Connecting brain and body:Transdiagnostic relevance of connective tissue variants to neuropsychiatric symptom expression

The mind is embodied;thoughts and feelings interact with states of physiological arousal and physical integrity of the body.In this context,there is mounting evidence for an association between psychiatric presentations and the expression variant connective tissue,commonly recognised as joint hypermobility.Joint hypermobility is common,frequently under-recognised,significantly impacts quality of life,and can exist in isolation or as the hallmark of hypermobility spectrum disorders(encompassing joint hypermobility syndrome and hypermobile Ehlers-Danlos syndrome).In this narrative review,we appraise the current evidence linking psychiatric disorders across the lifespan,beginning with the relatively well-established connection with anxiety,to hypermobility.We next consider emerging associations with affective illnesses,eating disorders,alongside less well researched links with personality disorders,substance misuse and psychosis.We then review related findings relevant to neurodevelopmental disorders and stress-sensitive medical conditions.With growing understanding of mind-body interactions,we discuss potential aetiopathogenetic contributions of dysautonomia,aberrant interoceptive processing,immune dysregulation and proprioceptive impairments in the context of psychosocial stressors and genetic predisposition.We examine clinical implications of these evolving findings,calling for increased awareness amongst healthcare professionals of the transdiagnostic nature of hypermobility and related disorders.A role for early screening and detection of hypermobility in those presenting with mental health and somatic symptoms is further highlighted,with a view to facilitate preventative approaches alongside longer-term holistic management strategies.Finally,suggestions are offered for directions of future scientific exploration which may be key to further delineating fundamental mind-body-brain interactions.

An engineered Cas12i nuclease that is an efficient genome editing tool in animals and plants

The type V-I CRISPR-Cas system is becoming increasingly more attractive for genome editing.However,natural nucleases of this system often exhibit low efficiency,limiting their application.Here,we used structure-guided rational design and protein engineering to optimize an uncharacterized Cas12i nuclease,Cas12i3.As a result,we developed Cas-SF01,a Cas12i3 variant that exhibits significantly improved gene editing activity in mammalian cells.Cas-SF01 shows comparable or superior editing performance compared to SpCas9 and other Cas12 nucleases.Compared to natural Cas12i3,Cas-SF01 has an expanded PAM range and effectively recognizes NTTN and noncanonical NATN and TTVN PAMs.In addition,we identified an amino acid substitution,D876R,that markedly reduced the off-target effect while maintaining high on-target activity,leading to the development of CasSF01^(HiFi)(high-fidelity Cas-SF01).Finally,we show that Cas-SF01 has high gene editing activities in mice and plants.Our results suggest that CasSF01 can serve as a robust gene editing platform with high efficiency and specificity for genome editing applications in various organisms.

nfertility, impotence, and emasculation - psychosocia ：ontexts for abandoning reproduction

From a Darwinian perspective we live to reproduce, but in various situations genetic males elect not to reproduce by choosing medical treatments leading to infertility, impotence, and, in the extreme, emasculation. For many men, infertility can be psychologically distressing. However, for certain genetic males, being infertile may improve their quality of life. Examples include （1） men who seek vasectomy, （2） individuals with Gender Dysphoria （e.g., transwomen, and modern day voluntary eunuchs）, （3） most gay men, and （4） men treated for testicular and prostate cancer. Men who desire vasectomy typically have a Darwinian fitness W 〉1 at the time of their vasectomies; i.e., after they have their desired number of offspring or consider themselves past an age for parenting newborns. In contrast, prostate and testicular cancer patients, along with individuals with extreme Gender Dysphoria, do not necessarily seek to be sterile, but accept it as an unavoidable consequence of the treatment for their condition undertaken for survival （in case of cancer patients） or to achieve a better quality of life （for those with Gender Dysphoria）. Most gay men do not father children, but they may play an avuncular role, providing for their siblings＇ offspring＇s welfare, thus improving their inclusive fitness through kin selection. In a strictly Darwinian model, the primary motivation for all individuals is to reproduce, but there are many situations for men to remove themselves from the breeding populations because they have achieved a fitness W 〉1, or have stronger medical or psychological needs that preclude remaining fertile.