes is reported. The complexity of the associated local microenvironment can be described by the distinct features of the probe fluorescence. The self-assembly of the probe molecules in phospholipid bilayers was sensitive to membrane order and phase state. The self-assembled probes showed a unique emission, influenced by dye-dye interactions and excited-state charge transfer. Moreover, this emission was sensitive to interfacial hydration, with very specific changes in emission wavelengths and fluorescence lifetimes upon variation of lipid compositions and properties. In parallel, changes in the lipid order and hydration affected the ground-state interactions in the dye aggregates and, thus, could be measured through ratiometric changes in the excitation and emission readouts. In addition, fluorescence anisotropy measurements provided another way to study the nature of dye aggregates in lipid bilayers. Overall, this report demonstrates how multiple aspects of the membrane microenvironment can be sensed through the unique fluorescence signatures of this ``smart'' probe in lipid membranes, and it establishes a new paradigm in lipid-membrane sensing.

Euchromatic histone methyltransferases (EHMTs), members of the KMT1 family, methylate histone and non-histone proteins. Here we uncover a novel role for EHMTs in regulating heterochromatin anchorage to the nuclear periphery (NP) via non-histone (LaminB1) methylations. We show that EHMTs methylates and stabilizes LaminB1 (LMNB1), which associates with the H3K9me2-marked peripheral heterochromatin. Loss of LMNB1 methylation or EHMTs abrogates the heterochromatin anchorage from the NP. We further demonstrate that the loss of EHMTs induces many hallmarks of aging including global reduction of H3K27methyl marks along with altered nuclear-morphology. Consistent with this, we observed a gradual depletion of EHMTs, which correlates with loss of methylated LMNB1 and peripheral heterochromatin in aging human fibroblasts. Restoration of EHMT expression reverts peripheral heterochromatin defect in aged cells. Collectively our work elucidates a new mechanism by which EHMTs regulate heterochromatin domain organization and reveals their impact on fundamental changes associated with the intrinsic aging process.