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1.
Sci Rep ; 14(1): 11051, 2024 05 14.
Article in English | MEDLINE | ID: mdl-38745001

ABSTRACT

Distressing low sexual desire, termed Hypoactive Sexual Desire Disorder (HSDD), affects approximately 10% of women and 8% of men. In women, the 'top-down' theory of HSDD describes hyperactivity in higher-level cognitive brain regions, suppressing lower-level emotional/sexual brain areas. However, it is unknown how this neurofunctional disturbance compares to HSDD in men. To investigate this, we employed task-based functional MRI in 32 women and 32 men with HSDD to measure sexual-brain processing during sexual versus non-sexual videos, as well as psychometric questionnaires to assess sexual desire/arousal. We demonstrate that women had greater activation in higher-level and lower-level brain regions, compared to men. Indeed, women who had greater hypothalamic activation in response to sexual videos, reported higher psychometric scores in the evaluative (r = 0.55, P = 0.001), motivational (r = 0.56, P = 0.003), and physiological (r = 0.57, P = 0.0006) domains of sexual desire and arousal after watching the sexual videos in the scanner. By contrast, no similar correlations were observed in men. Taken together, this is the first direct comparison of the neural correlates of distressing low sexual desire between women and men. The data supports the 'top-down' theory of HSDD in women, whereas in men HSDD appears to be associated with different neurofunctional processes.


Subject(s)
Brain , Libido , Magnetic Resonance Imaging , Sexual Dysfunctions, Psychological , Humans , Female , Male , Adult , Brain/diagnostic imaging , Brain/physiology , Sexual Dysfunctions, Psychological/psychology , Sexual Dysfunctions, Psychological/physiopathology , Libido/physiology , Sex Characteristics , Young Adult , Sexual Behavior/psychology , Sexual Behavior/physiology , Brain Mapping , Surveys and Questionnaires , Middle Aged
2.
ACS Nano ; 18(17): 11311-11322, 2024 Apr 30.
Article in English | MEDLINE | ID: mdl-38623826

ABSTRACT

Hierarchical structure-within-structure assemblies offer a route toward increasingly complex and multifunctional materials while pushing the limits of block copolymer self-assembly. We present a detailed study of the self-assembly of a series of fluorinated high-χ block copolymers (BCPs) prepared via postmodification of a single poly(styrene)-block-poly(glycidyl methacrylate) (S-b-G) parent polymer with the fluorinated alkylthiol pendent groups containing 1, 6, or 8 fluorinated carbons (termed trifluoro-ethanethiol (TFET), perfluoro-octylthiol (PFOT), and perfluoro-decylthiol (PFDT), respectively). Bulk X-ray scattering of thermally annealed samples demonstrates hierarchical molecular assembly with phase separation between the two blocks and within the fluorinated block. The degree of ordering within the fluorinated block is highly sensitive to synthetic variation; a lamellar sublattice was formed for S-b-GPFOT and S-b-GPFDT. Thermal analyses of S-b-GPFOT reveal that the fluorinated block exhibits liquid crystal-like ordering. The complex thin-film self-assembly behavior of an S-b-GPFOT polymer was investigated using real-space (atomic force microscopy and scanning electron microscopy) and reciprocal-space (resonant soft X-ray scattering (RSoXS), grazing incidence small- and wide-angle scattering) measurements. After thermal annealing in nitrogen or vacuum, films thicker than 1.5 times the primary lattice spacing exhibit a 90-degree grain boundary, exposing a thin layer of vertical lamellae at the free interface, while exhibiting horizontal lamellae on the preferential (polystyrene brush) substrate. RSoXS measurements reveal the near-perfect orthogonality between the primary and sublattice orientations, demonstrating hierarchical patterning at the nanoscale.

3.
bioRxiv ; 2024 Mar 14.
Article in English | MEDLINE | ID: mdl-38559113

ABSTRACT

Factors that contribute to durable immunological memory remain incompletely understood. In our longitudinal analyses of CD4+ T cell responses to the yellow fever virus (YFV) vaccine by peptide-MHC tetramers, we unexpectedly found naïve phenotype virus-specific CD4+ T cells that persisted months to years after immunization. These Marker negative T cells (TMN) lacked CD95, CXCR3, CD11a, and CD49d surface protein expression, distinguishing them from previously discovered stem-cell memory T cells. Functionally, they resembled genuine naïve T cells upon in vitro stimulation. Single-cell TCR sequencing detected expanded clonotypes within the TMN subset and identified a shared repertoire with memory and effector T cells. T cells expressing TMN-associated TCRs were rare before vaccination, suggesting their expansion following vaccination. Longitudinal tracking of YFV-specific responses over the subsequent years revealed superior stability of the TMN subset and their association with the longevity of the overall population. The identification of these long-lived, antigen-experienced T cells may inform the design of durable T cell-based vaccines and engineered T cell therapies.

4.
Cureus ; 16(3): e55380, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38562361

ABSTRACT

The female athlete triad is a syndrome occurring in young female athletes defined by menstrual dysfunction, decreased energy availability (EA), and low bone mineral density (BMD). Although the triad includes these three conditions, not all three need to occur simultaneously for the diagnosis to be made. The goal of this review is to analyze published research on the female athlete triad and determine prevention methods in athletics. A review of 23 published sources using the PubMed database identified key recommendations, including education resources, psychological factors, and nutrition. It is recommended that athletes, parents, coaches, and healthcare professionals should learn about the risk factors, warning signs, and diagnosis for better prevention. Research revealed that eating disorders, self-esteem issues, and coach-athlete relationships should be evaluated and potentially managed with counseling. Finally, nutritional recommendations included maintaining EA, providing nutritional counseling, and proper nutritional education. Early intervention with proper education, psychological support, and nutritional management are vital to preventing the onset of the female athlete triad.

5.
Proc Natl Acad Sci U S A ; 121(9): e2313617121, 2024 Feb 27.
Article in English | MEDLINE | ID: mdl-38377215

ABSTRACT

Additive manufacturing capable of controlling and dynamically modulating structures down to the nanoscopic scale remains challenging. By marrying additive manufacturing with self-assembly, we develop a UV (ultra-violet)-assisted direct ink write approach for on-the-fly modulation of structural color by programming the assembly kinetics through photo-cross-linking. We design a photo-cross-linkable bottlebrush block copolymer solution as a printing ink that exhibits vibrant structural color (i.e., photonic properties) due to the nanoscopic lamellar structures formed post extrusion. By dynamically modulating UV-light irradiance during printing, we can program the color of the printed material to access a broad spectrum of visible light with a single ink while also creating color gradients not previously possible. We unveil the mechanism of this approach using a combination of coarse-grained simulations, rheological measurements, and structural characterizations. Central to the assembly mechanism is the matching of the cross-linking timescale with the assembly timescale, which leads to kinetic trapping of the assembly process that evolves structural color from blue to red driven by solvent evaporation. This strategy of integrating cross-linking chemistry and out-of-equilibrium processing opens an avenue for spatiotemporal control of self-assembled nanostructures during additive manufacturing.

6.
Endocr Rev ; 45(1): 30-68, 2024 Jan 04.
Article in English | MEDLINE | ID: mdl-37467734

ABSTRACT

Kisspeptin (KP) and neurokinin B (NKB) are neuropeptides that govern the reproductive endocrine axis through regulating hypothalamic gonadotropin-releasing hormone (GnRH) neuronal activity and pulsatile GnRH secretion. Their critical role in reproductive health was first identified after inactivating variants in genes encoding for KP or NKB signaling were shown to result in congenital hypogonadotropic hypogonadism and a failure of pubertal development. Over the past 2 decades since their discovery, a wealth of evidence from both basic and translational research has laid the foundation for potential therapeutic applications. Beyond KP's function in the hypothalamus, it is also expressed in the placenta, liver, pancreas, adipose tissue, bone, and limbic regions, giving rise to several avenues of research for use in the diagnosis and treatment of pregnancy, metabolic, liver, bone, and behavioral disorders. The role played by NKB in stimulating the hypothalamic thermoregulatory center to mediate menopausal hot flashes has led to the development of medications that antagonize its action as a novel nonsteroidal therapeutic agent for this indication. Furthermore, the ability of NKB antagonism to partially suppress (but not abolish) the reproductive endocrine axis has supported its potential use for the treatment of various reproductive disorders including polycystic ovary syndrome, uterine fibroids, and endometriosis. This review will provide a comprehensive up-to-date overview of the preclinical and clinical data that have paved the way for the development of diagnostic and therapeutic applications of KP and NKB.


Subject(s)
Kisspeptins , Neurokinin B , Pregnancy , Female , Humans , Neurokinin B/genetics , Neurokinin B/metabolism , Kisspeptins/therapeutic use , Gonadotropin-Releasing Hormone/metabolism , Reproduction/physiology , Hypothalamus
7.
J Gynecol Oncol ; 35(2): e19, 2024 Mar.
Article in English | MEDLINE | ID: mdl-37921603

ABSTRACT

OBJECTIVE: To study clinical characters and outcomes in patients of malignant ovarian germ cell tumor (MOGCT) undergoing surgery following neoadjuvant chemotherapy (NACT). METHODS: Retrospective study of patients undergoing surgery following NACT for MOGCT at our institute. Platinum based chemotherapy was given in all patients in NACT. RESULTS: Between March 2013 and February 2023, 30 patients had surgery after NACT. Patient's median age was 22 years (range, 12 to 35 years) and median follow up 42months (range, 6 to 132 months). Majority had endodermal sinus tumor (n=12), dysgerminoma (n=9) and mixed GCT (n=7). All had either International Federation of Gynecology and Obstetrics (FIGO) stage 3 (n=19) or FIGO stage 4 disease (n=11). Complete response to NACT seen in 5 patients and 23 patients had partial response. Fertility sparing surgery in 18 patients and complete surgery in 12 patients. Suboptimal surgery was seen in 4 patients. Currently, 20 of 30 patients are alive and disease free, 3 lost for follow up and 7 patients had progression after adjuvant therapy. Five patients had mortality-4 with progression and 1 with bleomycin toxicity. Fifteen of 17 eligible patients have resumed menstruation and one had successful pregnancy. Prognostic factors noted in study are stage, optimal surgery and viable tumor in histopathology. Dysgerminoma had better outcome than other histology. CONCLUSION: NACT may be a reasonable option in patients with extensive unresectable disease or in whom fertility sparing is not possible or in the poor general condition. Fertility sparing surgery can be attempted post neoadjuvant chemotherapy without adversely affecting prognosis.


Subject(s)
Dysgerminoma , Neoplasms, Germ Cell and Embryonal , Ovarian Neoplasms , Pregnancy , Female , Humans , Young Adult , Adult , Neoadjuvant Therapy , Dysgerminoma/drug therapy , Dysgerminoma/etiology , Dysgerminoma/pathology , Retrospective Studies , Chemotherapy, Adjuvant/adverse effects , Neoplasm Staging , Ovarian Neoplasms/pathology , Neoplasms, Germ Cell and Embryonal/drug therapy , Neoplasms, Germ Cell and Embryonal/etiology , Neoplasms, Germ Cell and Embryonal/pathology
8.
PLoS One ; 18(9): e0291766, 2023.
Article in English | MEDLINE | ID: mdl-37738272

ABSTRACT

Tissue engineering has driven significant research in the strive to create a supply of tissues for patient treatment. Cell integration into engineered tissues maximizes functional capabilities, however, issues of rejection remain. Autologous cell sources able to solve this issue are difficult to identify for tissue engineering purposes. Here, we present the efficacy of patient-sourced cells derived from adipose (adipose-derived stem cells, ASCs) and skin tissue (dermal fibroblasts, PtFibs) to build a combined engineered tunica media and adventitia graft, respectively. Patient cells were integrated into our lab's vascular tissue engineering technique of forming vascular rings that are stacked into a tubular structure to create the vascular graft. For the media layer, ASCs were successfully differentiated into the smooth muscle phenotype using angiotensin II followed by culture in smooth muscle growth factors, evidenced by significantly increased expression of αSMA and myosin light chain kinase. Engineered media vessels composed of differentiated ASCs (ASC-SMCs) exhibited an elastic modulus (45.2 ± 18.9 kPa) between that of vessels of undifferentiated ASCs (71.8 ± 35.3 kPa) and control human aortic smooth muscle cells (HASMCs; 18.7 ± 5.49 kPa) (p<0.5). Tensile strength of vessels composed of ASCs (41.3 ± 15.7 kPa) and ASC-SMCs (37.3 ± 17.0 kPa) were higher compared to vessels of HASMCs (28.4 ± 11.2 kPa). ASC-based tissues exhibited a significant increase in collagen content and fiber maturity- both factors contribute to tissue strength and stability. Furthermore, vessels gained stability and a more-uniform single-tubular shape with longer-term 1-month culture. This work demonstrates efficacy of ASCs and PtFibs to create patient-specific vessels.


Subject(s)
Adventitia , Tunica Media , Humans , Aorta , Collagen , Stem Cells
10.
JAMA Netw Open ; 6(2): e2254313, 2023 02 01.
Article in English | MEDLINE | ID: mdl-36735255

ABSTRACT

Importance: The human physiological sexual response is crucial for reward, satisfaction, and reproduction. Disruption of the associated neurophysiological pathways predisposes to low sexual desire; the most prevalent psychological form is hypoactive sexual desire disorder (HSDD), which affects 8% of men but currently has no effective pharmacological treatment options. The reproductive neuropeptide kisspeptin offers a putative therapeutic target, owing to emerging understanding of its role in reproductive behavior. Objective: To determine the physiological, behavioral, neural, and hormonal effects of kisspeptin administration in men with HSDD. Design, Setting, and Participants: This double-blind, 2-way crossover, placebo-controlled randomized clinical trial was performed at a single academic research center in the UK. Eligible participants were right-handed heterosexual men with HSDD. Physiological, behavioral, functional magnetic resonance imaging (fMRI), and hormonal analyses were used to investigate the clinical and mechanistic effects of kisspeptin administration in response to visual sexual stimuli (short and long video tasks). The trial was conducted between January 11 and September 15, 2021, and data analysis was performed between October and November 2021. Interventions: Participants attended 2 study visits at least 7 days apart, in balanced random order, for intravenous infusion of kisspeptin-54 (1 nmol/kg/h) for 75 minutes or for administration of a rate-matched placebo. Main Outcomes and Measures: Changes in (1) brain activity on whole-brain analysis, as determined by fMRI blood oxygen level-dependent activity in response to visual sexual stimuli during kisspeptin administration compared with placebo, (2) physiological sexual arousal (penile tumescence), and (3) behavioral measures of sexual desire and arousal. Results: Of the 37 men randomized, 32 completed the trial. Participants had a mean (SD) age of 37.9 (8.6) years and a mean (SD) body mass index of 24.9 (5.4). On viewing sexual videos, kisspeptin significantly modulated brain activity in key structures of the sexual-processing network on whole-brain analysis compared with placebo (mean absolute change [Cohen d] = 0.81 [95% CI, 0.41-1.21]; P = .003). Furthermore, improvements in several secondary analyses were observed, including significant increases in penile tumescence in response to sexual stimuli (by up to 56% more than placebo; mean difference = 0.28 units [95% CI, 0.04-0.52 units]; P = .02) and behavioral measures of sexual desire-most notably, increased happiness about sex (mean difference = 0.63 points [95% CI, 0.10-1.15 points]; P = .02). Conclusions and Relevance: Collectively, this randomized clinical trial provides the first evidence to date showing that kisspeptin administration substantially modulates sexual brain processing in men with HSDD, with associated increases in penile tumescence and behavioral measures of sexual desire and arousal. These data suggest that kisspeptin has potential as the first pharmacological treatment for men with low sexual desire. Trial Registration: isrctn.org Identifier: ISRCTN17271094.


Subject(s)
Penile Erection , Sexual Dysfunctions, Psychological , Male , Humans , Adult , Kisspeptins/pharmacology , Kisspeptins/therapeutic use , Sexual Behavior , Sexual Dysfunctions, Psychological/drug therapy , Brain/diagnostic imaging
12.
Front Endocrinol (Lausanne) ; 13: 951938, 2022.
Article in English | MEDLINE | ID: mdl-36479214

ABSTRACT

Feedback from oestradiol (E2) plays a critical role in the regulation of major events in the physiological menstrual cycle including the release of gonadotrophins to stimulate follicular growth, and the mid-cycle luteinising hormone (LH) surge that leads to ovulation. E2 predominantly exerts its action via oestrogen receptor-alpha (ERα), however, as gonadotrophin releasing hormone (GnRH) neurons lack ERα, E2-feedback is posited to be indirectly mediated via upstream neurons. Kisspeptin (KP) is a neuropeptide expressed in hypothalamic KP-neurons that control GnRH secretion and plays a key role in the central mechanism regulating the hypothalamic-pituitary-gonadal (HPG) axis. In the rodent arcuate (ARC) nucleus, KP is co-expressed with Neurokinin B and Dynorphin; and thus, these neurons are termed 'Kisspeptin-Neurokinin B-Dynorphin' (KNDy) neurons. ARC KP-neurons function as the 'GnRH pulse generator' to regulate GnRH pulsatility, as well as mediating negative feedback from E2. A second KP neuronal population is present in the rostral periventricular area of the third ventricle (RP3V), which includes anteroventral periventricular (AVPV) nucleus and preoptic area neurons. These RP3V KP-neurons mediate positive feedback to induce the mid-cycle luteinising hormone (LH) surge and subsequent ovulation. Here, we describe the role of KP-neurons in these two regions in mediating this differential feedback from oestrogens. We conclude by considering reproductive diseases for which exploitation of these mechanisms could yield future therapies.


Subject(s)
Kisspeptins , Neurokinin B , Dynorphins , Luteinizing Hormone , Gonadotropin-Releasing Hormone , Neurons
13.
J Clin Invest ; 132(19)2022 10 03.
Article in English | MEDLINE | ID: mdl-36189794

ABSTRACT

BACKGROUNDHypoactive sexual desire disorder (HSDD) is characterized by a persistent deficiency of sexual fantasies and desire for sexual activity, causing marked distress and interpersonal difficulty. It is the most prevalent female sexual health problem globally, affecting approximately 10% of women, but has limited treatment options. Melanocortin 4 receptor (MC4R) agonists have emerged as a promising therapy for women with HSDD, through unknown mechanisms. Studying the pathways involved is crucial for our understanding of normal and abnormal sexual behavior.METHODSUsing psychometric, functional neuroimaging, and hormonal analyses, we conducted a randomized, double-blinded, placebo-controlled, crossover clinical study to assess the effects of MC4R agonism compared with placebo on sexual brain processing in 31 premenopausal heterosexual women with HSDD.RESULTSMC4R agonism significantly increased sexual desire for up to 24 hours after administration compared with placebo. During functional neuroimaging, MC4R agonism enhanced cerebellar and supplementary motor area activity and deactivated the secondary somatosensory cortex, specifically in response to visual erotic stimuli, compared with placebo. In addition, MC4R agonism enhanced functional connectivity between the amygdala and the insula during visual erotic stimuli compared with placebo.CONCLUSIONThese data suggest that MC4R agonism enhanced sexual brain processing by reducing self-consciousness, increasing sexual imagery, and sensitizing women with HSDD to erotic stimuli. These findings provide mechanistic insight into the action of MC4R agonism in sexual behavior and are relevant to the ongoing development of HSDD therapies and MC4R agonist development more widely.TRIAL REGISTRATIONClinicalTrials.gov NCT04179734.FUNDINGThis is an investigator-sponsored study funded by AMAG Pharmaceuticals Inc., the Medical Research Council (MRC) (MR/T006242/1), and the National Institute for Health Research (NIHR) (CS-2018-18-ST2-002 and RP-2014-05-001).


Subject(s)
Receptor, Melanocortin, Type 4 , Sexual Dysfunctions, Psychological , Brain/diagnostic imaging , Female , Humans , Interleukin-1 Receptor-Like 1 Protein , Sexual Behavior , Sexual Dysfunctions, Psychological/drug therapy
14.
ACS Polym Au ; 2(4): 232-244, 2022 Aug 10.
Article in English | MEDLINE | ID: mdl-35971423

ABSTRACT

Bottlebrush polymers are a class of semiflexible, hierarchical macromolecules with unique potential for shape-, architecture-, and composition-based structure-property design. It is now well-established that in dilute to semidilute solution, bottlebrush homopolymers adopt a wormlike conformation, which decreases in extension (persistence length) as the concentration and molecular overlap increase. By comparison, the solution phase self-assembly of bottlebrush diblock copolymers (BBCP) in a good solvent remains poorly understood, despite critical relevance for solution processing of ordered phases and photonic crystals. In this work, we combine small-angle X-ray scattering, coarse-grained simulation, and polymer synthesis to map the equilibrium phase behavior and conformation of a set of large, nearly symmetric PS-b-PLA bottlebrush diblock copolymers in toluene. Three BBCP are synthesized, with side chains of number-averaged molecular weights of 4500 (PS) and 4200 g/mol (PLA) and total backbone degrees of polymerization of 100, 255, and 400 repeat units. The grafting density is one side chain per backbone repeat unit. With increasing concentration in solution, all three polymers progress through a similar structural transition: from dispersed, wormlike chains with concentration-dependent (decreasing) extension, through the onset of disordered PS/PLA compositional fluctuations, to the formation of a long-range ordered lamellar phase. With increasing concentration in the microphase-separated regimes, the domain spacing increases as individual chains partially re-extend due to block immiscibility. Increases in the backbone degree of polymerization lead to changes in the scattering profiles which are consistent with the increased segregation strength. Coarse-grained simulations using an implicit side-chain model are performed, and concentration-dependent self-assembly behavior is qualitatively matched to experiments. Finally, using the polymer with the largest backbone length, we demonstrate that lamellar phases develop a well-defined photonic band gap in solution, which can be tuned across the visible spectrum by varying polymer concentration.

15.
Front Endocrinol (Lausanne) ; 13: 942664, 2022.
Article in English | MEDLINE | ID: mdl-35928889

ABSTRACT

Kisspeptin and its receptor are central to reproductive health acting as key regulators of the reproductive endocrine axis in humans. Kisspeptin is most widely recognised as a regulator of gonadotrophin releasing hormone (GnRH) neuronal function. However, recent evidence has demonstrated that kisspeptin and its receptor also play a fundamental role during pregnancy in the regulation of placentation. Kisspeptin is abundantly expressed in syncytiotrophoblasts, and its receptor in both cyto- and syncytio-trophoblasts. Circulating levels of kisspeptin rise dramatically during healthy pregnancy, which have been proposed as having potential as a biomarker of placental function. Indeed, alterations in kisspeptin levels are associated with an increased risk of adverse maternal and foetal complications. This review summarises data evaluating kisspeptin's role as a putative biomarker of pregnancy complications including miscarriage, ectopic pregnancy (EP), preterm birth (PTB), foetal growth restriction (FGR), hypertensive disorders of pregnancy (HDP), pre-eclampsia (PE), gestational diabetes mellitus (GDM), and gestational trophoblastic disease (GTD).


Subject(s)
Kisspeptins , Placenta , Pregnancy Complications , Biomarkers/metabolism , Female , Humans , Kisspeptins/physiology , Placenta/physiology , Placenta/physiopathology , Pre-Eclampsia/physiopathology , Pregnancy , Pregnancy Complications/physiopathology , Premature Birth/physiopathology
16.
Adv Mater ; 34(32): e2203055, 2022 Aug.
Article in English | MEDLINE | ID: mdl-35724384

ABSTRACT

Tuning structures of solution-state aggregation and aggregation-mediated assembly pathways of conjugated polymers is crucial for optimizing their solid-state morphology and charge-transport property. However, it remains challenging to unravel and control the exact structures of solution aggregates, let alone to modulate assembly pathways in a controlled fashion. Herein, aggregate structures of an isoindigo-bithiophene-based polymer (PII-2T) are modulated by tuning selectivity of the solvent toward the side chain versus the backbone, which leads to three distinct assembly pathways: direct crystallization from side-chain-associated amorphous aggregates, chiral liquid crystal (LC)-mediated assembly from semicrystalline aggregates with side-chain and backbone stacking, and random agglomeration from backbone-stacked semicrystalline aggregates. Importantly, it is demonstrated that the amorphous solution aggregates, compared with semicrystalline ones, lead to significantly improved alignment and reduced paracrystalline disorder in the solid state due to direct crystallization during the meniscus-guided coating process. Alignment quantified by the dichroic ratio is enhanced by up to 14-fold, and the charge-carrier mobility increases by a maximum of 20-fold in films printed from amorphous aggregates compared to those from semicrystalline aggregates. This work shows that by tuning the precise structure of solution aggregates, the assembly pathways and the resulting thin-film morphology and device properties can be drastically tuned.

17.
Nat Commun ; 13(1): 2738, 2022 05 18.
Article in English | MEDLINE | ID: mdl-35585050

ABSTRACT

Intimately connected to the rule of life, chirality remains a long-time fascination in biology, chemistry, physics and materials science. Chiral structures, e.g., nucleic acid and cholesteric phase developed from chiral molecules are common in nature and synthetic soft materials. While it was recently discovered that achiral but bent-core mesogens can also form chiral helices, the assembly of chiral microstructures from achiral polymers has rarely been explored. Here, we reveal chiral emergence from achiral conjugated polymers, in which hierarchical helical structures are developed through a multistep assembly pathway. Upon increasing concentration beyond a threshold volume fraction, dispersed polymer nanofibers form lyotropic liquid crystalline (LC) mesophases with complex, chiral morphologies. Combining imaging, X-ray and spectroscopy techniques with molecular simulations, we demonstrate that this structural evolution arises from torsional polymer molecules which induce multiscale helical assembly, progressing from nano- to micron scale helical structures as the solution concentration increases. This study unveils a previously unknown complex state of matter for conjugated polymers that can pave way to a field of chiral (opto)electronics. We anticipate that hierarchical chiral helical structures can profoundly impact how conjugated polymers interact with light, transport charges, and transduce signals from biomolecular interactions and even give rise to properties unimagined before.


Subject(s)
Liquid Crystals , Polymers , Liquid Crystals/chemistry , Polymers/chemistry , Stereoisomerism
19.
Clin Endocrinol (Oxf) ; 97(2): 156-164, 2022 08.
Article in English | MEDLINE | ID: mdl-35262967

ABSTRACT

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age and is the leading cause of anovulatory subfertility. Increased gonadotrophin releasing hormone (GnRH) pulsatility in the hypothalamus results in preferential luteinizing hormone (LH) secretion from the pituitary gland, leading to ovarian hyperandrogenism and oligo/anovulation. The resultant hyperandrogenism reduces negative feedback from sex steroids such as oestradiol and progesterone to the hypothalamus, and thus perpetuates the increase in GnRH pulsatility. GnRH neurons do not have receptors for oestrogen, progesterone, or androgens, and thus the disrupted feedback is hypothesized to occur via upstream neurons. Likely candidates for these upstream regulators of GnRH neuronal pulsatility are Kisspeptin, Neurokinin B (NKB), and Dynorphin neurons (termed KNDy neurons). Growing insight into the neuroendocrine dysfunction underpinning the heightened GnRH pulsatility seen in PCOS has led to research on the use of pharmaceutical agents that specifically target the activity of these KNDy neurons to attenuate symptoms of PCOS. This review aims to highlight the neuroendocrine abnormalities that lead to increased GnRH pulsatility in PCOS, and outline data on recent therapeutic advancements that could potentially be used to treat PCOS. Emerging evidence has investigated the use of neurokinin 3 receptor (NK3R) antagonists as a method of reducing GnRH pulsatility and alleviating features of PCOS such as hyperandrogenism. We also consider other potential mechanisms by which increased GnRH pulsatility is controlled, which could form the basis of future avenues of research.


Subject(s)
Hyperandrogenism , Polycystic Ovary Syndrome , Female , Gonadotropin-Releasing Hormone , Humans , Hyperandrogenism/drug therapy , Kisspeptins , Luteinizing Hormone , Polycystic Ovary Syndrome/drug therapy , Progesterone
20.
Soft Matter ; 18(8): 1666-1677, 2022 Feb 23.
Article in English | MEDLINE | ID: mdl-35133377

ABSTRACT

Favorable polymer-substrate interactions induce surface orientation fields in block copolymer (BCP) melts. In linear BCP processed near equilibrium, alignment of domains generally persists for a small number of periods (∼4-6 D0) before randomization of domain orientation. Bottlebrush BCP are an emerging class of materials with distinct chain dynamics stemming from substantial molecular rigidity, enabling rapid assembly at ultrahigh (>100 nm) domain periodicities with strong photonic properties (structural color). This work assesses interface-induced ordering in PS-b-PLA bottlebrush diblock copolymer films during thermal annealing between planar surfaces. To clearly observe the decay in orientational order from surface to bulk, we choose to study micron-scale films spanning greater than 200 lamellar periods. In situ optical microscopy and transmission UV-Vis spectroscopy are used to monitor photonic properties during annealing and paired with ex situ UV-Vis reflection measurement, cross-sectional scanning electron microscopy (SEM), and small-angle X-ray scattering (SAXS) to probe the evolution of domain microstructure. Photonic properties were observed to saturate within minutes of annealing at 150 °C, with distinct variation in transmission response as a function of film thickness. The depth of the highly aligned surface region was found to vary stochastically in the range of 30-100 lamellar periods, with the sharpness of the orientation gradient decreasing substantially with increasing film thickness. This observation suggests a competition between growth of aligned, heterogeneously nucleated, grains at the surface and orientationally isotropic, homogeneously nucleated, grains throughout the bulk. This work demonstrates the high potential of bottlebrush block copolymers in rapid fabrication workflows and provides a point of comparison for future application of directed self-assembly to BBCP ordering.

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