Observations towards a proof of the Collatz conjecture using 2jk+x2^{j}k+x number series

The document tries to put focus on sequences with certain properties and periods leading to the first value smaller than the starting value in the Collatz problem. With the idea that, if all starting numbers lead ultimately to a smaller number, all full sequences lead to 1 with a finite stopping time, the problem could be reduced to more structured shorter sequences. It is shown that this sequences exist and follow consistent rules. Potential features of an infinite cycle, also leading to a smaller number, are also discussed.Comment: 6 pages, 4 figure

Substance P and Alpha-Calcitonin Gene-Related Peptide Differentially Affect Human Osteoarthritic and Healthy Chondrocytes

Osteoarthritis (OA) is a degenerative joint disease that not only causes cartilage loss but also structural damage in all joint tissues. Joints are innervated by alpha-calcitonin gene-related peptide (αCGRP) and substance P (SP)-positive sensory nerve fibers. Alteration of sensory joint innervation could be partly responsible for degenerative changes in joints that contribute to the development of OA. Therefore, our aim was to analyze and compare the molecular effects of SP and αCGRP on the metabolism of articular chondrocytes from OA patients and non-OA cartilage donors. We treated the cells with SP or αCGRP and analysed the influence of these neuropeptides on chondrocyte metabolism and modulation of signaling pathways. In chondrocytes from healthy cartilage, SP had minimal effects compared with its effects on OA chondrocytes, where it induced inflammatory mediators, inhibited chondrogenic markers and promoted apoptosis and senescence. Treatment with αCGRP also increased apoptosis and senescence and reduced chondrogenic marker expression in OA chondrocytes, but stimulated an anabolic and protective response in healthy chondrocytes. The catabolic influence of SP and αCGRP might be due to activation of ERK signaling that could be counteracted by an increased cAMP response. We suggest that a switch between the G-subunits of the corresponding receptors after binding their ligands SP or αCGRP plays a central role in mediating the observed effects of sensory neuropeptides on chondrocytes

'It's because I like things… it's a status and he buys me airtime': exploring the role of transactional sex in young women's consumption patterns in rural South Africa (secondary findings from HPTN 068).

BACKGROUND: 'Transactional sex', defined as a non-marital, non-commercial sexual relationship in which money or material goods are exchanged for sex, is associated with young women's increased vulnerability to HIV infection. Existing research illustrates that the motivations for transactional sex are complex. The fulfilment of psycho-social needs such as the need to belong to a peer group are important factors underlying young women's desires to obtain certain consumption items and thus engage in transactional sex. METHODS: We use a mixed-methods approach to explore the relationship between transactional sex and consumption patterns among young women in rural Mpumalanga province, South Africa. In the secondary analysis of 693 sexually active young women, we use factor analysis to group the different consumption items and we use multivariable logistic regression to demonstrate the relationship between transactional sex and consumption patterns. The qualitative study uses five focus group discussions and 19 in-depth interviews to explore further young women's motivations for acquiring different consumption items. RESULTS: The quantitative results show that young women that engage in transactional sex have higher odds of consuming items for entertainment (e.g., movie tickets) than on practical items (e.g., food and groceries). The qualitative findings also revealed that young women's perceptions of items that were considered a 'need' were strongly influenced by peer pressure and a desire for improved status. Further, there was a perception that emerged from the qualitative data that relationships with sugar daddies offered a way to acquire consumer goods associated with a 'modern lifestyle', such as items for personal enhancement and entertainment. However, young women seem aware of the risks associated with such relationships. More importantly, they also develop relationship with partners of similar age, albeit with the continued expectation of material exchange, despite engaging in the relationship for love. CONCLUSION: This study shows that young women are willing to take certain risks in order to have a degree of financial independence. Interventions that provide alternative methods of attaining this independence, such as the provision of cash transfers may have potential in preventing them from engaging in transactional relationships. Further, the psycho-social reasons that drive young women's motivations for consumption items resulting in risky sexual behaviours need to be better understood

Insights into replicative senescence of human testicular peritubular cells

There is evidence for an age-related decline in male reproductive functions, yet how the human testis may age is not understood. Human testicular peritubular cells (HTPCs) transport sperm, contribute to the spermatogonial stem cell (SSC) niche and immune surveillance, and can be isolated and studied in vitro. Consequences of replicative senescence of HTPCs were evaluated to gain partial insights into human testicular aging. To this end, early and advanced HTPC passages, in which replicative senescence was indicated by increased cell size, altered nuclear morphology, enhanced beta-galactosidase activity, telomere attrition and reduced mitochondrial DNA (mtDNA), were compared. These alterations are typical for senescent cells, in general. To examine HTPC-specific changes, focused ion beam scanning electron microscopy (FIB/SEM) tomography was employed, which revealed a reduced mitochondrial network and an increased lysosome population. The results coincide with the data of a parallel proteomic analysis and indicate deranged proteostasis. The mRNA levels of typical contractility markers and growth factors, important for the SSC niche, were not significantly altered. A secretome analysis identified, however, elevated levels of macrophage migration inhibitory factor (MIF) and dipeptidyl peptidase 4 (DPP4), which may play a role in spermatogenesis. Testicular DPP4 may further represent a possible drug target

Inhibitory NKG2A⁺ and absent activating NKG2C⁺ NK cell responses are associated with the development of EBV⁺ lymphomas

Epstein-Barr virus (EBV) is a ubiquitous herpesvirus, which infects over 90% of the adult human population worldwide. After primary infections, EBV is recurrently reactivating in most adult individuals. It is, however, unclear, why these EBV reactivations progress to EBV+ Hodgkin (EBV+HL) or non-Hodgkin lymphomas (EBV+nHL) only in a minority of EBV-infected individuals. The EBV LMP-1 protein encodes for a highly polymorphic peptide, which upregulates the immunomodulatory HLA-E in EBV-infected cells, thereby stimulating the inhibitory NKG2A-, but also the activating NKG2C-receptor on natural killer (NK) cells. Using a genetic-association approach and functional NK cell analyses, we now investigated, whether these HLA-E-restricted immune responses impact the development of EBV+HL and EBV+nHL. Therefore, we recruited a study cohort of 63 EBV+HL and EBV+nHL patients and 192 controls with confirmed EBV reactivations, but without lymphomas. Here, we demonstrate that in EBV+ lymphoma patients exclusively the high-affine LMP-1 GGDPHLPTL peptide variant-encoding EBV-strains reactivate. In EBV+HL and EBV+nHL patients, the high-expressing HLA-E*0103/0103 genetic variant was significantly overrepresented. Combined, the LMP-1 GGDPHLPTL and HLA-E*0103/0103 variants efficiently inhibited NKG2A+ NK cells, thereby facilitating the in vitro spread of EBV-infected tumor cells. In addition, EBV+HL and EBV+nHL patients, showed impaired pro-inflammatory NKG2C+ NK cell responses, which accelerated the in vitro EBV-infected tumor cells spread. In contrast, the blocking of NKG2A by monoclonal antibodies (Monalizumab) resulted in efficient control of EBV-infected tumor cell growth, especially by NKG2A+NKG2C+ NK cells. Thus, the HLA-E/LMP-1/NKG2A pathway and individual NKG2C+ NK cell responses are associated with the progression toward EBV+ lymphomas.</p

Interventions that prevent or respond to intimate partner violence against women and violence against children: a systematic review.

Efforts to prevent or respond to intimate partner violence (IPV) and violence against children (VAC) are still disparate worldwide, despite increasing evidence of intersections across these forms of violence. We conducted a systematic review to explore interventions that prevent or respond to IPV and VAC by parents or caregivers, aiming to identify common intervention components and mechanisms that lead to a reduction in IPV and VAC. 30 unique interventions from 16 countries were identified, with 20 targeting both IPV and VAC. Key mechanisms for reducing IPV and VAC in primary prevention interventions included improved communication, conflict resolution, reflection on harmful gender norms, and awareness of the adverse consequences of IPV and VAC on children. Therapeutic programmes for women and children who were exposed to IPV facilitated engagement with IPV-related trauma, increased awareness of the effects of IPV, and promoted avoidance of unhealthy relationships. Evidence gaps in low-income and middle-income countries involved adolescent interventions, post-abuse interventions for women and children, and interventions addressing both prevention and response to IPV and VAC. Our findings strengthen evidence in support of efforts to address IPV and VAC through coordinated prevention and response programmes. However, response interventions for both IPV and VAC are rare and predominantly implemented in high-income countries. Although therapeutic programmes for parents, caregivers, and children in high-income countries are promising, their feasibility in low-income and middle-income countries remains uncertain. Despite this uncertainty, there is potential to improve the use of health services to address IPV and VAC together

Extracellular Vesicles Derived from Osteogenic-Differentiated Human Bone Marrow-Derived Mesenchymal Cells Rescue Osteogenic Ability of Bone Marrow-Derived Mesenchymal Cells Impaired by Hypoxia

In orthopedics, musculoskeletal disorders, i.e., non-union of bone fractures or osteoporosis, can have common histories and symptoms related to pathological hypoxic conditions induced by aging, trauma or metabolic disorders. Here, we observed that hypoxic conditions (2% O2) suppressed the osteogenic differentiation of human bone marrow-derived mesenchymal cells (hBMSC) in vitro and simultaneously increased reactive oxygen species (ROS) production. We assumed that cellular origin and cargo of extracellular vesicles (EVs) affect the osteogenic differentiation capacity of hBMSCs cultured under different oxygen pressures. Proteomic analysis revealed that EVs isolated from osteogenic differentiated hBMSC cultured under hypoxia (hypo-osteo EVs) or under normoxia (norm-osteo EVs) contained distinct protein profiles. Extracellular matrix (ECM) components, antioxidants and pro-osteogenic proteins were decreased in hypo-osteo EVs. The proteomic analysis in our previous study revealed that under normoxic culture conditions, pro-osteogenic proteins and ECM components have higher concentrations in norm-osteo EVs than in EVs derived from naïve hBMSCs (norm-naïve EVs). When selected for further analysis, five anti-hypoxic proteins were significantly upregulated (response to hypoxia) in norm-osteo EVs. Three of them are characterized as antioxidant proteins. We performed qRT-PCR to verify the corresponding gene expression levels in the norm-osteo EVs’ and norm-naïve EVs’ parent cells cultured under normoxia. Moreover, we observed that norm-osteo EVs rescued the osteogenic ability of naïve hBMSCs cultured under hypoxia and reduced hypoxia-induced elevation of ROS production in osteogenic differentiated hBMSCs, presumably by inducing expression of anti-hypoxic/ antioxidant and pro-osteogenic genes

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

'It’s because I like things… it’s a status and he buys me airtime': exploring the role of transactional sex in young women’s consumption patterns in rural South Africa (secondary findings from HPTN 068)

Abstract: Background ‘Transactional sex’, defined as a non-marital, non-commercial sexual relationship in which money or material goods are exchanged for sex, is associated with young women’s increased vulnerability to HIV infection. Existing research illustrates that the motivations for transactional sex are complex. The fulfilment of psycho-social needs such as the need to belong to a peer group are important factors underlying young women’s desires to obtain certain consumption items and thus engage in transactional sex. Methods We use a mixed-methods approach to explore the relationship between transactional sex and consumption patterns among young women in rural Mpumalanga province, South Africa. In the secondary analysis of 693 sexually active young women, we use factor analysis to group the different consumption items and we use multivariable logistic regression to demonstrate the relationship between transactional sex and consumption patterns. The qualitative study uses five focus group discussions and 19 in-depth interviews to explore further young women’s motivations for acquiring different consumption items. Results The quantitative results show that young women that engage in transactional sex have higher odds of consuming items for entertainment (e.g., movie tickets) than on practical items (e.g., food and groceries). The qualitative findings also revealed that young women’s perceptions of items that were considered a ‘need’ were strongly influenced by peer pressure and a desire for improved status. Further, there was a perception that emerged from the qualitative data that relationships with sugar daddies offered a way to acquire consumer goods associated with a ‘modern lifestyle’, such as items for personal enhancement and entertainment. However, young women seem aware of the risks associated with such relationships. More importantly, they also develop relationship with partners of similar age, albeit with the continued expectation of material exchange, despite engaging in the relationship for love. Conclusion This study shows that young women are willing to take certain risks in order to have a degree of financial independence. Interventions that provide alternative methods of attaining this independence, such as the provision of cash transfers may have potential in preventing them from engaging in transactional relationships. Further, the psycho-social reasons that drive young women’s motivations for consumption items resulting in risky sexual behaviours need to be better understood

A genome-wide association meta-analysis on apolipoprotein A-IV concentrations.

Apolipoprotein A-IV (apoA-IV) is a major component of HDL and chylomicron particles and is involved in reverse cholesterol transport. It is an early marker of impaired renal function. We aimed to identify genetic loci associated with apoA-IV concentrations and to investigate relationships with known susceptibility loci for kidney function and lipids. A genome-wide association meta-analysis on apoA-IV concentrations was conducted in five population-based cohorts (n = 13,813) followed by two additional replication studies (n = 2,267) including approximately 10 M SNPs. Three independent SNPs from two genomic regions were significantly associated with apoA-IV concentrations: rs1729407 near APOA4 (P = 6.77 × 10 (-)  (44)), rs5104 in APOA4 (P = 1.79 × 10(-)(24)) and rs4241819 in KLKB1 (P = 5.6 × 10(-)(14)). Additionally, a look-up of the replicated SNPs in downloadable GWAS meta-analysis results was performed on kidney function (defined by eGFR), HDL-cholesterol and triglycerides. From these three SNPs mentioned above, only rs1729407 showed an association with HDL-cholesterol (P = 7.1 × 10 (-)  (07)). Moreover, weighted SNP-scores were built involving known susceptibility loci for the aforementioned traits (53, 70 and 38 SNPs, respectively) and were associated with apoA-IV concentrations. This analysis revealed a significant and an inverse association for kidney function with apoA-IV concentrations (P = 5.5 × 10(-)(05)). Furthermore, an increase of triglyceride-increasing alleles was found to decrease apoA-IV concentrations (P = 0.0078). In summary, we identified two independent SNPs located in or next the APOA4 gene and one SNP in KLKB1 The association of KLKB1 with apoA-IV suggests an involvement of apoA-IV in renal metabolism and/or an interaction within HDL particles. Analyses of SNP-scores indicate potential causal effects of kidney function and by lesser extent triglycerides on apoA-IV concentrations